SAJDVD Volume 11, Issue 2

SAJDVD

The electronic version of the journal is available at www.diabetesjournal.co.za

The South African Journal of Diabetes & Vascular Disease

June 2014

Volume 11 Number 2

Featured in this issue: Treatment of hypercholesterolaemia Optimal utilisation of sulphonylureas New oral therapies for type 2 diabetes Diastolic heart failure in hypertensive diabetics Treating diabetes with exercise Type 1 diabetes and cardiovascular disease Guidelines address problems with injection technique SA diabetic retinopathy screening programme

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Reviews

Ethics Focus

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Achieving Best Practice

Diabetes Educator’s Focus

News

ISSN 1811-6515

THE SOUTH AFRICAN JOURNAL OF HYPE

RINSULINAEMIA

Diabetes & vascular disease VOLUME 11 NUMBER 2 • JUNE 2014 www.diabetesjournal.co.za

Corresponding Editor DR L Lombard Netcare, Kuilsriver Hospital, Cape Town Consulting Editor PROF J-C MBANYA Dr F mahomed National Editorial Board DR A AMOD Centre for Diabetes, Endocrinology and Metabolic Diseases, Life Healthcare, Chatsmed Gardens Hospital, Durban SR K BECKERT Diabetes Nurse, Paarl PROF F BONNICI Emeritus Professor, Faculty of Health Sciences, University of Cape Town and President of Diabetes South Africa PROF R DELPORT Department of Family Medicine, University of Pretoria DR L DISTILLER Director of the Centre of Diabetes and Endocrinology, Houghton, Johannesburg DR F MAHOMED Department of Internal Medicine, Grey’s Hospital, Pietermaritzburg PROF WF MOLLENTZE Head of Department of Internal Medicine, University of the Free State, Bloemfontein

CONTENTS

Editorial

51

The Internet is underutilised for diabetes education L Lombard

Research Articles

52

Treatment of hypercholesterolaemia in patients with diabetes mellitus WS Aronow

54

JPJ Halcox, MA Ozkor, G Mekonnen, AA Quyyumi

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PROF CD POTGIETER Specialist Nephrologist, University of Pretoria and Jakaranda Hospital, Pretoria PROF K SLIWA Associate Professor of Medicine and Cardiology, Baragwanath Hospital, University of the Witwatersrand, Johannesburg PROF YK SEEDAT Emeritus Professor of Medicine and Honorary Research Associate, University of Natal, Durban International Editorial Board PROF IW CAMPBELL Physician, Victoria Hospital, Kircaldy, Scotland, UK PROF PJ GRANT Professor of Medicine and head of Academic Unit of Molecular Vascular Medicine, Faculty of Medicine and Health, University of Leeds; honorary consultant physician, United Leeds Teaching Hospitals NHS Trust, UK PROF J-C MBANYA Professor of Endocrinology, Faculty of Medicine and Biomedical Sciences, University of Yaounde I, Cameroon and President, International Diabetes Federation PROF N POULTER Professor of Preventive Cardiovascular Medicine, Imperial College, School of Medicine, London, UK DR H PURCELL Senior Research Fellow in Cardiology, Royal Brompton National Heart and Lung Hospital, London, UK

Coronary endothelial dysfunction, obesity and the metabolic syndrome Barriers to self-management of diabetes: a qualitative study among lowincome minority diabetics NC Onwudiwe, CD Mullins, RA Winston, AT Shaya, FG Pradel, A Laird, E Saunders

Reviews

66

Optimal utilisation of sulphonylureas in resource-constrained settings P Naidoo, V Rambiritch, N Butkow, S Saman

69

On the horizon: new oral therapies for type 2 diabetes mellitus M Ukrainski, T Gandrabura, LA Bischoff, I Ahmed

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Treatment of diastolic heart failure in hypertensive diabetic patients: between illusion and achievements S Genel, F Emanuela, SM Lucia, SG Daniel, R Dan

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Treating diabetes with exercise: focus on the microvasculature CM Kolka

82

Diabetes mellitus and the brain: special emphasis on cognitive function SA Hamed

87

Type 1 diabetes and cardiovascular disease O Schnell, F Cappuccio, S Genovese, E Standl, P Valensi, A Ceriello

Best Practice

95

New guidelines address problems associated with suboptimal injection technique P Wagenaar

Diabetes News

96

The South African diabetic retinopathy screening programme launches S Cook

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SA JOURNAL OF DIABETES & VASCULAR DISEASE

EDITORIAL

The Internet is underutilised for diabetes education LANDI LOMBARD

T

he USA has reached a diabetes prevalence of 10% in the adult population and it is increasing exponentially. If no changes are made, it is feared the USA health system will be bankrupt. In South Africa, we are in the top five (currently number three) leading countries in the obesity race and we will soon see a similar increase in diabetes prevalence.

Type 2 diabetes mellitus is the biggest lifestylerelated health challenge the world is facing today. There is too much dependence on healthcare professionals and the health system, which cannot cope with the volume of patients. We can never train enough doctors to deal with the problem and we will be engulfed by the tsunami of diabetes patients that will hit us soon.

Self-management of diabetes and transferring the responsibility of care to the patient is essential. Training of large numbers of patients in proper lifestyle adaptations and self care is critical.

This could be done via the Internet, by setting up websites where newly diagnosed patients can educate themselves from a diabetes website that is evidenced based and regularly updated. The website could also have updates for the more experienced diabetic patient. Patients should be required (by their medical aid or the diabetes clinic) to register at these websites and then complete a course on their disease, to arm them with the knowledge to help themselves.

Self care is critical in the management of diabetes, but there is a daily challenge related to diet and exercise, as well as compliance with self-monitoring of blood glucose levels and blood pressure.

The healthcare practitioner should be involved only in checking the success of the strategy (HbA1c level and other risk factors) and adjusting therapy. On a daily basis, I find myself spending at least half of my consultation time on lifestyle issues and advice. This should be done through self-study, and we should be available to answer appropriate questions.

By using the Internet and referring patients to the correct websites, a huge burden could be carried by an unlimited, free resource. Patients often don’t follow up regularly because of

Correspondence to: Dr Landi Lombard Netcare Kuils River Hospital, Cape Town Tel: +27 0(21) 906-1637 e-mail: lclombard@mweb.co.za S Afr J Diabetes Vasc Dis 2014; 11: 3

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financial or medical funder limitations. They often don’t understand the importance of prevention of diabetes complications, and we know that by the time complications start to occur, we have probably already lost the battle. We should focus our resources and efforts on the patients with no complications.

This is however not what is happening. General practitioners and specialists dealing with diabetes are seeing the patients with complications, where intervention will make only a small difference, whereas we should be focusing on the huge number of newly diagnosed patients without complications, in order to prevent complications. Diabetes is a disease of prevention. We cannot cure the complications and this is often poorly understood by patients.

I believe we should challenge Government and the medical aid industry to fund such a website that is unbiased, up to date, easy to understand, and can be translated into all of our official languages. If we don’t start thinking clearly about the challenges in diabetes, this disease will engulf us and make healthcare unaffordable. We need to act now.

The article by Onwudiwe et al., ‘Barriers to self-management of diabetes’ is important because we need to overcome many of those same barriers and more, here in South Africa. Illiteracy is a huge problem and access to the Internet is also problematic.

However, with smart phone use increasing exponentially, these could be used to access the websites, which could be made available as free downloads, sponsored by Vodacom, MTN, Cell C and Government.

The pharmaceutical industry has responded to this huge challenge of diabetes and is investing in research and development.

New drug options are discussed in an article by Ukrainski et al., focusing on novel oral therapies for type 2 diabetes.

This edition also has some excellent articles on cardiovascular disease. These include a discussion on new cholesterol guidelines from the USA, endothelial dysfunction, diastolic heart failure and cardiovascular disease in type 1 diabetes.

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Treatment of hypercholesterolaemia in patients with diabetes mellitus Wilbert S Aronow Abstract Numerous studies have shown that statins reduce cardiovascular events, including stroke and mortality in diabetics. The American Diabetes Association 2013 guidelines recommend that diabetics at high risk for cardiovascular events should have their serum low-density lipoprotein (LDL) cholesterol reduced to < 70 mg/dl (1.8 mmol/l) with statins. Lower-risk diabetics should have their serum LDL cholesterol reduced to < 100 mg/dl (2.6 mmol/l). The 2013 American College of Cardiology/American Heart Association lipid guidelines recommend giving high-dose statins to adult diabetics aged ≤ 75 years with atherosclerotic vascular disease (ASCVD) unless contraindicated with a class I indication and moderate-dose or high-dose statins to diabetics with ASCVD ≥ 75 years with a class IIa indication. Diabetics ≥ 21 years with a serum LDL cholesterol of ≥ 190 mg/dl (4.9 mmol/l) should be treated with high-dose statins with a class I indication.

For primary prevention in diabetics aged 40 to 75 years and serum LDL cholesterol between 70 and 189 mg/dl (1.8 and 4.9 mmol/l), moderate-dose statins should be given with a class I indication. For primary prevention in diabetics aged 40 to 75 years, a serum LDL cholesterol between 70 and 189 mg/dl (1.8 and 4.9 mmol/l), and a 10-year risk of ASCVD of ≥ 7.5% calculated from the Pooled Heart Equation, highdose statins should be given with a class IIa indication. For primary prevention in diabetics aged 21 to 39 years or older than 75 years and a serum LDL cholesterol between 70 and 189 mg/dl (1.8 and 4.9 mmol/l), moderate-dose statins or highdose statins should be given with a class IIa indication. There is no additional ASCVD reduction from adding non-statin therapy to further lower non-high-density lipoprotein (HDL) cholesterol once an LDL cholesterol goal has been reached.

Clinical trials have found no lowering of cardiovascular events or mortality in diabetics treated with statins with the addition of nicotinic acid, fibric acid derivatives, ezetemibe, or drugs that raise serum HDL cholesterol.

Introduction Numerous studies have demonstrated that statins reduce cardiovascular events, including stroke and mortality in diabetics.1,8

Correspondence to: Wilbert S Aronow Cardiology Division, New York Medical College Valhalla, NY, USA. Tel: (914) 493-5311; Fax: (914)-235-6274 e-mail: wsaronow@aol.com Originally published in Int J Diabetol Vasc Dis Res 2014; 2: 301 S Afr J Diabetes Vasc Dis 2014; 11(2): 52–53

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A five-year follow up of 5 963 diabetics aged 40 to 80 years in the Heart Protection Study randomised to simvastatin 40 mg daily or to double-blind placebo, simvastatin reduced first major vascular event (coronary event, stroke or revascularisation) 22% from 25.1% to 20.2% compared with placebo (p < 0.0001).1 Of the 2 912 diabetics without occlusive arterial disease at study entry, simvastatin reduced first major vascular event by 33% (p = 0.0003).1 Of the 2 426 diabetics with a serum low-density lipoprotein LDL cholesterol level below 116 mg/dl (3 mmol/l) at study entry, simvastatin reduced first major vascular event by 27% (p = 0.0007).1 Treatment of diabetics without occlusive arterial disease for five years reduced one major vascular event in 45 patients per 1 000 treated, and prevented 70 first or subsequent major vascular events per 1 000 patients treated.1 At 5.4-year median follow up of 202 diabetics with coronary artery disease and hypercholesterolaemia in the Scandinavian Sim-vastatin Survival study, compared with double-blind placebo, dia-betics randomised to simvastatin 20 to 40 mg daily had a 43% reduction in all-cause mortality (p = 0.087), a 55% reduction in major coronary events (p = 0.002), and a 37% reduction in any atherosclerotic event (p = 0.018).2 At the five-year follow up of 586 diabetics with coronary artery diseases and a mean serum total cholesterol level of 209 mg/dl (5.4 mmol/l) in the Cholesterol and Recurrent Events trial, compared with double-blind placebo, pravastatin 40 mg daily decreased the incidence of fatal coronary events or nonfatal myocardial infarction 25% from 37% to 29% (p = 0.05).3 In the Collaborative Atorvastatin Diabetes Study, 2 838 diabetics with no cardiovascular disease and a serum LDL cholesterol less than 160 mg/dl (4.1 mmol/l) were randomised to atorvastatin 10 mg daily or to double-blind placebo.4 At the 3.9-year median follow up, compared with placebo, atorvastatin significantly reduced time to first occurrence of acute coronary events, coronary revascularisation or stroke by 37% (p = 0.001), acute coronary events by 36% (9 to 55%), stroke by 48% (11 to 69%), and all-cause mortality by 27% (p = 0.059).4 In an observational prospective study of 171 men and 358 women, mean age 79 years, with prior myocardial infarction, diabetes mellitus, and a serum LDL cholesterol of 125 mg/dl (3.24 mmol/l) or higher, 279 of 529 diabetics (53%) were treated with statins.5 At the 29-month follow up, compared with no treatment with statins, use of statins significantly decreased in elderly persons, coronary heart disease death or non-fatal myocardial infarction by 37% and stroke by 47%.5 The greater the reduction in serum LDL cholesterol, the greater the reduction in new coronary events6 and in stroke.7 A meta-analysis was performed of 14 randomised trials of statins used to treat 18 686 diabetics (1 466 with type 1 diabetes and 17 220 with type 2 diabetes).8 Mean follow up was 4.3 years. Allcause mortality was reduced 9% per mmol/l reduction in serum LDL cholesterol (p = 0.02). Major cardiovascular events were reduced 21% per mmol/l reduction in serum LDL cholesterol, p < 0.0001. Statins caused in diabetics a 22% reduction in myocardial infarction or coronary death (p < 0.0001), a 25% reduction in

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coronary revascularisation (p < 0.0001), and a 21% reduction in stroke (p = 0.0002). After five years, 42 fewer diabetics per 1 000 diabetics treated with statins had major cardiovascular events.8 In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, 9 795 type 2 diabetics (2 131 with cardiovascular disease) were randomised to fenofibrate or double-blind placebo.9 Mean follow up was 5.0 years. The primary outcome of coronary events was not significantly reduced by fenofibrate. Fenofibrate insignificantly increased coronary heart disease mortality by 19%.9 In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, 5 518 type 2 diabetics at high risk for cardiovascular disease were randomised to simvastatin plus fenofibrate or to simvastatin plus double-blind placebo.10 Mean follow up was 4.7 years. Compared with simvastatin plus placebo, simvastatin plus fenofibrate did not lower the incidence of fatal cardiovascular events, non-fatal myocardial infarction, or non-fatal stroke.10 Among 3 414 patients with atherosclerotic cardiovascular disease and low serum highdensity lipoprotein (HDL) cholesterol levels treated with simvastatin plus ezetimibe if needed to maintain the serum LDL cholesterol less than 70 mg/dl (1.8 mmol/l), at 36-month follow up, patients randomised to niacin had improvements in serum HDL cholesterol and triglyceride levels but no clinical improvement compared to patients randomised to placebo.11 At the American College of Cardiology meeting on 9 March 2013, Dr Jane Armitage presented results from the Heart Protection study 2 – Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) study. In this study, 25 673 high-risk patients were randomised to treatment with simvastatin or simvastatin/ezetimibe plus extended-release niacin plus the anti-flushing agent laropriprant or to treatment with simvastatin or simvastatin/ezetimibe. At the 3.9-year follow up, compared to treatment with simvastatin or simvastatin/ezetimibe, addition of niacin did not decrease the primary outcome of major vascular events but increased 31 serious adverse events per 1 000 niacin-treated patients. Excess diabetic complications were increased 3.7% (p < 0.0001). Excess new diabetes was increased 1.8% (p < 0.0001). Excess infection was increased 1.4% (p < 0.0001). Excess gastrointestinal complications were increased 1% (p < 0.0001). Excess bleeding (gastrointestinal and intracranial) was increased 0.7% (p < 0.0002).

The American Diabetes Association 2013 guidelines recommend that diabetics at high risk for cardiovascular events should have their serum LDL cholesterol reduced to less than 70 mg/dl (1.8 mmol/l) with statins.12 Lower-risk diabetics should have their serum LDL cholesterol reduced to less than 100 mg/dl (2.6 mmol/l).12 Combination therapy of a statin with either a fibrate or niacin has not been found to provide additional cardiovascular benefit above statin therapy alone and is not recommended.12 Hypertriglyceridaemia should be treated with dietary and lifestyle changes.12 Severe hypertriglyceridaemia should be treated with drug therapy to decrease the risk of acute pancreatitis.12 The 2013 American College of Cardiology/American Heart Association lipid guidelines recommend the use of high-dose statins (rosuvastatin 20 to 40 mg daily or atorvastatin 40 to 80 mg daily) to adults aged 75 years and younger with atherosclerotic vascular disease (ASCVD) with or without diabetes mellitus unless contraindicated with a class I indication.13 Moderatedose or high-dose statins are reasonable to administer to patients with ASCVD with or without diabetes mellitus older than 75 years with a class IIa indication. Persons aged 21 years and older with a serum LDL cholesterol of 190 mg/dl (4.9 mmol/l) or higher with or

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without diabetes mellitus should be treated with high-dose statins with a class I indication. For primary prevention in diabetics aged 40 to 75 years and a serum LDL cholesterol between 70 and 189 mg/dl (1.8 and 4.9 mmol/l), moderate-dose statins should be given with a class I indication. For primary prevention in diabetics aged 40 to 75 years, a serum LDL cholesterol between 70 and 189 mg/dl (1.8 and 4.9 mmol/l), and a 10-year risk of ASCVD of 7.5% or higher calculated from the Pooled Heart Equation, highdose statins should be administered with a class IIa indication. For primary prevention in diabetics aged 21 to 39 years or older than 75 years and a serum LDL cholesterol between 70 and 189 mg/dl (1.8 and 4.9 mmol/l), moderate- or high-dose statins should be given with a class IIa indication. These guidelines also state that there is no additional ASCVD reduction from adding non-statin therapy to further lower non-HDL cholesterol once an LDL cholesterol goal has been reached. Clinical trials have demonstrated no lowering of cardiovascular events or mortality in persons treated with statins by addition of nicotinic acid, fibric acid derivatives, ezetemibe, or drugs that raise HDL cholesterol.13

References 1. Collins R, Armitage J, Parish S, et al. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastain in 5963 patients with diabetes: a randomised placebo-controlled trial. Lancet 2003; 361: 2005–2016.

2. Pyorala K, Pedersen TR, Kjekshus J, et al. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease, A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 1997; 20: 614–620.

3. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 1001–1009.

4. Calhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes mellitus in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomized placebo-controlled trial. Lancet 2004; 364: 685–696.

5. Aronow WS, Ahn C, Gutstein H. Reduction of new coronary events and of new atherothrombotic brain infarction in older persons with diabetes mellitus, prior myocardial infarction, and serum low-density lipoprotein cholesterol ≥125 mg/dL treated with statins. J Gerontol: Med Sci 2002; 57A: M747–M750.

6. Aronow WS, Ahn C. Incidence of new coronary events in older persons with prior myocardial infarction and serum low-density lipoprotein cholesterol ≥ 125 mg/dL treated with statins versus no lipid-lowering drug. Am J Cardiol 2002; 89: 67–69.

7. Aronow WS, Ahn C, Gutstein H. Incidence of new atherothrombotic brain infarction in older persons with prior myocardial infarction and serum low-density lipoprotein cholesterol ≥125 mg/dL treated with statins versus no lipid-lowering drug. J Gerontol: Med Sci 2002; 57A: M333–M335.

8. Cholesterol Treatment Trialists’ (CTT) collaborators, Kearney PM, Blackwell L, et al. Efficacy of cholesterol-lowerring therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 2008; 371: 117–125.

9. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9,795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005; 366: 1849–1861.

10. The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Eng J Med 2010; 362: 1563–1574.

11. AIM-HIGH Investigators, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011; 365: 2255–2267.

12. American Diabetes Association. Standards of medical care in diabetes – 2013.

Diabetes Care 2013; 36 (supplement 1): S11–S66.

13. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; Nov 7 published online ahead of print PMID: 24239923.

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Coronary endothelial dysfunction, obesity and the metabolic syndrome JULIAN PJ HALCOX, MUHIDDIN A OZKOR, GIRUM MEKONNEN, ARSHED A QUYYUMI Abstract

Introduction

Objective: To define the impact of the metabolic syndrome (MetS) and obesity on coronary vascular function, with the hypothesis that subjects with MetS will have endothelial dysfunction.

Background: Obesity or the metabolic syndrome is associated with a higher risk of diabetes and coronary artery disease (CAD). Endothelial dysfunction is a common causal pathway in the initiation and progression of CAD. Methods: A total of 418 patients (165 obese, 239 MetS) with and without angiographic evidence of CAD underwent coronary vascular function testing by measuring coronary blood flow (CBF) velocity in response to intracoronary infusion of acetylcholine (ACH) and sodium nitroprusside (SNP) and coronary flow reserve with adenosine.

Results: Endothelium-dependent microvascular vasodilation correlated with body mss index (BMI) (r = –0.12, p = 0.02), with ACH responses significantly lower in overweight, obese and MetS subjects (p = 0.003). The number of MetS components correlated with the response to ACH in both the coronary microcirculation and the epicardial coronary arteries, and with impaired coronary microcirculatory responses to adenosine. No significant correlation was observed with SNP. In multivariable analysis, beyond age, only the total number of MetS components, and not BMI, emerged as an independent predictor of impaired microvascular response to ACH (CBF: β = –0.18, p < 0.001). Low-grade inflammation (C-reactive protein) was higher in patients with MetS, but was not associated with coronary vascular function.

Conclusions: We demonstrate that the clustering of MetS components is an important and independent determinant of coronary endothelial dysfunction in subjects with and without CAD.

The prevalence of obesity has increased dramatically worldwide whereby at least a third of adult Americans are obese and twothird overweight.1,2 Obese subjects are at high risk of multiple morbidities, foremost among which are the development of diabetes and cardiovascular disease (CVD).3,4 Abdominal obesity in particular is frequently associated with a clustering of multiple interrelated cardiovascular risk factors associated with insulin resistance that characterises the metabolic syndrome (MetS). In addition to a large waist circumference, subjects with MetS have increased blood pressure, dyslipidaemia characterised by low high-density lipoproteins (HDL), high triglycerides and small dense low-density lipoproteins (LDL) particles, and glucose intolerance commonly accompanied by low-grade systemic inflammation and a pro-thrombotic state.3,5 The clustering of three or more of these risk factors in an individual defines the MetS,6 the incidence of which has progressively risen.2,7,8 Because of its frequent association with the MetS variables, the role of obesity as an independent risk factor for CVD remains controversial.2,9-11 Endothelial dysfunction, often a consequence of exposure of the vasculature to risk factors, is predictive of adverse cardiovascular outcomes, and appears to provide a common causal pathway in the initiation and progression of CVD.12-15 Peripheral arterial endothelial dysfunction has been observed in obese children and adults, and in those with MetS, even after adjustment for conventional risk factors.16-21 Although an independent association between obesity and coronary endothelial dysfunction has been described,22 the incremental influence of the MetS variables and low-grade systemic inflammation on coronary endothelial function remains unknown.

Herein we investigated these relationships in a large, wellcharacterised cohort of patients with and without angiographic evidence of coronary artery disease (CAD) undergoing invasive assessment of coronary vascular function. Our hypothesis was that MetS will be associated with more profound and selective dysfunction of the coronary vascular endothelium.

Keywords: atherosclerosis, metabolic syndrome, obesity, endothelium, inflammation Correspondence to: Arshed A Quyyumi Division of Cardiology, Department of Medicine, Emory University, Atlanta, USA Tel: 404 727 3655 Fax: 404 712 8785 e-mail: aquyyum@emory.edu Julian PJ Halcox Cardiovascular Research Group Cymru, Swansea University, UK Muhiddin A Ozkor The Heart Hospital, University College of London Hospitals, London, UK Girum Mekonnen Division of Cardiology, Department of Medicine, Emory University, Atlanta, USA Originally published in J Diabetes Metab 2014; 5(4): 1000362.

S Afr J Diabetes Vasc Dis 2014; 11(2): 54–60

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Methods Patients We prospectively studied 418 patients (239 males) undergoing diagnostic cardiac catheterisation for evaluation of symptoms of chest pain or abnormal cardiac stress test findings. CAD was defined as angiographic evidence of plaque or more severe occlusive disease, and normal coronary arteries (NCA) defined as angiographically smooth appearing coronary arteries. Patients with three-vessel disease, recent myocardial infarction, severe heart failure or valvular heart disease were excluded. Diabetes was defined as a fasting blood glucose level ≥ 126 mg/dl or treatment with dietary modification, insulin, or oral hypoglycemic agents at the time of the study. Hypercholesterolaemia was defined as a fasting serum total cholesterol > 240 mg/dl or if the subject was being treated with

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lipid-lowering medication or dietary modification. Hypertension was defined as a seated systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg on at least three occasions, or if such a diagnosis had been made in the past and the patient was being treated with medications or lifestyle modification.

Cardiac medications were withdrawn for > 48 hours and at least five half-lives before the study. Angiotensin converting enzyme inhibitors and aspirin or other cyclooxygenase inhibitors were discontinued ≥ seven days before the study. The protocol was approved by the institutional review board of the National Heart, Lung and Blood Institute, and informed written consent was obtained from each subject.

Anthropometric variables and atherosclerosis risk factors Subjects had their height (m) and weight (kg) measured and body mass index (BMI) calculated (weight/height2). Subjects were categorised as normal weight if BMI was < 25 kg/m2, overweight if BMI was between 25 and < 30 kg/m2, and obese if BMI was ≥ 30 kg/m2. Blood pressure, fasting lipid profile, fasting glucose and high sensitivity C-reactive protein (CRP) levels were also measured.

All subjects with a history of current or prior tobacco smoking were classified as smokers.

Subjects were also categorised according to a modified definition of the NCEP/ATPIII criteria for MetS. Waist circumference data were not available for most subjects; therefore BMI values were used to define adiposity. Five MetS components were identified: 1 = overweight or obesity (BMI ≥ 25 kg/m2); 2 = elevated blood pressure (≥ 130/≥ 85 mmHg or treatment with antihypertensive medication); 3 = elevated triglycerides (≥ 150 mg/dl); 4 = low HDL [< 40 mg/dl (male) or < 50 mg/dl (female)]; 5= elevated fasting glucose (≥ 110 mg/dl or treatment with glucose-lowering medication). Subjects were deemed to have MetS if they fulfilled three or more of these criteria.

Vascular function studies A 6-French guide catheter was introduced into an unobstructed (< 30% stenosis) coronary artery, and coronary blood flow (CBF) velocity was measured using a 0.014- or 0.018-inch Doppler flow wire (Flowire, Volcano Corp, Rancho Cordova, CA) as described previously.23 Endothelium-dependent vasodilation was estimated by measuring CBF responses to an infusion of intracoronary acetylcholine (ACH) at a rate of 15 µg/min for two minutes to obtain an estimated 10-6 mol/l intracoronary concentration. Endotheliumindependent vasomotion was estimated with intracoronary sodium nitroprusside (SNP) (20 µg/min) infusion for three minutes. When drugs were infused into the left main coronary artery, the infusion rate was doubled. Coronary flow reserve was determined with adenosine infused at 2.2 mg/min for two minutes.

For calculating CBF, diameter was measured in a 0.25- to 0.5-cm segment of vessel beginning 0.25 cm beyond the tip of the flow wire. CBF was determined from the Doppler-derived flow velocity and diameter measurements using the formula: π × average peak velocity × 0.125 × diameter2 as previously described.23 Coronary vascular resistance (CVR) was calculated as mean arterial pressure divided by CBF. Additionally, mid and distal segments of the study vessel that were straight and free of overlap or major branch points were also measured after each intervention. Epicardial coronary responses in these segments were determined by assessment of the percent change in diameter (∆Diam) with each drug compared to baseline. Quantitative angiography was performed with the ARTREK software (Quantim 2001, Statview, Image Comm Systems, Inc) or PIE medical CAAS system.24 Statistical analysis Continuous variables are expressed as mean value ± standard deviation (SD). Normality was tested using the Kolmogorov-Smirnov criterion. Logarithmic transformation was performed for skewed

Table 1. Baseline characteristics of the whole study population and according to presence of overweight/obesity and metabolic syndrome (MetS).

All patients Normal weight n (%) 418 90 (22) Age, years 55.2 ± 11.3 55.8 ± 13.0 Gender, males/females 239/179 49/41 Weight, kg 85 ± 19 66 ± 9 Height, cm 169 ± 10 168 ± 10 BMI, kg/m2 29.7 ± 6.2 22.7 ± 2.1 Mean blood pressure, mmHg 109 ± 15 105 ± 15 Total cholesterol, mg/dl 214 ± 46 209 ± 48 LDL-cholesterol, mg/dl 138 ± 42 132 ± 45 HDL-cholesterol, mg/dl 43 ± 14 49 ± 17 Triglycerides, mg/dl 145 (97−218) 112 (70−165) Glucose, mg/dl 101 (92−120) 96 (89107) hsCRP, mg/l 0.82 (0.46−1.15) 0.59 (0.40−0.89) Risk factors Hypertension, n (%) 213 (51) 35 (39) Diabetes, n (%) 89 (22) 15 (4) Hypercholesterolaemia, n (%) 261 (62) 52 (58) Smoking, n (%) 245 (59) 54 (60) CAD, n (%) 215 (51) 40 (44) Diseased coronary arteries 1.7 ± 0.9 1.8 ± 1.0

Overweight/obese p-value 328 (78) 55.1 ± 10.8 0.59 190/138 0.55 90 ± 18 < 0.001 169 ± 11 0.64 31.6 ± 5.5 < 0.001 110 ± 15 0.018 216 ± 46 0.21 140 ± 41 0.13 42 ± 12 < 0.001 151 (106−229) 0.02 103 (93−126) 0.002 0.91 (0.48−1.20) 0.043 178 (55) 74 (18) 209 (64) 191 (59) 175 (53) 1.8 ± 0.9

0.13 0.004 0.16 0.83 0.13 0.98*

No MetS 179 (43) 53.7 ± 10.3 91/88 77 ± 17 168 ± 10 27.1 ± 5.8 105 ± 15 212 ± 48 139 ± 42 51 ± 15 108 (76−136) 95 (88−102) 0.59 (0.25−0.93)

MetS 239 (57) 56.3 ± 10.3 148/91 91 ± 19 169 ± 11 31.7 ± 5.8 111 ± 15 216 ± 45 138 ± 42 38 ± 9 184 (135−261) 112 (98−140) 0.99 (0.65−1.34)

p-value

47 (26) 7 (4) 103 (62) 96 (54) 69 (39) 1.6 ± 0.9

166 (70) 74 (31) 158 (75) 149 (63) 146 (61) 1.8 ± 0.9

< 0.001 < 0.001 0.007 0.051 < 0.001 0.10*

0.021 0.023 < 0.001 0.2 < 0.001 < 0.001 0.34 0.77 < 0.001 < 0.001 < 0.001 0.005

BMI: body mass index; CAD: coronary artery disease; hsCRP: high-sensitivity C-reactive protein, LDL: low-density lipoprotein, HDL: high-density lipoprotein.

Categorical variables are presented as absolute (relative) frequencies; continuous variables, as mean ± SD or median (interquartile range). p-values for between groups comparisons are derived from student’s t-test for unpaired measures (for continuous variables) or from chi-square tests (for categorical variables). *p-value for comparison within the CAD patients.

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distributions before any parametric analyses. Skewed variables are expressed as a median value (interquartile range). Categorical data are expressed as absolute frequencies and percentages. Comparisons between two groups were performed using the student’s t-test for unpaired measures (continuous data) and Pearson’s chi-square test (categorical data). Univariate correlations were performed using the Pearson’s correlation coefficient. Linear trends between the number of MetS components and coronary function indices were evaluated by a one way analysis of variance. Multivariable analysis adjusting for potential confounders was performed by either analysis of co-variance (ANCOVA) or forward linear regression analysis. The assumptions for linearity and homoscedasticity were tested based on the standardised residuals plots. Exact p-values < 0.05 were considered statistically significant. Data analysis was performed with SPSS software, version 14.0 (SPSS Inc, Chicago, IL).

Results Subject characteristics Of the 418 patients (239 males and 179 females) enrolled, 165 were obese, 163 overweight, and 239 (57.2%) fulfilled the criteria for MetS. Clinical characteristics of the population according to the presence of obesity and MetS are shown in Table 1. As expected, the presence of MetS was associated with a higher frequency and severity of all of the components of MetS in addition to diabetes.

Overweight/obese patients also had a higher incidence of these risk factors, except for diabetes. Total and LDL cholesterol levels were similar in the subgroups. Overall, patients with MetS had a higher prevalence of CAD. Individual risk factors and vascular responses Microvascular responses: Endothelium-dependent microvascular vasodilation, measured as the % increase in flow with ACH, correlated with BMI (r = –0.12, p = 0.02). The ACH responses were significantly lower in both overweight and obese compared to normal weight subjects (100% in overweight/obese vs 135% in subjects with normal weight, p = 0.003) (Fig. 1). Responses to ACH were similar in the overweight and obese subjects. The percentage increase in CBF with ACH also correlated with age (r = –0.17, p = 0.001) and HDL levels (r = 0.12, p = 0.021) and was diminished in those with elevated blood pressure (95% in hypertensives vs 122% in normotensives, p = 0.014), diabetes (70% in diabetics vs 117% in non-diabetics, p = 0.001) and CAD (99% in CAD patients vs 117% in patients without CAD, p = 0.02).

Following multivariable adjustment (ANCOVA), overweight/ obesity remained an independent predictor of impaired flow response to ACH (p = 0.049) along with age (p = 0.003) and diabetes (p = 0.013). Similar relationships were observed between abnormal BMI and the change in CVR inresponse to ACH after both univariable (Fig. 1) and multivariable analysis. Furthermore, if BMI was considered as a continuous variable in the multivariable model, it remained a significant predictor of impaired ACH responses (CBF: standardised β = −0.13, p = 0.014; CVR: β = −0.1, p = 0.05).

By contrast, BMI was not correlated with the flow response to the endothelium-independent vasodilator, SNP, or the flow and resistance responses to adenosine (Fig. 1). Although overweight/obesity was related to a lower resistance response to SNP (Fig. 1), this was no longer significant after adjustment for aforementioned covariates.

Epicardial responses: Age (r = −0.10, p = 0.048) and triglyceride levels (r = −0.11, p = 0.028) correlated with epicardial responses to ACH, as was presence of CAD (mean % diameter change of

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Figure 1: Coronary vascular function in obesity. Percentage change in coronary blood flow, coronary vascular resistance and coronary epicardial diameter in response to (A) endothelium-dependent vasodilation with acetylcholine and (B) endothelium-independent vasodilation with sodium nitroprusside. (C) Percentage change in coronary blood flow and coronary vascular resistance in response to adenosine. Overweight and obese subjects (BMI ≥ 25 kg/m2) in dark columns and normal weight subjects (BMI < 25 kg/m2) in open columns. Results expressed as mean ± SEM. Probability values by student’s t-test.

−2.3% in CAD vs 0.5% in no CAD patients, p = 0.002). A trend towards epicardial vasoconstriction with ACH was observed in overweight/obese subjects compared to those with normal BMI, and a weaker trend to impaired vasodilation in response to SNP was also observed (Fig. 1). Following multivariate adjustment, there was no independent association between the presence of overweight or obesity and an impaired dilator response to ACH or SNP (both p = NS).

Components of MetS and coronary vascular function The impact on vascular function of other components of the MetS in addition to BMI was also studied. Although there were no significant differences in baseline measurements between subjects with or without the MetS, microvascular vasodilator responses to ACH were significantly impaired in subjects with MetS compared to those without MetS (Table 2). However, the epicardial diameter changes with ACH and endothelium-independent responses to SNP were similar in the epicardial vessels and the microvasculature.

Microvascular responses to adenosine were also impaired in patients with MetS (Table 2).

In the entire population, significant correlations between the number of MetS components and the response to ACH in both the coronary microcirculation and the epicardial coronary arteries were

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Table 2. Coronary artery characteristics of the whole study population and according to presence of metabolic syndrome (MetS).

Baseline coronary function CBF, ml/min CVR, mmHg × min/ml Coronary artery diameter, mm Responses to acetylcholine Change of CBF, % Change of CVR, % Change of coronary diameter, % Responses to nitroprusside Change of CBF, % Change of CVR, % Change of coronary diameter, % Responses to adenosine Change of CBF, % Change of CVR, %

All patients

MetS

No MetS

p-value

43.9 ± 31.7 3.59 ± 2.39 2.62 ± 0.73

45.4 ± 27.9 3.46 ± 2.37 2.65 ± 0.73

42.0 ± 36.0 3.77 ± 2.42 2.57 ± 0.72

0.29 0.20 0.25

108 ± 98 −40 ± 29 −0.92 ± 11.01

97 ± 93 -37 ± 31 −1.72 ± 11.32

122 ± 102 -45 ± 27 0.12 ± 10.56

0.015 0.008 0.10

126 ± 85 −52 ± 21 17.40 ± 14.07

126 ± 81 −52 ± 19 16.85 ± 14.38

125 ± 90 −51 ± 23 18.16 ± 13.64

0.95 0.50 0.45

314 ± 157 −72 ± 11

298 ± 156 −71 ± 11

335 ± 157 −74 ± 10

0.03 0.029

BMI: body mass index; CAD: coronary artery disease; CBF: coronary blood flow; CVR: coronary vascular resistance Categorical variables are presented as absolute (relative) frequencies; continuous variables, as mean ± SD. p-values for comparisons between patients with and without MetS are derived from student’s t-test for unpaired measures.

observed (Fig. 2). Differences in the epicardial circulation became apparent between individuals with none or one component of MetS and those with two or more components (p = 0.035). Furthermore,

Figure 2. Coronary vascular function and metabolic syndrome. Percentage change in coronary blood flow, coronary vascular resistance and coronary epicardial diameter in response to (A) endothelium-dependent vasodilation with acetylcholine and (B) endothelium-independent vasodilation with sodium nitroprusside.

(C) Percentage change in coronary blood flow and coronary vascular resistance in response to adenosine. Subjects with 0/1 component of the MetS in open boxes, 2/3 components of the MetS in speckled boxes and 4/5 components of the MetS in grey boxes. The centre line of the box denotes the median value; the extremes of the box, the interquartile range; and the bars, the upper and lower limits of 95% of the data. Probability values by one-way ANOVA.

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a linear trend between the number of components of MetS and impaired coronary microcirculatory responses to adenosine was observed (Fig. 2). No significant correlation was observed between the number of MetS components and responses to SNP. Thus, exposure to increasing number of risk factors of MetS was associated with greater endothelial dysfunction in both the epicardial coronaries and coronary microcirculation, and with diminished coronary flow reserve.

To investigate further the impact of individual components of the MetS on coronary vascular responses to ACH, we performed multivariable forward linear regression analysis in which the individual risk factors for MetS, total number of the components of MetS (0−5), and the presence of CAD (0/1) were also introduced as covariates.

Beyond age, only the total number of MetS components emerged as an independent predictor of impaired microvascular response to ACH (CBF: β = −0.18, p < 0.001; CVR: β = −0.16, p = 0.002). Thus, it is the clustering of the components of MetS rather than any individual component that best predicts abnormal coronary endothelial function in the microcirculation. By contrast, presence of CAD was the only determinant of an abnormal epicardial endothelial response to ACH (β = −0.12, p = 0.017) and of microcirculatory response to adenosine (CBF: β = −0.33, p < 0.001; CVR: β = −0.30, p < 0.001).

MetS, coronary vascular function and low-grade inflammation Inflammation, estimated as Hs-CRP level, was higher in patients with MetS (Table 1). By contrast, Hs-CRP level was not associated with coronary microvascular or epicardial endothelium-dependent responses to ACH (CBF: r = −0.015, p = 0.83; CVR: r = 0.022, p = 0.74; epicardial diameter: r = −0.022, p = 0.73). In subsequent analyses where it was included as an additional covariate in the multiple regression models, Hs-CRP level did not significantly alter the relationship observed between coronary vascular function and MetS, number of MetS components, or BMI.

Discussion We have demonstrated for the first time an independent and graded relationship between the MetS risk factor burden and

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coronary endothelial dysfunction. In one of the largest cohorts to date evaluating coronary vascular function, we found that MetS is associated with coronary microvascular endothelial dysfunction in those with and without atherosclerosis. In particular, a striking relationship emerged between increasing MetS risk factor burden and coronary endothelial dysfunction; for every additional component of MetS, the coronary flow response to ACH was approximately 13% lower. Although obesity appeared to be an independent predictor of coronary microvascular responses, this relationship was no longer apparent when the number of MetS components was introduced into the model, suggesting that it is the burden of metabolic risk factors in the context of obesity which are most likely to determine the coronary pathology rather than the body habitus per se. Notably, neither obesity nor MetS (whether considered as a discrete entity or as number of MetS components) was related to endothelium-independent coronary vascular responses, indicating that the abnormal response to ACH is most likely due to an abnormality in the endothelial layer rather than the ability of the coronary smooth muscle to respond to exogenous nitric oxide. Intriguingly, we also found that the microvascular flow reserve in response to intracoronary infusion of adenosine was depressed in subjects with MetS. The endothelium is a fundamental regulator of vascular homeostasis. Alteration in endothelial function is not only one of the earliest recognisable changes in the atherosclerotic disease process, but is also an indicator of an increased risk of later clinical complications.13,14,24-27 Exposure to conventional risk factors for atherosclerosis results in endothelial dysfunction which is, in part, explained by the risk factor burden28-30 and is predictive of future cardiovascular events even in vascular territories remote from the site of testing.14,31,32 In fact, recent studies have shown that endothelial dysfunction predates future development of hypertension and diabetes, and predicts more rapid progression of atherosclerosis.33,34 While non-invasive methods assessing peripheral vascular endothelial function appear to correlate modestly with coronary endothelial status, and clearly have great value for assessment of low to intermediate risk groups, invasive testing remains the ‘gold-standard’ technique for assessment of coronary vascular physiology.35,36 The MetS is a clustering of the risk factors characterised by abdominal adiposity, hypertension, dyslipidaemia (low HDL, high triglycerides and small dense LDL particles) and impaired glucose homeostasis characteristic of insulin resistance.7 Although under normal conditions insulin promotes the release of NO from normal endothelium, when individuals have developed tissue insensitivity to insulin, there is clear evidence of reduced endothelial NO availability.37-39 We found a statistically independent association between MetS and coronary microvascular endothelial dysfunction particularly in relation to increasing MetS risk factor burden. Our results are in agreement with findings in the peripheral circulation where endothelial responses to pressure alterations to finger cuff (using digital arterial tonometry), to increased flow in the brachial artery and to ACH in the femoral microcirculation were impaired in subjects with MetS.16,19,20 Although we also observed increasing epicardial endothelial dysfunction with exposure to MetS components, this relationship did not persist after adjustment for the presence of CAD. The lower microcirculatory responses to both ACH and adenosine suggest that both endothelial function and flow reserve, respectively, are adversely affected by MetS. However, the magnitude of reduction

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in flow reserve (10%) in the presence of MetS was far more modest than the nearly 25% reduction in flow response to ACH, indicating a proportionately greater effect on the endothelium. Vasodilation in response to adenosine is multifactorial in nature, including a small but significant contribution of nitric oxide (NO).40 Therefore adenosine responses, unlike the response to SNP, cannot be considered to entirely represent endothelium-independent function. It is therefore possible that the reduced response we observed with adenosine in subjects with MetS may also reflect reduced availability of NO. Nevertheless the reduced coronary flow reserve may contribute to reduced vasodilation during physiologic stress such as exercise in these patients, potentially contributing to myocardial ischaemia.

Mechanisms responsible for the development of endothelial dysfunction in obesity include increased levels of oxidative stress leading to reduced NO bioavailability,41 reduced generation of endothelium-derived hyperpolarising factor42 and increased production of endothelium-dependent constricting factors such as endothelin-1.43,44 Of the individual components of MetS, the presence of obesity was a consistent determinant of vascular endothelial dysfunction in the coronary microcirculation in our study. Several investigators have previously shown both in adults and children that obesity is independently associated with impaired peripheral endothelial function and that this can be improved by appropriate lifestyle interventions.17,18,38,41,45-47 One previous study examining coronary microvascular endothelial function confirmed these finding in a population with minimal or no coronary artery disease.22 Our study extends these observations to patients with CAD and in the context of the associated MetS risk factor burden.

The cluster of abnormalities that emerge with visceral obesity may also have both direct and indirect adverse effects on the vascular endothelium. When the total number of components of MetS was introduced as a covariate, obesity was no longer a predictor of endothelial dysfunction in our study. Therefore it appears to be the clustering of the components of MetS that typically associate with increasing obesity, that best predict an increased risk of endothelial dysfunction rather than the obesity itself or any one of the other associated individual risk factors.

Visceral adipose tissue is a rich source of pro-inflammatory cytokines such as TNF-α and IL-6 which also contribute to both insulin resistance and endothelial dysfunction.48 Moreover, markers of inflammation, such as elevated CRP levels, and endothelial dysfunction have both been associated with poor long term prognosis in subjects with and without known CAD.25,49-51 Although a previous study found a correlation between CRP levels and forearm vascular endothelial function, adjustment for obesity or MetS was not performed.52 Others have confirmed our observations.16,22,53 Furthermore, despite higher CRP levels in obese subjects and in those with MetS as previously reported, the association between endothelial dysfunction and MetS was not affected by further adjustment for CRP levels. These observations suggest that the degree of coronary endothelial dysfunction is best explained by the conventional MetS risk factor burden rather than the level of systemic inflammation as assessed by CRP levels. Indeed, during long term follow-up of a subset of these subjects, we found that adverse cardiovascular events were predicted by presence of coronary endothelial dysfunction and not by CRP levels.14 Limitations Although BMI is a good marker for increased risk of adverse ‘cardiometabolic’ outcomes, the subjects in this study were not

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categorised according to abdominal circumference or measures of body fat content and distribution which are most closely linked to an adverse risk state. Additionally, data on other measures of body fat distribution such as dual-energy X-ray absorptiometry (DEXA) scan was notavailable for these subjects. However, viscerally obese subjects with a normal BMI are rare when compared to those with an elevated BMI.21,54 Although we observed a correlation between obesity or MetS and the epicardial responses to ACH after univariate analysis, these differences were no longer significant after adjustment for other risk factors. Because coronary atherosclerosis causes epicardial constriction with ACH, and the majority of our cohort had CAD, we may have underestimated the influence of these factors on epicardial endothelial function in this cohort.

Since this was a cross sectional study, its findings do not infer causality between obesity or MetS and endothelial dysfunction.

However, the emergence of obesity as an independent risk factor in recent surveys linking it to cardiovascular events supports our observations.55 Furthermore, although the ability of angiography to confirm a diagnosis of normal coronaries is limited, as eccentric atheroma is often undetectable with this technique, those with abnormal angiographic appearances are likely to have a greater disease burden than those with angiographically ‘smooth’ vessels.

Finally, our cohort consists of highly selected patients and although not entirely representative of the population as a whole, is well representative of subjects with and at risk of CAD undergoing cardiac catheterization in routine clinical practice.

Conclusion We have shown that clustering of MetS components is an important and independent determinant of coronary endothelial dysfunction in subjects with and without CAD. Since, endothelial dysfunction predates development of overt disease, aggressive risk factor prevention and earlier therapeutic interventions to ameliorate endothelial dysfunction in these individuals are likely to be of great value and require further study.

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48. Kim JA, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation 2006; 113: 1888â&#x2C6;&#x2019;1904.

49. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352: 1685â&#x2C6;&#x2019;1695.

50. Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004; 350: 1387â&#x2C6;&#x2019;1397.

51. Berk BC, Weintraub WS, Alexander RW. Elevation of C-reactive protein in â&#x20AC;&#x153;activeâ&#x20AC;? coronary artery disease. Am J Cardiol 1990; 65: 168â&#x2C6;&#x2019;172.

52. Fichtlscherer S, Rosenberger G, Walter DH, Breuer S, Dimmeler S, et al. Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease. Circulation 2000; 102: 1000â&#x2C6;&#x2019;1006.

53. Vita JA, Keaney JF Jr, Larson MG, Keyes MJ, Massaro JM, et al. Brachial artery vasodilator function and systemic inflammation in the Framingham Offspring Study. Circulation 2004; 110: 3604â&#x2C6;&#x2019;3609.

54. Williams IL, Chowienczyk PJ, Wheatcroft SB, Patel A, Sherwood R, et al. Effect of fat distribution on endothelial-dependent and endothelial-independent vasodilatation in healthy humans. Diabetes Obes Metab 2006; 8: 296â&#x2C6;&#x2019;301.

55. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364: 937â&#x2C6;&#x2019;952.

THE MISSING PIECE IN LIPID MANAGEMENT

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RESEARCH ARTICLE

Barriers to self-management of diabetes: a qualitative study among low-income minority diabetics NNEKA C ONWUDIWE, C DANIEL MULLINS, REED A WINSTON, AIDA T SHAYA, FRANCOISE G PRADEL, AURELIA LAIRD, ELIJAH SAUNDERS Abstract Objectives: Diabetes self-management is a key element in the overall management of diabetes. Identifying barriers to disease self-management is a critical step in achieving optimal health outcomes. Our goal was to explore patients’ perceptions about barriers to self-management of diabetes that could possibly help explain poor health outcomes among minority patients.

Study design: Four focus groups were conducted among 31 predominately African-American patients with diabetes who were enrolled in the Baltimore Cardiovascular Partnership Study, a NIH-funded multi-year prospective partnership study.

The topic guide consisted of a series of open-ended questions about knowledge of current health status, medication use, continuity of care, blood glucose level and nutrition.

Results: The focus groups confirmed that previously reported barriers to self-management persisted, and identified new concerns that could be associated with poor health outcomes among minority patients with diabetes. Attitudes, perceptions and behaviours surrounding diabetes and selfmanagement of the condition did vary across individuals, however, the variation appeared to reflect the individual’s knowledge and opinions rather than patient’s age, gender or culture. The primary barrier to diabetes self-management resulted from lack of knowledge of target blood glucose level and blood pressure. Several participants found some of the health information quite confusing.

Conclusions: Diabetes is a major public health concern and the lack of awareness of target blood glucose level and blood pressure further complicates the problem. The limited health literacy seen in this study could help explain several Correspondence to: Nneka C Onwudiwe Pharmaceutical Health Services Research, University of Maryland School of Pharmacy, Baltimore, Maryland, USA Tel: 410-706-0908 Fax: 410-706-5394 e-mail: nonwu001@umaryland.edu C Daniel Mullins, Faida T Shaya, Francoise G Pradel University of Maryland School of Pharmacy, Department of Pharmaceutical Health Services Research, Baltimore, Maryland, USA Reed A Winston, Aurelia Laird Bon Secours, Baltimore Health Systems, Baltimore, Maryland, USA Elijah Saunders Department of Medicine, Division of Cardiology, University of Maryland School of Medicine, Baltimore, Maryland, USA Originally published in Ethnicity Dis 2011; 21: 27–32.

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of the barriers to self-management. The barriers to selfmanagement identified in this qualitative study are amenable to intervention that could improve health outcomes.

Keywords: diabetes, self-management, barriers

Introduction Diabetes is the fifth leading cause of death by disease in the United States.1 The burden of diabetes disproportionately affects minorities. The prevalence of diabetes is about 11% in AfricanAmericans and 8% in Caucasians and is about twice as prevalent in African-American females (14%) as in Caucasian (7%) females.2 The incidence of type 2 diabetes is four times higher for AfricanAmericans than for non-Hispanic whites.3 Genetic and lifestyle factors, such as history of gestational diabetes, excessive food consumption and physical inactivity, are likely to account for the increased prevalence of type 2 diabetes among ethnic minorities.4 Numerous studies have documented a higher prevalence of insulin resistance in minority groups after controlling for diabetes, obesity and lifestyle factors.5-7 Socioeconomic factors such as income may also play a role in the increasing prevalence of diabetes and diabetes related complications.4,8 Socioeconomic status (SES) is a determinant of health and a significant contributor to health disparities.9,10 Typically, SES is associated with poorer access to healthcare; however, healthcare access and utilisation among diabetics is high.11 Yet despite the high rates of healthcare access and utilisation among diabetics, health status and outcomes seen in low-income minorities is unsatisfactory.12-14 One possible explanation for the poor health outcomes among patients with diabetes is poor self-management practices.11,15-18 Poor adherence to standard diabetes care recommendations is associated with adverse outcomes in clinical practice.13,14 Suboptimal adherence to standard diabetes care recommendations is frequently observed in patients who have poor communication with their provider, lack of understanding/knowledge of the disease, polytherapy, suboptimal self-monitoring of blood glucose levels and psychosocial factors such as depression.14-24 Suboptimal adherence, once viewed as a patient problem, is now seen as an indication of patients’ self-management of chronic disease within the interactive framework of providers, healthcare systems, families and communities.25 Within this framework, the dynamic interaction of patient, healthcare providers and systemic factors can influence the overall management of diabetes.26 The care of patients with diabetes has largely encompassed new and more efficacious diabetic treatments and improved medication delivery systems,27 but literature highlights the importance of integrating self-management education.26,28-33 To adequately address barriers to diabetes self-management and identify strategies to overcome them, it is important to examine whether there are additional barriers that still exist.

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The University of Maryland Baltimore (UMB), the research intensive medical center, partnered with the Bon Secours Baltimore Health System (BSBHS), the minority serving system, as part of a NIH-funded multi-year prospective study. The partnership was intended to offer a unique opportunity to investigate how a partnership between BSBHS and UMB, supported by the community, can provide a platform to improve patient, physician and system adherence.

The study enrolled primary-care physicians and patients of these physicians. Patients were recruited from both clinics. Within each clinic, they were randomised to either patient education group or to the control group.

To underscore the collaborative partnership and the interactive learning between the two institutions, complementary disease areas were examined where UMB focused on hypertension and BSBHS focused on diabetes. As part of this partnership study, the overall objective of this research was to explore the patients’ perceptions about barriers to self-management of diabetes from the target population. Several focus group interviews of the target population were conducted and this article presents the methodology and key findings of the four focus group sessions.

Methods This was a qualitative study conducted among 31 predominately African-American patients with diabetes who were enrolled in the multi-year prospective partnership study. Each participant was told the purpose of the focus group and asked to complete an informed consent to allow the tape recording of the focus group.

Study sample The sample for this analysis was restricted to patients enrolled in the U-01 grant described in the introduction. The sampling technique used purposive sampling for the selection of individuals in order to yield some information about barriers to the self-management of their diabetes. The sampling method allowed recruiting participants who were more likely to participate in a focus group session and who possessed characteristics relevant to the aim of the study. To reach the target sample quickly and since sampling for propor-tionality was not a concern, we sampled participants with a diagnosis of diabetes enrolled in the U-01 grant who were aged 50 to 90 years and who were more likely to be available during daytime hours. A purposive sample of 150 participants was selected and contacted from a list of patients in the diabetes section of the U-01 grant.

Data collection To meet the objectives of this research, four traditional interactive and focused discussions were conducted between December 2007 and April 2008, with a minimum of five people in each group.

Each focus group followed a similar format. The focus groups were used to explore perceptions about barriers to self-management of diabetes from the target population and to aid in the development of a quantitative access to care questionnaire. A structured topic guide that consisted of a series of open-ended questions was used to collect information about knowledge of current health status, medication use, continuity of care, blood glucose level and nutrition.

These topics were selected after careful review of the literature on diabetes self-management. Appendix A contains the topic guide used in the study.

The focus group interviews were moderated by a diabetes nurse educator and a graduate student. Discussions were audiotaped and written notes were taken.

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Analysis From the tape recordings of the focus group interviews, the extensive conversations were transcribed verbatim within the relevant response topics. An independent assessment of the transcripts by another researcher was not conducted; however, notes taken by the moderator and by the assistant were compared.

Results From the purposive sample of 150 patients in the diabetes section of the U-01 grant, all participants were contacted by telephone.

After a series of follow-up calls, a total of 31 patients, 23 intervention and 11 non-intervention, participated in the four focus groups. Several patients did not participate due to refusal, change of address/number disconnected, and not being home at the time of the phone call.

Four focus groups were completed where intervention and nonintervention participants were mixed to allow different opinions or views. The majority of the participants were African-American and females. The mean age of the participants was 74, with a range of 43 to 81 years. None of the patients participated in more than one group. The majority of the respondents felt comfortable enough during the 60-minute session to discuss their opinions openly while others only responded when asked.

Knowledge of current health status Participants’ understanding and knowledge about diabetes came from various sources. For example, participants identified the Bon Secours Health System, TV/radio, physician, insurance company, library, pamphlets in the mail, glucose meter, diabetes clinic, church, a family member and the news as sources of health information.

More participants identified their physician, insurance company and a family member as sources of health information. The majority of the participants thought the health information received was great and very useful. One patient stated, ‘The information was very helpful and I’m always eager to read more.’ The patient went further to say that he eats three meals a day, exercises and watches his carbohydrate and sugar intake. The patient also mentioned that this led him to get involved in a community service programme that grows organic vegetables and teaches people how to buy and cook healthy foods. Another patient said, ‘The information I received from my doctor was wonderful. It helped me to get my blood sugar under control.’

Although the majority of the participants made positive comments about the health information they received from their doctor, a few of the participants were not so pleased. One woman, who was newly diagnosed with diabetes, was disappointed with the lack of information she received. ‘I did not find the information I received from my doctor as useful. The doctor just wrote something down on a piece of paper and gave it to me.’ Another woman pointed out that her doctor is not very forthcoming with information. ‘It’s like pulling teeth to get him to say something.’ Several of the participants mentioned that they try to exercise like the doctor told them, but their arthritis prevents them from doing so.

The participants’ perceptions about eating habits seem to be quite diverse. ‘I have learnt how to discipline myself, so I can eat anything I want,’ said one patient. ‘I took myself off of red meat, so I don’t care for it anymore,’ said another patient. One patient mentioned that she doesn’t eat when she’s hungry, but acknowledged that ‘skipping meals is not good.’ There seemed

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to be a general consensus about consuming little to no red meat.

Spouses of two participants who also have diabetes heavily influenced their eating habits. The participants pointed out that, for the most part, they enjoy eating sweet and starchy foods, but try to keep it to a minimum by eating smaller portions.

Nearly all the participants in the focus group did find the health information they received from various sources as useful; however, several of the participants found some of the health information to be quite confusing. One participant talked about the information that she read on the label of products in the grocery store, ‘I read a lot in the grocery store, but I’m confused about the sugar alcohol labelled on some items.’ The same participant went on to say that she needed clarification on the controversy surrounding SplendaH. One female participant found her target number for diabetes and cholesterol to be confusing. The same participant was also confused about the difference between baby aspirin and regular aspirin. Another female participant, who acknowledged her caloric goal, didn’t understand how to count the amount of calories she consumes per day. One participant expressed frustration with the fluctuation in his blood glucose levels, ‘I don’t understand why my blood sugar is fluctuating. I don’t feel I need to pay for my medicine if it’s not working.’

Identifying medications and understanding prescriptions The most common method of identifying medication for which the drug is prescribed was by looking at the name on the medication bottle followed by pill colour, shape, size and imprint. Looking at the name on the medication bottle and colour was by far the most preferred methods of identification. More participants in the intervention group had a greater preference for the name on the bottle, while more of the participants in the non-intervention group had preference for pill colour. One participant identified the use of a pill box, ‘I don’t like it when themedicine changes,’ said one patient.

‘My doctor wants me to take generics and that messes me up… sometimes it’s the same colour.’ Another participant identified her medications by keeping them in separate places around the home.

A few others mentioned that they have been on the medications for so long that they know what their medication look like. When asked if there was an alternative way they would prefer to identify their medication, some preferred drug name on the medication bottle, colour, shape, size, imprint, asking a pharmacist, reading the package insert, looking at the actual pill or verifying based on strength. An overwhelming majority still preferred the name on the medication bottle and colour.

Continuity of care The most common deciding factor that made participants visit their doctor for follow-up care was for an emergency followed by an appointment scheduled by the primary-care physician. The most common type of health reason mentioned that made patients visit their primary-care physician were diabetes, hypertension, eye problems, arthritis and prescription refills. One patient stated that he does not visit the primary-care physician by scheduled appointments, but continuously because of his diabetes. Participants consistently stated that they see their primary care physician every three months. There seemed to be a variation in the responses to the question about how often they visit other healthcare providers because of a referral by a primary-care doctor. The responses ranged from every two months to every year. A significant number of participants stated their physician does not ask about other

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medications they are taking. According to one participant, ‘If I don’t take my medicines to my doctor’s appointment, he/she doesn’t ask.’

Besides the weather, all of the participants stated that they have no problem in keeping their scheduled appointments. ‘I’m a diabetic and it’s important’, said one patient.

Self-monitoring of blood glucose/knowledge of BP and glucose goal/management of high or low glucose levels Lack of awareness of target blood glucose and blood pressure goal was acknowledged by an overwhelming majority of both the intervention and non-intervention participants. At least two women spoke of how they came up with their own blood glucose goal, ‘I didn’t get a number, but I read up on it myself.’ Another woman said, ‘My doctor didn’t give me a target level. I developed one for myself.’ A few participants were only aware of their morning blood glucose level specified by their doctor while others were only aware of their after-meals value. Others stated that they could not remember what goal was specified for them. Nearly all participants stated that they have no problems in checking their blood glucose, however, a few participants didn’t like the idea of sticking their finger because it was too painful or that the meter they used required a lot of blood.

When asked about how they will respond to feeling shaky, hungry and sweaty or feeling thirsty, tired and weak, nearly all said that they will first check their blood sugar and then eat a piece of candy or drink orange juice. A few stated that they would proceed and eat something or drink orange juice.

Knowledge of nutrition-related goals/weight management All participants agreed that they benefited from controlling their blood sugar through eating plenty of vegetables and less meat.

They were aware of foods such as candy that increases their blood sugar. They were equally aware of foods that decrease their blood glucose such as vinegar, lemon juice, water, vegetables, broiled chicken, turkey bacon, and fish. ‘It’s not so much the food you eat, but what you put on it,’ said one patient.

Discussion The focus groups did help to identify barriers to self-management that could be associated with poor health outcomes among minority patients with diabetes. Differences in gender, age, marital status and culture did not seem to have an impact on the attitudes and behaviours toward the topics under discussion. Participants’ understanding and knowledge about diabetes came from various sources.

The participants’ perceptions about eating habits were quite diverse, no gender difference was noticed. Nearly all the participants in the focus group did find the health information they received from various sources as useful, however, there were several of the participants who found some of the health information quite confusing. The limited health literacy seen in this study supports the results of previous studies that have shown that inadequate or marginal health literacy can limit a person’s ability to care for their medical problems.21,22 The most common method of identifying medication for which the drug is prescribed was by looking at the name on the medication bottle followed by pill colour, shape, size, and imprint. Looking at the name on the medication bottle and colour was by far the most

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preferred methods of identification. The most common deciding factor that made participants visit their doctor for follow-up care was an emergency office visit followed by an appointment scheduled by the primary care physician. This study also provides additional evidence that inadequate health literacy can lead to an inefficient use of health services.34,35 Lack of awareness of target blood glucose and blood pressure goal was acknowledged by an overwhelming majority of both the intervention and non-intervention participants. The lack of awareness of target blood glucose may provide a possible explanation for suboptimal self-monitoring of blood glucose seen in previous studies.17,18

Conclusion The focus group discussions revealed many similar experiences and perceptions among the 31 participants, yet there also were important differences across certain issues. Several themes relating to barriers to self-management of diabetes were highlighted during the focus group discussions. First, several of the participants found some of the health information received on diabetes to be quite confusing, despite the source of the information. Secondly, physicians are not forthcoming with information pertaining to diabetes. Lastly, a lack of awareness of target blood glucose and blood pressure goal was acknowledged by an overwhelming majority of participants.

The aim of these focus groups was to identify perceptions and behaviours related to diabetes self-management that do exist in the real world setting, and possible explanations for these behaviours.

There are many documented factors that contribute to successful blood glucose control, but the ability of patients to manage their diabetes is critical because adherence with therapeutic regimens may prevent or delay the onset of complications and improve health outcomes. The key to successful diabetes management is heavily dependent upon the education, knowledge and diabetes self-management skills of each individual. Interventions directed towards improvement of outcomes in diabetes management should focus on behavioural change, which is developed on the basis of self-efficacy in the context of social cognitive theory.36 Motivation and self-efficacy in the management of chronic illnesses are known to be important determinants of patients’ performance of self-care. A patient’s ability to care for themselves is enhanced by first identifying barriers and developing effective strategies to overcome them.

The findings of this research indicate that most patients do not know their target blood glucose and blood pressure goals and/ or the importance of those values. Physicians should inform their patients that knowledge of target blood glucose and blood pressure goals is necessary for effective diabetes self-management but is not sufficient to achieve successful health-related outcomes.

Acknowledgments The project described was supported by Grant Number 5U01HL079151 from the National Heart, Lung, and Blood Institute.

Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

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American Diabetes Association. Economic costs of diabetes in the U.S. in 2002.

Diabetes Care 2003; 26(3): 917–932.

2. Centers for Disease Control and Prevention. National Health and Nutrition Survey, 1999– 2000.

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3. Bloomgarden ZT. American Diabetes Association annual meeting, 1998. Insulin resistance, exercise, and obesity. Diabetes Care 1999; 22(3): 517–522.

4. Dagogo-Jack S. Ethnic disparities in type 2 diabetes: pathophysiology and implications for prevention and management. J Natl Med Assoc 2003; 95(9): 779–789.

5. Gary TL, Crum RM, Cooper-Patrick L, Ford D, Brancati FL. Depressive symptoms and metabolic control in African-Americans with type 2 diabetes. Diabetes Care 2000; 23(1): 23–29.

6. Osei K, Gaillard T, Schuster DP. Pathogenetic mechanisms of impaired glucose tolerance and type II diabetes in African-Americans. The significance of insulin secretion, insulin sensitivity, and glucose effectiveness. Diabetes Care 1997; 20(3): 396–404.

7. Polonsky KS, Sturis J, Bell GI. Seminars in Medicine of the Beth Israel Hospital, Boston. Non-insulin-dependent diabetes mellitus – a genetically programmed failure of the beta cell to compensate for insulin resistance. N Engl J Med 1996; 334(12): 777–783.

8. Rabi DM, Edwards AL, Southern DA, et al. Association of socio-economic status with diabetes prevalence and utilization of diabetes care services. BMC Health Serv Res 2006; 6: 124.

9. Andersen R, Newman JF. Societal and individual determinants of medical care utilization in the United States. Milbank Mem Fund Q Health Soc 1973; 51(1): 95–124.

10. Adler NE, Newman K. Socioeconomic disparities in health: pathways and policies.

Health Aff 2002; 21(2): 60–76.

11. Harris MI. Health care and health status and outcomes for patients with type 2 diabetes. Diabetes Care 2000; 23(6): 754–758.

12. Schillinger D, Grumbach K, Piette J, et al. Association of Health Literacy with Diabetes Outcomes. J Am Med Assoc 2002; 288(4): 475–482.

13. Pladevall M, Williams LK, Potts LA, Divine G, Xi H, Lafata JE. Clinical outcomes and adherence to medications measured by claims data in patients with diabetes.

Diabetes Care 2004; 27(12): 2800–2805.

14. Ho PM, Rumsfeld JS, Masoudi FA, et al. Effect of medication nonadherence on hospitalization and mortality among patients with diabetes mellitus. Arch Intern Med 2006; 166(17): 1836–1841.

15. Cramer JA. A systematic review of adherence with medications for diabetes.

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16. Lerman I, Lozano L, Villa AR, et al. Psychosocial factors associated with poor diabetes self-care management in a specialized center in Mexico City. Biomed Pharmacother 2004; 58(10): 566–570.

17. Vincze G, Barner JC, Lopez D. Factors associated with adherence to selfmonitoring of blood glucose among persons with diabetes. Diabetes Educ 2004; 30(1): 112–125.

18. Zgibor JC, Simmons D. Barriers to blood glucose monitoring in a multiethnic community. Diabetes Care 2002; 25: 1772–1777.

19. Ciechanowski PS, Katon WJ, Russo JE, Walker EA. The patient-provider relationship: attachment theory and adherence to treatment in diabetes. Am J Psychiatry 2001; 158(1): 29–35.

20. Sprague MA, Shultz JA, Branen LJ, Lambeth S, Hillers VN. Diabetes educators’ perspectives on barriers for patients and educators in diabetes education.

Diabetes Educ 1999; 25: 907–916.

21. Gazmararian JA, Baker DW, Williams MV, et al. Health literacy among Medicare enrollees in a managed care organization. J Am Med Assoc 1999; 281(6): 545– 551.

22. Sudore RL, Mehta KM, Simonsick EM, et al. Limited literacy in older people and disparities in health and healthcare access. J Am Geriatr Soc 2006; 4(5): 770– 776.

23. Bayliss EA, Steiner JF, Fernald DH, Crane LA, Main DS. Descriptions of barriers to self-care by persons with comorbid chronic diseases. Ann Fam Med 2003; 1(1): 15–21.

24. Peyrot M, Rubin RR, Lauritzen T, Snoek FJ, Matthews DR, Skovlund SE. Psychosocial problems and barriers to improved diabetes management: results of the Cross-National Diabetes Attitudes, Wishes and Needs (DAWN) Study. Diabet Med 2005; 22(10): 1379–1385.

25. Walker EA, Usher JA. Understanding and enhancing adherence in adults with diabetes. Curr Diab Rep 2003; 3(2): 141–148.

26. Brown JB, Harris SB, Webster-Bogaert S, Wetmore S, Faulds C, Stewart M. The role of patient, physician and systemic factors in the management of type 2 diabetes mellitus. Fam Pract 2002; 19(4): 344–349.

27. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care 2003; 26(1): S33–S50.

28. Norris SL, Lau J, Smith SJ, Schmid CH, Engelgau MM. Self-management education for adults with type 2 diabetes: a meta-analysis of the effect on glycemic control.

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29. Von Korff M, Gruman J, Schaefer J, Curry SJ, Wagner EH. Collaborative management of chronic illness. Ann Intern Med 1997; 127(12): 1097–1102.

30. Nagelkerk J, Reick K, Meengs L. Perceived barriers and effective strategies to diabetes self-management. J Adv Nurs 2006; 54(2): 151–158.

31. Bodenheimer T, Lorig K, Holman H, Grumbach K. Patient self-management of chronic disease in primary care. J Am Med Assoc 2002; 288(19): 2469–2475.

32. Van den Arend IJ, Stolk RP, Krans HM, Grobbee DE, Schrijvers AJ. Management of type 2 diabetes: a challenge for patient and physician. Patient Educ Couns 2000; 40(2): 187–194.

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33. Po YM. Telemedicine to improve patients’ self-efficacy in managing diabetes. J Telemed Telecare 2000; 6(5): 263–267.

34. Baker DW, Gazmararian JA, Williams MV, et al. Functional health literacy and the risk of hospital admission among Medicare managed care enrollees. Am J Public Health 2002; 92(8): 1278–1283.

35. Howard DH, Gazmararian J, Parker RM. The impact of low health literacy on the medical costs of Medicare managed care enrollees. Am J Med 2005; 118(4): 371–377.

36. Clark NM, Dodge JA. Exploring self-efficacy as a predictor of disease management.

Health Educ Behav 1999; 26(1): 72–89.

APPENDIX A Knowledge of current health status 1. Let’s talk about where you get information for diabetes.

Where do you go to get information about your diabetes?

2. What do you think about the information you received?

Probe: How useful was the information you received?

What was not useful about the information you received?

How satisfied were you with the information you received?

How helpful was the information in addressing your medical problems?

3. What information about your diabetes do you find confusing?

Probe: What makes the information confusing?

Ability to identify medication and condition for which the drug is prescribed /Ability to read and understand prescription instructions

How often do you visit your primary-care doctor for regular check-ups?

How often do you visit other health-care providers because your primary-care doctor has referred you?

2. How often does your primary-care doctor ask about other medications you are taking?

3. What problems do you face when trying to keep your doctor appointments?

Probe: What is it about your doctor’s _______________ that make it difficult for you to keep appointments?

In what way will having __________ help you to keep appointments?

How does the ______________ of the office visit make it difficult for you keep appointments?

What do you think will make it easier for you to ____________

Ability to indentify medication and condition for which the drug is prescribed/ability to read and understand prescription instructions 1. Some of you may have other health problems in addition to your diabetes. How do you identify which of your medications are used to treat diabetes?

Self-monitoring of blood glucose/knowledge of BP and glucose goal/management of high or low glucose levels 1. What blood sugar level has your doctor suggested is good for you?

2. Some of you mentioned that you identify the pill based on _______ . If there were another way, how would you prefer to identify it?

3. What do you do when you feel shaky, hungry and sweaty or when you feel thirsty, tired and weak or what do you do when you don’t feel well?

Continuity of care 1. For the following questions, I want you to think about those visits to your doctor related to your diabetes. If you saw a doctor for both your diabetes and another condition, that would still count as a visit related to your diabetes.

What makes you decide when you should go to visit your doctor for follow-up care?

Probe: What types of health problems make you visit the primary care doctor?

Knowledge of nutrition-related goals/weight management 1. What do you think about controlling your blood sugar through healthy food choices?

Probe: What do you mean?

In what way will make it easier for you?

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2. Do you face any problems when checking your blood sugar?

2. What food choices would make a difference in your blood sugar control?

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Optimal utilisation of sulphonylureas in resourceconstrained settings POOBALAN NAIDOO, VIRENDRA RAMBIRITCH, NEIL BUTKOW, SELVARAJAH SAMAN Abstract Sulphonylureas (SUs) are oral anti-diabetic drugs (OADs) that were introduced more than 60 years ago. Clinicians are familiar with their use and they remain extensively used.

However, the SU class is associated with adverse effects of weight gain and hypoglycaemia. In addition, their effects on cardiovascular events remain contentious. Newer classes of anti-diabetic agents have been developed and these agents are weight neutral (di-peptidyl peptidase IV inhibitors), while others reduce weight (glucagon-like peptide analogues and sodium glucose co-transporter inhibitors). Furthermore, the newer agents are less likely to cause hypoglycaemia and have a potentially better cardiovascular safety profile. However, the newer agents are more costly than SUs and their longterm safety is unknown. It is therefore likely that SUs will continue to be used, and more so in resource-limited settings.

One may mitigate the adverse effects of weight gain and hypoglycaemia associated with the SU class by using members within this class that are less probable to cause these adverse effects. Furthermore, the specific SU must be used at the lowest effective therapeutic dose. In patients at high risk of SU-induced hypoglycaemic episodes (frail, clinically significant renal impairment), or patients in whom hypoglycaemic episodes may have devastating effects (bus drivers), newer anti-diabetic agents may be a justifiable alternative option.

Keywords: type 2 diabetes mellitus, sulphonylureas, resourceconstrained settings

Introduction Sulphonylureas (SUs) were developed in the 1950s.1 They reduce blood glucose levels by increasing insulin secretion from the pancreatic beta-cells. At the cellular level SUs block potasssium (KATP) channels and increase calcium influx, which results in the release of insulin from the vesicles.1

Correspondence to: Dr Poobalan Naidoo Boehringer Ingelheim, Johannesburg e-mail: poobalan.naidoo@boehringer-ingelheim.com Virendra Rambiritch University of Kwa-Zulu Natal, Durban Neil Butkow University of Witwatersrand, Johannesburg Selvarajah Saman Port Shepstone Regional Hospital and University of Kwa-Zulu Natal, Durban Originally published in Cardiovascular J Afr 2014; 25(2): 88.

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Currently there is an expansion in the therapeutic armamentarium of agents for type 2 diabetes. The therapeutic landscape is complex and comprises pharmacologically distinct molecules, including biguanides, sulphonylureas, incretin-based therapies and renal sodium glucose co-transporter (SGLT) inhibitors.2 As novel therapies are inevitably associated with increased costs, this article focuses on ways to utilise SUs in a manner that maximises efficacy and concurrently minimises adverse effects.

Efficacy and durability of glycaemic effect Type 2 diabetes patients benefit from intensive multifactorial riskfactor modification.3 In addition to control of blood glucose and glycosylated haemoglobin (HbA1c) levels, lifestyle modification (diet and exercise), and control of blood pressure and cholesterol levels are crucial to reduce the risk of cardiovascular disease in type 2 diabetes patients.3 For blood glucose control, HbA1c level is the most robust endpoint used in clinical trials to evaluate the efficacy of anti-diabetic drugs.

HbA1c is an indicator of three-month average blood glucose levels.

Reduction in HbA1c levels reduces microvascular complications.4-6 SUs reduce HbA1c levels by approximately 1.5%,2 but their effect on cardiovascular outcomes is contentious. Their HbA1c level-reducing ability is adequate but durability is limited.7 Limited durability is probably secondary to type 2 diabetes mellitus being a progressive disease characterised by gradual reduction in betacell mass and function. If there are limited numbers of beta-cells, then the action of this class is limited because the mode of action necessitates the presence of beta-cells; they cannot increase insulin secretion if there are no beta-cells present to synthesise and release insulin.

Furthermore, secondary failure has also been attributed to the detrimental effects of SUs on residual pancreatic beta-cells.8 Secondary failure rates were found to be lowest with gliclazide (7%), compared with glibenclamide (17.9%) and glipizide (25.6%).9

Safety data SUs cause weight gain2,10 and significantly increase the risk of hypoglycaemia.11,12 Hypoglycaemia appears to be associated with adverse vascular events and death.13 There are also issues with regard to cardiovascular safety. There is inconsistency in the results of clinical studies in respect of SUs and cardiovascular safety. The University Group Diabetes Program14 demonstrated increased cardiovascular mortality in patients treated with tolbutamide. However, the United Kingdom Prospective Diabetes Study (UKPDS)4 and the ADVANCE Collaborative Group5 did not show an association between treatment with an SU and adverse cardiovascular outcomes.

In a meta-analysis of 33 studies, with more than a million study subjects, SU use was associated with a significantly increased risk of cardiovascular death (relative risk 1.27, 95% confidence interval 1.18–1.34, n = 27 comparisons).15 Monami et al.16 conducted a

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meta-analysis of randomised clinical trials to evaluate the cardiovascular safety of SUs. They concluded that ‘in type 2 diabetes, the use of sulfonylureas is associated with increased mortality and a higher risk of stroke, whereas the overall incidence of major adverse cardiovascular events (MACE) appears to be unaffected.’

Given the inconsistency of the literature with regard to SUs and cardiovascular outcomes, a SU cardiovascular outcome trial is required to clarify the effect of SUs on cardiovascular outcomes.16,17

Dose–response relationships The literature supports the use of SUs at doses lower than the maximum manufacturer’s recommended dose.18 Studies have shown that as the dose of SU is increased, there is initially a direct relationship between dose and blood glucose-lowering effect.18 However, further dose increase results in no further reduction in blood glucose levels, and, when the dose is further increased, the glycaemic profile actually worsens.18 Modified-release formulations have further reduced the SU dose that is required, compared to the immediate-release pharmaceutical preparation.19 For example gliclazide is available in a modified-release formulation that uses less than half of the dose of the immediate-release formulation.19

Cost considerations SUs remain affordable. This is relevant in countries that have limited resources and competing healthcare problems. In subSaharan Africa, there are epidemics of not just metabolic and cardiovascular disease, but also infectious diseases.20 Tuberculosis and parasitic diseases such as malaria remain major healthcare challenges, while diabetes, hypertension and traumatic injuries are increasing.21 Therefore scarce medical resources must be distributed to various disease-management programmes.

However, one may argue that managing SU-induced hypoglycaemic events (the cost of treating and in some cases the cost of admission), raises their cost. One may mitigate this added cost by using the newer SUs that have fewer propensities to cause hypoglycaemia compared to older agents.

Newer classes of anti-diabetic agents The ideal anti-diabetic drug should be safe, efficacious and cost effective. It should not only reduce HbA1c levels but also reduce macro- and microvascular complications. Furthermore, it must not cause weight gain and hypoglycaemia, and must have durable efficacy and long- term safety. There is continuing research to develop newer agents to emulate the characteristics of an ideal anti-diabetic agent, and therefore better manage type 2 diabetes patients.

Sodium glucose co-transport (SGLT) inhibitors and incretin-based therapies are new classes of anti-diabetic agents. SGLT inhibitors reduce weight and have fewer propensities to cause hypoglycaemic events.22 This is in contrast to the SU class that increases weight and the number of hypoglycaemic episodes.

Incretin-based therapies include glucagon-like peptide (GLP) analogues and di-peptidyl dipeptidase IV (DPPIV) inhibitors. GLP analogues reduce weight but are administered via the parenteral route. DPPIV inhibitors are weight neutral, have a low propensity for hypoglycaemia and are administered orally.

The uncertainty surrounding adverse cardiovascular events associated with therapy with SUs remains,15 in contrast to the DPPIV

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class, which has both meta-analysis23 and a cardiovascular outcome trial24 that demonstrate cardiovascular safety of this new class.

There are safety concerns with newer anti-diabetic agents.

For example, issues related to pancreatitis and pancreatic cancer remain with incretin-based therapies.25 However, the American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD) and the International Diabetes Federation (IDF) have issued a joint statement saying that there is inadequate information presently to demonstrate a causal relationship between incretin-based therapy and pancreatitis and pancreatic cancer.26 There are also concerns with the SGLT inhibitor class and bladder and breast malignancies, and urinary and genital tract infections.22 The newer agents require further phase IV data to inform clinical use.

Maximising benefits and minimising adverse effects of SUs After considering the adverse effects, safety concerns, efficacy data and cost, one must use SUs in a manner that maximises efficacy while limiting the potential for adverse effects. The question is how does the clinician do this? One way is to choose the ‘right sulphonylurea, at the right dose, for the right patient’.

The right sulphonyureas: The SUs share a common mode of action. However, there are differences in pharmacokinetics and pharmacodynamics between individual SUs. Some SUs have fewer propensities for hypoglycaemia and weight gain than others.27 South African treatment guidelines for type 2 diabetes specifically mention that glibenclamide must be phased out, and in the interim it must be dispensed only if renal function is known.28 Data derived from the UK General Practice Research Database (719 general practitioner practices, 34 052 patient-years of SU therapy) reported that in users of SUs, the annual risk of any hypoglycaemic event was 1.8%, rising to 2.0% in those aged > 65 years. The risk of SUs was greatest for glibenclamide; the study reported 25% fewer recorded episodes for gliclazide and 40% fewer for glipizide compared with glibenclamide.29 At the right dose: Given the data on dose-response relationships of the class, it is prudent to use the lowest effective dose of SU, guided by efficacy parameters such as HbA1c levels.

For the right patient: SUs are more likely to cause adverse effects in patients with risk factors for hypoglycaemia, including older, frail patients and patients with clinically significant renal impairment.30 In addition, any hypoglycaemic effect may be devastating for specific patients, such as bus drivers. Therefore SUs should perhaps be avoided in these groups and newer antidiabetic drugs considered.

Conclusion Cost issues remain a barrier between the newer anti-diabetic drugs and the majority of South African type 2 diabetes patients. SUs, if used at the right dose (the lowest possible effective dose), for the right patient (in younger patients without renal impairment), remain an option for the management of type 2 diabetes patients in resource-constrained settings.

References 1.

2.

McGill JB. Pharmacotherapy in type 2 diabetes: a functional schema for drug classification. Curr Diabetes Rev 2012; 8(4): 257–267.

Mazzola N. Review of current and emerging therapies in type 2 diabetes mellitus.

Am J Manag Care 2012; 18(1 Suppl): S17–26.

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3. Gaede P, Lund-Andersen H, Parving HH, et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008; 358(6): 580–591.

4. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complication in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–853.

5. The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Eng J Med 2008; 358: 2560–2572.

6. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360(2): 129–139.

7. Holman RR. Long-term efficacy of sulfonylureas: a United Kingdom Prospective Diabetes Study perspective. Metabolism 2006; 55(5 Suppl 1): S2–5.

8. Rendell M. The role of sulphonylureas in the management of type 2 diabetes mellitus. Drugs 2004; 64(12): 1339–1358.

9. Harrower AD. Comparison of efficacy, secondary failure rate, and complications of sulfonylureas. J Diabetes Complication 1994; 8(4): 201–203.

10. Sehra D, Sehra S, Sehra ST. Sulfonylureas: do we need to introspect safety again?

Expert Opin Drug Saf 2011; 10(6): 851–861.

11. Holstein A, Egberts E-H. Risk of hypoglycaemia with oral anti-diabetic agents in patients with type 2 diabetes. Exp Clin Endocrinol Diabetes 2003; 111: 405–414.

12. Burge MR, Sood V, Sobhy TA, et al. Sulphonylurea-induced hypoglycaemia in type 2 diabetes mellitus: a review. Diabetes Obesity Metabolism 1999; 1: 199–206.

13. Zoungas S, Patel A, Chalmers J, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med 2010; 363(15): 1410–1418.

14. Klimt CR, Knatterud GL, Meinert CL, et al. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. Diabetes 1970; 19: 747–830.

15. Phung OJ, Schwartzman E, Allen RW, et al. Sulphonylureas and risk of cardiovascular disease: systematic review and meta-analysis. Diabet Med 2013; 30(10): 1160–1171.

16. Monami M, Genovese S, Mannucci E. Cardiovascular safety of sulfonylureas: a metaanalysis of randomized clinical trials. Diabetes Obes Metab 2013; 15(10): 938–953.

17. Rosenstock J, Marx N, Kahn SE, et al. Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy: rationale for the active-comparator CAROLINA trial. Diab Vasc Dis Res 2013; 10(4): 289–301.

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18. Rambiritch V, Naidoo P, Butkow N. Dose-response relationships of sulfonylureas: will doubling the dose double the response? South Med J 2007; 100(11): 1132– 1136.

19. Rambiritch V, Naidoo P. Gliclazide modified release. Drugs 2005; 65(10): 1449– 1450.

20. Ikem I, Sumpio BE. Cardiovascular disease: the new epidemic in sub-Saharan Africa. Vascular 2011; 19(6): 301–307.

21. Mollentze WF, Levitt NS, Delport R, et al. Round-table discussion: Management of the diabetic patient in a resource constrained environment. S Afr J Diabetes Vasc Dis 2009; 6(2): 66–73.

22. Riser Taylor S, Harris KB. The clinical efficacy and safety of sodium glucose cotransporter-2 inhibitors in adults with type 2 diabetes mellitus. Pharmacotherapy 2013; 33(9): 984–999.

23. Johansen OE, Neubacher D, von Eynatten M, et al. Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme. Cardiovasc Diabetol 2012; 11: 3.

24. Scirica BM, Bhatt DL, Braunwald E et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013; 369(14): 1317– 1326.

25. Labuzek K, Kozłowski M, Szkudłapski D, et al. Incretin-based therapies in the treatment of type 2 diabetes--more than meets the eye? Eur J Intern Med 2013; 24(3): 207–212.

26 ADA/EASD/IDF Statement Concerning the Use of Incretin Therapy and Pancreatic Disease. http://www.diabetes.org/for-media/2013/recommendations-for.html.

Accessed August 08/2013.

27. Tessier D, Dawson K, Tetrault JP, et al. Glibenclamide vs. gliclazide in type 2 diabetes of the elderly. Diabet Med 1994; 11: 974–980.

28. Amod A, Ascott-Evans BH, Berg GI, et al. 2012 SEMDSA Guideline for the Management of Type 2 Diabetes. J Endocrinol Metabol Diabetes S Afr 2012; 17(2)(Suppl 1): S1–S95.

29. van Staa T, Abenhaim L, Monette J. Rates of hypoglycemia in users of sulphonylureas. J Clin Epidemiol 1997; 50: 735–741.

30. Amiel SA, Dixon T, Mann R, et al. Hypoglycaemia in Type 2 diabetes. Diabet Med 2008; 25(3): 245–254.

Bariatric surgery has better outcomes after 15 years

B

ariatric surgery comes out ahead, with greater weight loss, diabetes remission and fewer cardiovascular disease (CVD) complications than standard medical care. Fifteen years after undergoing bariatric surgery, 30% of patients no longer had diabetes, but only 7% of patients who received usual care were in diabetes remission.

These long-term findings from the Swedish Obese Subjects (SOS) prospective, matched-cohort study by Dr Lars Sjöström, from Sahlgrenska University Hospital, in Gothenburg, Sweden, and colleagues (J Am Med Assoc 2014; 311: 2297–2304, 2277– 2278) were published to coincide with the American Diabetes Association Conference in San Francisco.

The study also shows that ‘obese diabetics whose diabetes was of shorter duration or who had the greatest weight loss between the time of surgery and two years later were the most likely to have a sustained remission at 15 years. These patients likely had bariatric surgery before the failure of the insulin-producing cells of the pancreas was irreversible.’

The SOS study enrolled 4 047 obese patients in Sweden between 1987 and 2001. The current analysis looked at those who had diabetes at baseline: 260 patients who then received usual medical care and 343 patients who underwent bariatric surgery: vertical banded gastroplasty (227 patients), non-adjustable or adjustable banding (61), or Roux-en-Y gastric bypass (55).

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The patients had a mean age of around 50 years, a mean body mass index (BMI) of close to 41 kg/m2 and almost 60% were women. They had had diabetes for approximately three years.

The researchers tracked microvascular complications of the kidney, eyes and peripheral nerves and macrovascular complications (coronary heart disease, heart failure, stroke and peripheral arterial disease) after a median of 17 years. Diabetes remission was defined as having a blood glucose level below 110 mg/dl and not taking antidiabetic medication.

Bariatric surgery was associated with higher diabetes remission rates and weight loss compared with usual care, although these rates declined over time in both groups. This surgery was also associated with a significantly decreased risk for microvascular and macrovascular complications (hazard ratios: 0.43 and 0.74, respectively).

Additional follow up of newer studies is required to answer the question of which bariatric procedure is best for inducing longterm remission of diabetes, but those data will not be available for another five to 10 years.

Source: http://www.diabetesincontrol.com/articles/diabetes-news/16456-bariatric-surgeryhas-better-outcomes-after-15-years

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On the horizon: new oral therapies for type 2 diabetes mellitus MELINDA UKRAINSKI, TATIANA GANDRABURA , LINDSAY ANN BISCHOFF, INTEKHAB AHMED Abstract

Introduction

The first documented case of diabetes mellitus occurred earlier than 4000 BC. Since then, many of the brightest minds in medicine have dedicated their time and effort toward developing treatments that can reverse the course of this deadly disease. As our understanding of the pathogenesis of diabetes increases, so does the availability of treatment options. The fight against diabetes once only had metformin and sulfonylureas as the cornerstone of oral treatment, but now, multiple classes have been added to this armamentarium including thiazolidenediones (TZDs) and dipeptidyl peptidase IV (DDP IV) inhibitors. These therapies provide reasonable durable glycemic control but are unable to arrest the natural progression of diabetes or the eventual need for insulin. By utilizing our growing knowledge on the pathogenesis of diabetes, a number of new therapeutic agents are in development to overcome the shortcomings of current therapies. Promising options on the horizon include sodium-coupled glucose co-transport 2 (SGLT2) inhibitors, ranolazine, salicylates, second-generation peroxisome proliferator-activator receptor agonists (PPARs), and 11-beta hydroxysteroid dehydrogenase type 1 inhibitors (11-beta HSD1 inhibitors). Various molecules, including some enzymes, are also in development, particularly to address beta-cell preservation and its sensitivity to glucose, while minimising hypoglycaemia. Most of these new classes of drugs consist of daily administration, simplifying the regimen for patients and likely increasing medication compliance.

This article reviews the new agents that are advancing through clinical trials, their mechanism of actions, glucose lowering effect and possible side effects and limitations.

Diabetes mellitus afflicts approximately 400 million people worldwide and, without any significant change in this trend, by 2030 more than 552 million people will be diabetic.1 Our current treatment options are able to maintain reasonable glycaemic control for a period of time; however, they are unable to stop the progression of disease leading to deteriorating glycaemic control over time and subsequent need for increasingly complicated treatment regimens.

The two core defects of type 2 diabetes mellitus (T2DM) are insulin resistance and pancreatic beta-cell dysfunction or failure.2 Insulin resistance appears to be the first and main defect, resulting in an increased demand of insulin release from beta-cells to normalise glucose levels. Overtime, the the beta-cells’ ability to maintain this level of hyperinsulinemia deteriorates resulting in the hyperglycaemia characteristic of T2DM. Insulin resistance is attributed to ectopic lipid deposition in the liver and skeletal muscle, and changes in adipose tissue, resulting in inflamed tissue leading to the release of a multitude of inflammatory cytokines and decreased release of favorauble cytokines and hormones.3,4 By the time a person develops diabetes, 50–80% of insulin secretory function of the beta-cells is lost.4 Additional factors influencing beta-cell dysfunction include aging, genetic factors and biochemical abnormalities such as lipotoxicity, glucotoxicity, inflammation, amyloid deposition, and reactive oxygen species.5 Current therapies for T2DM are based on targeting these two core defects. Metformin and sufonylureas (SUs) are by far the most commonly prescribed medications for T2DM management.

Unfortunately, they are unable to arrest the natural course of decline in beta-cell function, their effects are not long lasting,6 and they each carry their own side-effect profile, with hypoglycaemia of particular concern with SU use. Thiazolidinediones (TZDs) improve insulin sensitivity but are notorious for their side effects, such as fluid retention, weight gain, fracture, and potential risk of bladder cancer.7,8 Members of the incretin family include DPP-IV inhibitors and glucagon-like peptide (GLP-1) analogs and each have their own limitations. The former have a limited effect on A1c reduction and a potentially increased risk of pancreatitis, while the latter are injectable and also carry the risk of pancreatitis.9,10 New therapies, while continuing to address the same two core defects, are being designed to also target various molecular pathways involved in the pathogenesis of T2DM, normalise hyperglycaemia, and minimise the complications of T2DM.

Keywords: type 2 diabetes, SGLT2 inhibitors, ranolazine, salicylates, second-generation Ppars, 11β-HSD1 inhibitors, glucokinase activators, fructose 1,6-bisphosphatase inhibitors

Correspondence to: Intekhab Ahmed Thomas Jefferson University and Hospitals, Philadelphia, PA, USA Tel: 215-955-5752; Fax: 215-928-3160 e-mail: Intekhab.ahmed@jefferson.edu Melinda Ukrainski, Lindsay Ann Bischoff Thomas Jefferson University Hospital, Philadelphia, PA, USA

Sodium-coupled glucose co-transporter 2 inhibitors (SGLT2 inhibitors)

Tatiana Gandrabura Atlanticare Regional Medical Center, Atlantic City, NJ, USA

The kidneys play a significant role in maintaining glucose homeostasis via the filtration and reabsorption of glucose. The reabsorption of glucose predominantly occurs on the brush border membrane of the convoluted segment of the proximal tubule.

Glucose enters the tubular cells by a sodium-dependent active carrier-mediated transport process and exits via the basolateral

Originally published in Int J Diabetol Vasc Dis Res 2013; 1: 301.

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membrane by facilitated diffusion utilising a sodium-independent glucose transporter (GLUTs).11 The sodium-dependent glucose co-transporters are a family of glucose transporters found in the intestinal mucosa of the small intestine (SGLT1) and the proximal tubule of the nephron (SGLT2, predominantly, and SGLT1).12 SGLT1 and SGLT2 are members of the SLC5A gene family (also known as the sodium substrate symporter gene family. Twelve of these have been identified in the human genome, and several of these (including SGLT1 and SGLT2) are associated with sodium glucose transport. These transporters use the electrochemical sodium gradient generated by the Na+/K+-ATPase is the driving force for the symporter activity. SGLT2 is the principal transporter and is responsible for 90% of glucose reabsorption in the kidney. SGLT2 is expressed in the S1 segment of the proximal tubule while SGLT1 is expressed in the S3 segment of proximal tubule and estimated to account for 10% of glucose reabsorption.11,12 Sodium-coupled glucose co-transporter 2 inhibitors are a class of agents initially derived from phlorizin, a natural component of apple tree bark, that blocks glucose reabsorption in the proximal tubule of the kidney.13 T2DM patients have increased activity of SGLT2 resulting in increased glucose reabsorption14 and, therefore, its inhibition is a logical site for intervention. Several oral SGLT2 inhibitors are in different phases of clinical trial. Canagliflozin, dapaglifozin, ipraglifozin, topoglifozin and empaglifozin are the most studied drugs in this class. The FDA recently approved Canagliflozin, with the requirement that five post-marketing studies be done including: a study to examine cardiovascular outcomes, a pharmacovigilance program to report the incidences of malignancies, severe pancreatitis, liver abnormalities, adverse events during pregnancy; a study to evaluate bone safety, and two paediatric studies.15 Dapaglifozin is approved for use in the European Union but its approval is delayed in the USA due to concerns about an imbalance in breast and bladder cancer events with more cases developing in patients taking the drug.16 The drop in haemoglobin A1c (HbA1c) with most of these drugs is in the range of 0.7–0.96% with modest weight loss, which is dose dependent, and ranges from 1.35 kg with small dose and 2 kg with maximum tolerable doses.17 Some side effects of these agents include hypoglycaemia, urinary tract infections, genital mycotic infections, salt and volume depletion, and other electrolyte losses such as calcium and magnesium.16,17 It has not been approved for patients with significant renal impairment and those requiring haemodialysis. If further data on safety and efficacy continue to be reassuring, SGLT2 inhibitors have a promising future in the management of diabetes.

Ranolazine Ranolazine, an anti-anginal medication with proven cardiovascular safety profile, acts by inhibiting late sodium current in cardiac tissue.18 Its mechanism of action for glucose lowering is unknown, but may include augmentation of glucose-induced insulin release and a beta-cell protective effect.20 A post hoc analysis of a study using ranolazine in T2DM patients revealed that the participants on ranolazine had a lower HbA1c level. The placebo-adjusted drop in HbA1c level after four months of treatment was 0.42–0.59%.

Another notable finding was that the patients on ranolazine did not have a significant difference in hypoglycaemic episodes when compared to placebo, and also did not change the incidence of hypoglycaemic episodes in patients already on anti-hyperglycaemic therapies, including sulfonylureas.19,20

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Salicylate derivatives The use of salicylates for the treatment of diabetes was proposed over 100 years ago based on the observation that diabetic patients taking salicylates showed improvement in their blood sugar levels.21 Our understanding of T2DM as a result of a chronic inflammatory state has re-invigorated the interest in salicylates as a therapeutic option for T2DM. The proposed mechanism of action is via inhibition of NF-kB, which increases the production of pro-inflammatory cytokines, promoting insulin resistance and down-regulating the insulin-sensitising adiponectin.21,22 Some studies have reported evidence that salicylates also directly inhibit adipocyte lipolysis, resulting in decreased FFA levels and increased insulin sensitivity.

Multiple small clinical trials have been done to evaluate the effect of salicylates on T2DM. Most of these are limited by small sample size and length of study. They also required very high doses of salicylates to achieve the effect, and these were associated with numerous side effects, particularly gastrointestinal bleeding, tinnitus, and hearing loss.23 Salsalate, a non-acetylated salicylate, is a promising new therapy for T2DM. Salsalate does not affect the COX enzymes, making it a much safer and tolerable option at higher doses than aspirin and other acetylated salicylates. One study examining the benefit of salsalate in T2DM revealed a significant dose-dependent drop in HbA1c levels of up to 0.49% with 4g of salsalate. Potential concerns include mild increases in microalbumin-to-creatinine ratio and in LDL cholesterol levels.23-25

Peroxisome proliferator activator receptor agonists (PPARs) The PPARs are a group of nuclear receptors known as ligandinducible transcription factors, which play diverse roles in regulating growth and metabolism. There are three major isotypes, PPAR-α, -γ and -δ. They form heterodimers with retinoid X receptors (RXR) to either stimulate or repress gene transcription. PPAR-α is mainly expressed in liver, heart and kidney, and plays a role in fatty acid oxidation and lipoprotein metabolism. PPAR-γ is expressed in adipose tissue, macrophages, and osteoblasts. It is involved in adipose tissue differentiation and triglyceride synthesis. PPAR-δ is expressed in skeletal muscle, cardiac muscle, and adipose tissue, where it stimulates fat oxidation.26 It also is expressed in liver and immune cells where it has a role in reducing hepatic glucose production and inflammation, respectively.

TZDs are an example of PPAR-β agonists, and have had a major impact on reducing insulin resistance to date. Unfortunately, their use has dramatically decreased due to their potential untoward side effects.

The first TZD, troglitazone, was associated with liver toxicity; rosiglitazone showed increased cardiovascular morbidity, and pioglitazone is linked with a potentially increased risk of bladder cancer and osteoporosis.8 These side effects appear to be secondary to the non-selectivity of these molecules. Because of their impressive effectiveness in T2DM, there is an ongoing effort to the develop second generation of PPAR agonists with more selective action and fewer side effects.

Balaglitazone, a newer partial PPAR-y agonist, has been suggested to be as efficacious in lowering blood glucose with less adverse systemic effects.24,25 In the BALLET trial, Henriksen et al. compared the effects of balaglitazone to pioglitazone. After 26 weeks, 10 mg of balaglitazone lowered HbA1c levels by 0.99%, compared to –1.11% for 20 mg balaglitazone, and –1.22% for

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45 mg pioglitazone. This study also showed that balaglitazone was effective in reducing total insulin requirements and increased insulin sensitivity. While there were no statistically significant differences in adverse effects between the two agents, the 10-mg dose of balaglitazone showed a trend towards less weight gain, fluid retention, cardiovascular complications, and effects on bone density. Multiple phase III trials are underway in Europe and the USA to further examine balaglitazone.

Aleglitazar is a member of a new class of dual PPAR-γ and -β agonists, named glitazars, which is being investigated in phase III trials. Aleglitazar has been reported to improve levels of HbA1c, triglycerides and HDL-C in a dose-dependent manner.26 Given these promising results, these agents have great potential for management of T2DM.

Therapies targeting metabolic enzymes 11β Hydoroxysteroid dehydrogenase type 1 (11β -HSD1) inhibitors The role of glucocorticoids in adipose tissue metabolism and distribution, lipid and glucose metabolism has long been known, with high levels of glucocorticoids promoting hyperglycaemia and insulin resistance, hyperlipidaemia, and visceral obesity.27, 28 11β- HSD is an enzyme that is involved in the interconversion of cortisol and cortisone and is present in two isoforms, 11β-HSD1 and 11β-HSD2. 11β-HSD1 is predominantly expressed in the liver and adipose tissue and its main function appears to be conversion of cortisone to cortisol.27 11β-HSD2 is primarily expressed in the kidneys and colon and acts to inactivate cortisol by converting it to cortisone.27-31 The incentive to develop 11β-HSD1 inhibitors for the treatment of diabetes has come from our increased understanding of the role between glucocorticoid excess and insulin resistance. The potential benefits of developing compounds that inhibit 11β-HSD1 include weight loss, and decreased serum insulin, glucose LDL-C and TG levels.27,30,31 However, many compounds that have an inhibitory effect on 11β-HSD1 also inhibit 11β-HSD2. For example, carbenoxolone is a non-selective inhibitor of both 11β-HSD1 and 11β-HSD2 derived from licorice root. In type 2 diabetics, it was found to improve hepatic insulin sensitivity, but also led to sodium retention, hypertension and hypokalaemia due to its 11β-HSD2 inhibition.29, 31 11β-HSD1 inhibitory effects have been demonstrated in previously known compounds including rosiglitazone, oestrogens, which may help to explain the protective effect they demonstrate in premenopausal women, and fibrates.31 Many new 11β-HSD1 selective compounds are in development, which include INCB13739, an antisense oligonucleotide. In one study, INCB13739 was added to metform-in, resulting in an average reduction in HbA1c level of 0.6% and up to 1.1 kg weight loss. Concerning limitations include interference with the hypothalamic–pituitary–adrenal (HPA) axis leading to mineralocorticoid excess resulting in sodium retention, hypertension, virilisation, and menstrual irregularities.30,31 While the potential utility of these compounds is clear, phase III studies are needed to determine the safety and efficacy of these 11β-HSD1 inhibitors.

Glucokinase activators Glucokinase (GK) or hexokinase IV is an enzyme that catalyzes the addition of phosphate to glucose for further intracellular metabolism. It serves as a glucose sensor in beta-cells and initiates

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the release of insulin from the beta-cell. In the liver, this enzyme directs glucose toward glycogen synthesis and lipogenesis. In diabetics, activity of GK is preserved, although decreased due to a lesser number of functional beta-cells.32 Currently, several GK activators are undergoing studies to evaluate their efficacy and safety. This class of molecules targets beta-cell core defect in T2DM and liver production of glucose.

In a phase I trial, piragilatin resulted in a decrease in fasting and post-prandial glucose in mild diabetes.32 Concerns include a timedependent effect on the central nervous system and reproductive system due to the expression of GK in these tissues.

Protein tyrosine phosphatase 1B (PTP1B) inhibitors This enzyme acts as a negative regulator of insulin signalling by deactivating the insulin receptor. Current data show its inhibition improves both insulin and leptin action in animals.33 It may be an option for the treatment of diabetes, but due to its expression in multiple other tissues, other studies are needed to ensure selectivity of these inhibitors to the desired tissues.

Fructose 1,6-bisphosphatase (FBP) inhibitors FBP is a rate-limiting enzyme for gluconeogenesis and its inhibition can result in improved blood sugars. A small phase I trial showed improvement in fasting blood sugars in individuals with diabetes.34

Conclusion In the coming years, multiple new therapeutic options will be available to address hyperglycaemia and its undesirable side effects.

These new therapeutics show great promise for controlling and managing T2DM, but are by no means a cure. The corner stone of prevention of T2DM lies in healthy lifestyle. Dietary modification and adequate physical activity is the ideal intervention for keeping the threat of diabetes development and its complications at bay.

We should continue to emphasise and allocate resources to the education and prevention of T2DM rather than solely depending on treating diabetes after it has occurred.

References 1.

Whiting D, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: Global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 2011; 94(3): 311–321.

2. Gerich J. Contributions of insulin-resistance and insulin-secretory defects to the pathogenesis of type 2 diabetes mellitus. Mayo Clin Proc 2003; 78(4): 447–456.

3. Pickup J. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 2004; 27(3): 813–823.

4. Matveyenko A, Butler P. Relationship between beta-cell mass and diabetes onset.

Diabetes Obes Metab 2008; 10(4): 23–31.

5. LeRoith, D, MD, PhD, FACP. Beta-cell dysfunction and insulin resistance in type 2 diabetes: Role of metabolic and genetic abnormalities. Am J Med 2002; 113(Suppl 6A): 3S–11S. 6. Nathan D, Buse J, Davidson M, Heine R, Holman R, Sherwin R, et al. Management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2006; 28(8): 1963.

7. Yki-Järvinen H. Thiazolidenediones. N Engl J Med 2004; 351(11): 1106.

8. FDA drug safety communication: Update to ongoing safety review of actos (pioglitazone) and increased risk of bladder cancer. [Internet].: US Food and Drug Administration; 2011 [updated June 15, 2011. Available from: http://www.fda. gov/Drugs/DrugSafety/ucm259150.htm.

9. Elashoff M, Matveyenko A, Gier B, Elashoff R, Butler P. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology 2011; 141(1): 150–156.

10. Demuth H, McIntosh H, Pederson R. Type 2 diabetes – therapy with dipeptidyl

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peptidase IV inhibitors. Biochim Biophys Acta 2005; 1751(1): 33–44.

11. Kanai Y, Lee W, You G, Brown D, Hediger M. The human kidney low affinity Na+/glucose cotransporter SGLT2. delineation of the major renal reabsorptive mechanism for D-glucose. J Clin Invest 1994; 93(1): 397–404.

12. Wells R, Pajor A, Kanai Y, Turk E, Wright E, Hediger M. Cloning of a human kidney cDNA with similarity to the sodium-glucose cotransporter. Am J Physiol 1992; 263(3 Part 2): 459–465.

13. Ehrenkranz J, Lewis N, Kahn C, Roth J. Phlorizin: A review. Diabetes Metab Res Rev 2005; 21(1): 31–38.

14. List J, Woo V, Morales E, Tang W, Fiedorek F. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 2009; 32(4): 650–657.

15. FDA approves invokana to treat type 2 diabetes [Internet]: FDA: US Food and Drug Administration; 2013 [updated March 29, 2013. Available from: http:// www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm345848.htm.

16. Clar C, Gill J, Court R, Waugh N. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. Br Med J Open 2012; 2(5): 1–12.

17. Shah N, Deeb W, Choksi R, Epstein B. Dapagliflozin: a novel sodium-glucose cotransporter type 2 inhibitor for the treatment of type 2 diabetes mellitus.

Pharmacotherapy 2012; 32(1): 80–94.

18. Chaitman B. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. Circulation 2006; 113(20): 2462–2472.

19. Chisholm J, Goldfine A, Dhalia A, Braunwald E, Morrow D, KarwatowskaProkopczuk E, et al. Effect of ranolazine on A1c and glucose levels in hyperglycemic patients with non-ST elevation acute coronary syndrome. Diabetes Care 2010; 33(6): 1163–1168.

20. Ning Y, Zhen W, Fu Z, Jiang J, Liu D, Belardinelli L, et al. Ranolazine increases beta-cell survival and improves glucose homeostasis in low-dose streptozotocininduced diabetes in mice. J Pharmacol Exp Ther 2011; 337(1): 50–58.

21. Rumore M, Kim K. Potential role of salicylates in type 2 diabetes. Ann Pharmacother 2010; 44(7–8): 1207–1221.

22. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li Z, Karin M, et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 2001; 293(5535): 1673–1677.

23. Goldfine A, Fonesca V, Jablonski K, Pyle L, Staten M, Shoelson S, et al. The effects of salsalate on glycemic control in patients with type 2 diabetes: A randomized trial. Ann Intern Med 2010; 152(6): 346–357.

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24. Agrawal R, Jain P, Dikshit S. Balaglitaone: a second generation peroxisome proliferator-activated receptor (PPAR) gamma. Mini Rev Med Chem 2012; 12(2): 87–97.

25. Henriksen K, Byrjalsen I, Qvist P, Beck-Nielsen H, Hansen G, Riis B, et al. Efficacy and safety of PPAR-gamma partial agonist balaglitazone compared with pioglitazone and placebo: A phase III, randomized, parallel-group study in patients with type 2 diabetes on stable insulin therapy. Diabetes Metab Res Rev 2011; 27(4): 392– 401.

26. Rosenson R, Wright R, Farkouh M, Plutzky J. Modulating peroxisome proliferatoractivated receptors for therapeutic benefit? biology, clinical experience, and future prospects. Am Heart J 2012; 164(5): 672–680.

27. Joharapurkar A, Dhanesha N, Shah G, Kharul R, Jain M. 11-beta hydroxysteroid dehydrogenase type 1: Potential therapeutic target for metabolic syndrome.

Pharmacol Rep 2012; 64(5): 1055–1065.

28. Walker B, Soderberg S, Lindahl B, Olsson T. Independent effects of obesity and cortisol in predicting cardiovascular risk in men and women. J Intern Med 2000; 247(2): 198–204.

29. Stewart P, Wallace A, Atherden S, Shearing C, Edwards C. Mineralocorticoid activity of carbenoxolone: Contrasting effects of carbenoxolone and liquorice on 11-beta hydroxysteroid dehydrogenase activity in man. Clin Sci 1990; 78(1): 49–54.

30. Berthiaume M, Laplante M, Festuccia W, Gelinas Y, Poulin S, Lalonde J, et al.

Depot-specific modulation of rat intraabdominal adipose tissue lipid metabolism by pharmacological inhibition of 11-beta hydroxysteroid dehydrogenase type 1.

Endocrinology 2007; 148(5): 2391–2397.

31. Anagnostis P, Katsiki N, Adamidou F, Athyros V, Karagiannis A, Kita M, et al.

11-beta hydroxysteroid dehydrogenase type 1 inhibitors: Novel agents for the treatment of metabolic syndrome and obesity-related disorders? Metabolism 2013; 62(1): 21–33.

32. Cheruvallath Z, Gwaltney S2, Sabat M, Tang M, Feng J, Wang H, et al. Design, synthesis and SAR of novel glucokinase activators. Bioorg Med Chem Lett 2013; 23(7): 2166–2171.

33. Cho H. Protein tyrosine phosphatases 1B (PTP1B) and obesity. Vitamin Hormone 2013; 91: 405–24.

34. Heng S, Harris K, Kantrowitz E. Designing inhibitors against fructose 1,6bisphosphatase: Exploring natural products for novel inhibitor scaffolds. Eur J Med Chem 2010; 45(4): 1478–1484.

What two minutes a week of high-intensity exercise can do

R

esearchers from Abertay University report that high-intensity training (HIT) of short duration not only reduces the risk of disease, but is also just as effective at doing so as the exercise guidelines currently recommended, according to a study by Simon Adamson and colleagues published in Biology 2014; 3(2): 333–344.

Current guidelines state that five 30-minute sessions of exercise should be carried out each week, something that very few people manage to achieve. The most common reason cited for this is lack of time, and the researchers believe that HIT is the perfect way for people who are time-poor to improve their health.

In the study, overweight adults took part in an HIT programme for a period of eight weeks. This involved completing twiceweekly sprint series on an exercise bike, with each sprint lasting just six seconds. Ten sprints were completed in total during each session, amounting to just two minutes of exercise per week.

This short HIT programme was enough to significantly improve cardiovascular health and insulin sensitivity in the participants, and this is the first time that so little exercise has been shown to have such significant health benefits. Previous research by the same team had shown that three HIT sessions a week were required, but this study has eclipsed these results by showing that the same results can be achieved with just two.

Dr John Babraj, head of the HIT research team at Abertay University, explains: ‘with this study, we investigated the benefits of HIT in a population group known to be at risk of developing

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diabetes: overweight, middle-aged adults. We found that not only does HIT reduce the risk of their developing the disease, but also that the regimen needs to be performed only twice a week in order for them to reap the benefits.

‘And you don’t have to be able to go at the speed of Usain Bolt when you’re sprinting. As long as you are putting your maximal effort into the sprints, it will improve your health. This is the beauty of HIT: it is quick to do and it is effective.

‘Although it is well-established that exercise is a powerful therapy for the treatment and prevention of type 2 diabetes, only 40% of men and 28% of women achieve the recommended 30 minutes of moderate-intensity exercise on five days of the week.

Lack of time to exercise, due to work or family commitments, is cited as the most common barrier to participation, so HIT offers a really effective solution to this problem and has the added benefit of reducing disease risk, which activities such as walking – even if done five days a week for 30 minutes – don’t offer.

‘There is a clear relationship between the intensity of exercise and the magnitude of health improvement, so it is only through these short, high-intensity sprints that health improvements can be seen.’

Source: http://www.diabetesincontrol.com/articles/diabetes-news/16355-what-twominutes-a-week-of-high-intensity-exercise-can-do

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Treatment of diastolic heart failure in hypertensive diabetic patients: between illusion and achievements SUR GENEL, FLOCA EMANUELA, SUR M LUCIA, SUR G DANIEL, RADULESCU DAN Abstract Hypertension is the most prevalent cardiovascular disease in the world. Because of associated morbidity and mortality, it is in one of the most important public health problems.

Hypertension is the most important cause of heart failure with low or preserved ejection fraction. If hypertension develops concomitantly with diabetes mellitus, treatment of the two diseases becomes more complex. It is known that beta-blockers may induce type 2 diabetes, but new generation drugs such as nebivolol do not have this effect.

There are many drugs with proven efficacy in lowering blood pressure, but the optimal treatment to prevent progression to heart failure is uncertain. Beta-blockers are a class of drugs with benefits for both hypertension and heart failure. Drugs in this class have different pharmacological properties in terms haemodynamic and cardiovascular effects.

Nebivolol is a beta-blocker that causes vasodilatation mediated by nitric oxide release. This medicine lowers blood pressure, prevents endothelial dysfunction and improves coronary flow reserve and diastolic function independent of ventricular geometry changes. The action of nebivolol is superior to classic beta-blockers due to reversibility of subclinical changes in the left ventricle before the onset of heart failure.

In the early stages of heart failure with preserved ejection fraction management is not yet established. Therefore it is important to know that in these situations nebivolol has beneficial effects.

Keywords: diastolic, heart failure, nebivolol, diabetes, hypertension

Introduction There is a high prevalence of hypertension worldwide. Prevalence is higher for males than females up to the age of 50 years. There is an increasing prevalence of this pathology with age. Hypertension and Correspondence to: Sur Genel University of Medicine and Pharmacy, Iuliu Hatieganu, Cluj-Napoca, and Emergency Clinical Hospital for Children, Cluj-Napoca, Romania Tel: 0724504964 e-mail: surgenel@yahoo.com Floca Emanuela, Sur M Lucia, Sur G Daniel, Radulescu Dan University of Medicine and Pharmacy, Iuliu Hatieganu, Cluj-Napoca, Romania Radulescu Dan Department of Cardiology, Municipal Hospital Cluj Napoca, Romania Originally published in Diabetes Metab 2014; 5(3): e113 S Afr J Diabetes Vasc Dis 2014; 11: 73–74

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diabetes are the main causes of heart failure, with the preservation or decrease of the ejection fraction thus representing an important public health problem.1

Diastolic heart failure In patients with hypertension, structural changes, both cardiac and vascular, occur as a consequence of increasing blood pressure. At the same time, these structural changes develop in an attempt to normalise wall stress. Cardiac remodelling has functional consequences by which cardiovascular risk is increased. These consequences are related to individual aspects such as age, 24-hour blood pressure, the rigidity of blood pressure, plasma volume, neuro-hormonal status, and genetic aspects.2,3 Ventricular hypertrophy involves both myocytes and interstitial tissue. Interstitial tissue can lead to fibrosis, a phenomenon that contributes to cardiac dysfunction in hypertension. The neuroendocrine changes that occur with aging, such as decreased β-adrenergic receptor density, decreased β-adrenergic inotropic response, and increased angiotensin receptors and angiotensinogen and angiotensin-converting enzyme concentrations contribute to myocyte hypertrophy. Hypertrophy and fibrosis of the left ventricle reduce ventricular compliance, finally leading to diastolic heart failure.4-6 There are numerous studies showing that arterial stiffness is increased in hypertension. Vascular stiffness influences the propagation velocity of the pressure wave generated by cardiac contraction. The pressure wave is transmitted through the vessels back to the heart in a short time, resulting in increased pressure of the anterograde wave and decreased blood flow. Aortic compliance is low.4,6 Wave reflection can be accelerated, increasing left ventricular ejection resistance. This mechanism contributes to left ventricular hypertrophy, which is associated with impaired diastolic function. Arterial stiffness contributes to myocardial ischaemia by altering ventriculo-arterial coupling. In patients with hypertension, microvascular ischaemia and interstitial fibrosis determine subendocardial dysfunction.7,8 Regarding myocardial architecture, some studies have shown that shortening in the fibres of the longitudinal axis is followed by shortening in the circumferential axis. Longitudinal shortening plays a role in the contractile function of the heart being involved in ventricular ejection.6 Diabetes contributes to the development of heart failure by excessive myocardial fibrosis, interstitial accumulation of glycoproteins, and an altered release from dysfunctional coronary endothelium of mediators such as nitric oxide, which has a vascular relaxation effect.9,10

How to diagnose diastolic heart failure A diagnosis of diastolic heart failure requires the mandatory presence of three criteria: (1) presence of signs or symptoms of congestive heart failure; (2) presence of normal or mildly reduced left ventricular systolic function; (3) evidence of abnormal left

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ventricular relaxation, filling, diastolic distensibility or diastolic stiffness.2,8 Signs and symptoms of congestive heart failure include paroxysmal nocturnal dyspnoea, orthopnoea, gallop sounds, lung crepitations, pulmonary oedema, and peripheral oedema.3 A diagnosis of diastolic heart failure requires the presence of normal or mildly abnormal left ventricular systolic function. To meet this criterion, ventricular ejection fraction must be at least 45%.

Left ventricular relaxation and filling affect left ventricular diastolic distensibility. So diagnostic of diastolic heart failure can be obtained from analysis of indices of diastolic function such as relaxation, chamber and myocardial stiffness, and diastolic filling characteristics.

This analysis can be performed using invasive or non-invasive techniques. Therefore echo-Doppler studies can provide information about relaxation (isovolumic relaxation time), abnormalities of filling and changes in left ventricular diastolic pressure.5

How to treat diastolic heart failure Treatment of diastolic heart failure is not well documented.

Nevertheless there are studies that attempt to show the role of nebivolol in the treatment of diastolic heart failure.1,3 Via the action of nitric oxide release, nebivolol is one of the most powerful lusitropic agents with additional vasodilating properties.

Therefore nebivolol has important therapeutic implications against cardiovascular risk factors and especially on atherosclerosis.11 Prospective randomised trials comparing the effects of nebivolol and atenolol in hypertensive patients with diastolic dysfunction showed that nebivolol improves haemodynamic status both at rest and stress. Nebivolol improves the diastolic function and lowers blood pressure and heart rate at rest and at peak stress; it also decreases ventricular mass. The beneficial effect of nebivolol versus atenolol may be explained by the secondary vasodilatory action of nitric oxide release.12,13 It is known that drugs that increase the release of nitric oxide significantly reduce the arterial reflected wave. Other studies have shown that in hypertension nebivolol decreases not only aortic stiffness but also reflected wave and the central aortic pulse pressure. Several studies have shown that early longitudinal diastolic function significantly increased only in patients treated with nebivolol.13,14 Nebivolol also significantly increased the longitudinal displacement and the ejection time, thus providing an improved haemodynamic profile. The latest beta-blockers such as nebivolol improve filling pressure independently of the presence of left ventricular hypertrophy. Effects of nebivolol on diastolic function are influenced by the duration of treatment and the potential release of nitric oxide. To achieve the desired effects duration of treatment must be at least three months.11,12 Regarding the metabolic effect, nebivolol has recently been

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shown not to worsen glucose tolerance compared with placebo.

The haemodynamic profile of nebivolol, characterised by preserving cardiac output, ejection time prolongation, reduction of peripheral resistance and improved diastolic function, has relevant benefits on the impairment in diastolic function.15 We followed 48 patients diagnosed with hypertension and diabetes who had left ventricular hypertrophy without coronary heart disease. They were treated for six months with nebivolol and this treatment resulted in improved diastolic function.

References 1. The task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC). 2013 ESH/ ESC guidelines for the management of arterial hypertension. J Hypertens 2013; 31: 1281–1357.

2. McDonald K. Diastolic heart failure in the elderly: underlying mechanisms and clinical relevance. Int J Cardiol 2008; 125: 197–202.

3. Shammas RL, Khan NU, Nekkanti R, Movahed A. Diastolic heart failure and left ventricular diastolic dysfunction: what we know, and what we don’t know! Int J Cardiol 2007; 115: 284–292.

4. Cheng S, Fernandes VR, Bluemke DA, McClelland RL, Kronmal RA, et al. Agerelated left ventricular remodeling and associated risk for cardiovascular outcomes: the Multi-Ethnic Study of Atherosclerosis. Circ Cardiovasc Imaging 2009; 2: 191– 198.

5. Gary R, Davis L. Diastolic heart failure. Heart Lung 2008; 37: 405–416.

6. Kane GC, Karon BL, Mahoney DW, Redfield MM, Roger VL, et al. Progression of left ventricular diastolic dysfunction and risk of heart failure. J Am Med Assoc 2011; 306: 856–863.

7. Brahmajee K Nallamothu, Timir S Baman, Anubhav Garg, Scott L Hummel. Inpatient Cardiovas Med 2013.

8. Borlaug BA, Redfield MM. Diastolic and systolic heart failure are distinct phenotypes within the heart failure spectrum. Circulation 2011; 123: 2006–2013.

9. From AM, Scott CG, Chen HH. The development of heart failure in patients with diabetes mellitus and pre-clinical diastolic dysfunction a population-based study. J Am Coll Cardiol 2010; 55: 300–305.

10. Tribouilloy C, Rusinaru D, Mahjoub H, Tartière JM, Kesri-Tartière L, et al. Prognostic impact of diabetes mellitus in patients with heart failure and preserved ejection fraction: a prospective five-year study. Heart 2008; 94: 1450–1455.

11. Conraads VM, Metra M, Kamp O, De Keulenaer GW, Pieske B, et al. Effects of the long-term administration of nebivolol on the clinical symptoms, exercise capacity, and left ventricular function of patients with diastolic dysfunction: results of the ELANDD study. Eur J Heart Fail 2011; 14: 219–225.

12. Zhou X, Ma L, Habibi J, Whaley-Connell A, Hayden MR, et al. Nebivolol improves diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the Zucker obese rat. Hypertension 55: 880–888.

13. Vinereanu D, Gherghinescu C, Ciobanu AO, Magda S, Niculescu N, et al. Reversal of subclinical left ventricular dysfunction by antihypertensive treatment: a prospective trial of nebivolol against metoprolol. J Hypertens 2011; 29: 809–817.

14. Fang Y, Nicol L, Harouki N, Monteil C, Wecker D, et al. Improvement of left ventricular diastolic function induced by β-blockade: a comparison between nebivolol and metoprolol. J Mol Cell Cardiol 2011; 51: 168–176.

15. Ma L, Gul R, Habibi J, Yang M, Pulakat L, et al. Nebivolol improves diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the transgenic (mRen2) rat. Am J Physiol Heart Circ Physiol 2012; 302: 2341– 2351.

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Treating diabetes with exercise: focus on the microvasculature CM KOLKA Abstract The rising incidence of diabetes and associated metabolic diseases, including obesity, cardiovascular disease and hypertension, have led to investigation of a number of drugs to treat these diseases. However, lifestyle interventions, including diet and exercise, remain the first line of defence.

The benefits of exercise are typically presented in terms of weight loss, improved body composition and reduced fat mass, but exercise can have many other beneficial effects.

Acute effects of exercise include major changes in blood flow through active muscle, and an active hyperaemia that increases the delivery of oxygen to the working muscle fibres. Longer-term exercise training can affect the vasculature, improving endothelial health and possibly basal metabolic rates. Further, insulin sensitivity is improved both acutely after a single bout of exercise and shows chronic effects with exercise training, effectively reducing diabetes risk. Exercise-mediated improvements in endothelial function may also reduce complications associated with both diabetes and other metabolic diseases. Therefore, while drugs to improve microvascular function in diabetes continue to be investigated, exercise can also provide many similar benefits on endothelial function and should remain the first prescription when treating insulin resistance and diabetes. This review will investigate the effects of exercise on the blood vessels and the potential benefits of exercise on cardiovascular disease and diabetes.

Keywords: exercise, diabetes, insulin, muscle, vasculature, blood vessels The prevalence of diabetes has been increasing steadily in the United States and in many other parts of the world. In 2010, 25.8 million individuals in the United States were diagnosed with diabetes, a figure almost double that of 10 years previously.1 Diabetes frequently occurs with other diseases, including dislipidaemia, hypertension, cardiovascular disease and obesity. Common complications of diabetes include heart disease, blindness, kidney disease and peripheral neuropathy, often leading to amputation.

People with type 2 diabetes are typically sedentary, overweight, and have decreased physical fitness,2 and the Center for Disease Control Correspondence to: CM Kolka Department of Biomedical Sciences, Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, CA, USA Tel: (310) 967-2791 Fax: (310) 967-3869 e-mail: Cathryn.Kolka@cshs.org Originally published in Diabetes Metab 2013; 4(9): 308.

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and Prevention and the American Heart Association consider lack of physical activity as a risk factor for heart disease.3 Currently the first treatment prescribed for type 2 diabetes is lifestyle modification, including diet and exercise, though drugs are used when lifestyle changes are not sufficient. Weight loss is a primary recommendation in overweight or obese patients, particularly those with type 2 diabetes, and can show many shortterm benefits, such as improvements in glycaemic control, reduction in cardiovascular risk factors, and resolution of co-existing illnesses.

Lifestyle intervention alone can cause significant weight loss and at least a partial remission of diabetes.4 The contribution of exercise to weight loss specifically is controversial, and studies have shown only an incrementally greater weight loss by exercise and diet over dietary interventions alone. However, weight loss is not required for the resolution of diabetes, and some drugs increase body weight while improving insulin sensitivity, such as the thiazolidinediones.5 Therefore obesity and increased fat mass are not always directly linked to diabetes: while the majority of those with type 2 diabetes are overweight, a large proportion of obese individuals are not diabetic. Yet obesity is a major risk factor for developing diabetes. The location of fat tissue is a major determinant of insulin resistance, as visceral fat is associated with insulin resistance,6 and subcutaneous fat deposition confers a protective effect against diabetes.7 Obesity and increased fat mass can determine diabetes and cardiovascular risk,8 thus an intervention to reduce body fat will also reduce diabetes risk. Exercise can reduce fat mass independently of changes in total body weight.9 Exercise is also associated with significant improvements in other aspects of disease, such as the reduction of complications, associated metabolic diseases, and other risk factors.9 The metabolic syndrome, typified by high blood pressure, high triglyceride levels, low high-density lipoprotein (HDL) cholesterol levels, high fasting glucose levels, and central obesity, is recognised to predispose individuals to the development of diabetes and atherosclerosis.

Interestingly, most of the criteria of the metabolic syndrome pertain to blood measurements, and can therefore affect blood vessels. Further, many of the complications of diabetes, including retinopathy, kidney disease and peripheral neuropathy, also have a vascular basis. In their review, Joyner and Green note that exercise is much more protective against cardiovascular disease than would be expected based on changes in traditional risk factors, including body mass index (BMI), blood lipid levels and blood pressure.10 They suggest a vicious circle between autonomic dysfunction and endothelial dysfunction, leading to cardiovascular disease, which can be prevented by exercise.10 Here, the role of the endothelium and microvasculature in exercise and diabetes is reviewed.

Exercise as treatment for diabetes Type 2 diabetes occurs when the body cannot maintain normal blood sugar levels. In the early stages of the disease, insulin is unable to stimulate glucose storage in the appropriate tissues. To

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compensate, the pancreas releases more hormone, but eventually fatigues, leading to insulin deficiency. Skeletal muscle11 and liver insulin resistance12 have both been proposed as the primary defect in type 2 diabetes, and the implication is that cellular insulin resistance is the major issue.

There have been many studies investigating insulin signalling cascades in skeletal muscle13-15 and a variety of other cell types,16,17 and both receptor defects and post-receptor signalling defects have been observed18 yet insulin must get to the cells before it can engage the receptors, and relies on a functioning microvasculature for access.

In the vasculature both endothelial19-21 and vascular smooth muscle cells22 have shown insulin signalling defects, and functional vascular impairments are also evident. In healthy individuals insulin signalling in the endothelium can increase perfusion of muscle, improving the delivery of nutrients and hormones to muscle.23 Insulin sensitivity is strongly related to the ability of insulin to access muscle; this access is impaired in cases of both acute and chronic insulin resistance,24,25 and is likely due to impaired endothelial function. Endothelial dysfunction is evident in diabetes and even pre-diabetes,26,27 and men with diabetes have both impaired endothelium-dependent and endothelium-independent vasodilation.28 Further, endothelial dysfunction is associated with a family history of diabetes,29 even in otherwise healthy individuals.

Vascular effects of exercise Muscle is the focal point during exercise, but is also a major metabolic organ, and the primary site for insulin-mediated glucose metabolism. Incremental changes in exercise intensity are matched by the amplitude increase in blood flow specifically to muscle, with only small effects or even decreases observed in other tissues.30 This increase in blood flow to active tissue is termed active hyperaemia, or functional hyperaemia. Bulk blood flow to muscle can change significantly, particularly with exercise,31 but the distribution of blood through the muscle can be altered even with no changes in total flow.32 Light exercise in humans causes a short-term increase in forearm blood flow within five seconds of contraction. However, exercise also has a major effect also on microvascular blood volume,

Figure 1. Structural differences between artery, arteriole and capillary. No vascular smooth muscle is located on the capillary; therefore flow through capillaries is modified by pre-capillary arterioles. Cessation of flow through arterioles will prevent flow through a portion of the muscle.

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even when the blood flow effects had returned to normal.32 At rest, a low proportion of capillaries are exposed to blood flow at one time, with a rapid increase in the number of perfused capillaries after exercise,31 thus increasing functional capillary density. The microvasculature in the working muscle is selectively recruited,33 and those areas with lowest perfusion in the working muscle are recruited first.34 Different muscle fibres serve different roles in the body, with highly oxidative muscle being engaged during exercise, and glycolytic muscle fibres performing more of a postural or structural role. Blood flow is closely coupled with the contraction of the muscle fibres,35 such that the magnitude of flow in each muscle fibre type reflects activity and oxidative metabolism of the muscle.36 The mediators responsible for controlling muscle blood flow during exercise can arise from the muscle, nerves and the endothelium of blood vessels.34,37 Vascular smooth muscle cells are located around the arterioles and some venules, and can constrict to change blood flow patterns, while capillaries do not typically contribute to blood flow changes30 (Fig. 1). Blood flow through capillaries is controlled upstream by small arterioles at rest, and the rapid recruitment of unperfused capillaries by exercise could suggest that nerves are responsible for this action.34 The sympathetic nervous system is mainly responsible for the vasoconstrictor responses, and as the arterioles and larger vessels are innervated,38 the majority of sympathetic nervous system activity is localised to that area of the vascular tree. Physical exercise can enhance sympathetic nerve activity39 to maintain arterial pressure, and may be involved in maintaining exercise tolerance, as reviewed by Thomas and Segal.38 More recent studies have suggested organ-specific differences in sympathetic nervous system activity with weight loss.40 While exercise training has short-term effects to improve sympathetic response,39 addition of aerobic exercise to a weight-loss programme did not augment any sympathetic changes,41 therefore exercise training effects on the sympathetic nervous system may be due purely to a reduction in body weight. We suggest that short-term effects of exercise on the sympathetic response are evident, but the contribution of the sympathetic nervous system activity to the beneficial effects of a long-term exercise intervention is uncertain, and instead functional improvement of the blood vessels remains a likely contributor to the benefits of exercise.

Insulin relies on endothelium-dependent vasodilation to enhance perfusion, therefore endothelial dysfunction reduces insulinmediated increases in muscle perfusion, which can contribute to the metabolic deficit in diabetes. As exercise-mediated changes in perfusion are typically endothelium-independent, exercise is still able to recruit capillaries and thus increase muscle perfusion in obesity and type 2 diabetes, even in the face of endothelial dysfunction. Numerous studies have now shown that while insulinâ&#x20AC;&#x2122;s vascular effects may be blocked in diabetes, exercise still maintains its ability to increase the distribution of blood flow through muscle.42 While physical inactivity is associated with impaired microvascular function,43 training programmes improve endothelial function.44 However, while uncomplicated type 2 diabetic patients show normal capillary recruitment responses to exercise, in type 2 diabetic patients who also have microvascular complications, this response is impaired,45 likely due to a functional impairment of blood vessels rather than morphological changes. The reduced exercise capacity observed in type 2 diabetes subjects can be overcome with an exercise training programme, although even when matched for physical activity and weight, diabetic patients have decreased physical fitness levels.2

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Nitric oxide (NO) is the main vasodilator from the endothelium specifically involved in blood flow and blood distribution, and while reduction in nitric oxide synthesis lowered total blood flow, exercise-mediated capillary recruitment was not affected.46 In fact, inhibition of NO formation enhances both resting and exercisemediated muscle oxygen uptake;47 despite a reduction in total flow, microvascular flow was not affected, suggesting that NO is not involved in the vascular response to exercise. However, other studies have shown that exercise training required nitric oxide for improvement in flow-induced dilation.44 It is therefore possible that while NO is not involved in the acute response to exercise, exercise training restores general endothelial health, as evidenced by a restored endothelium-dependent vasodilation in response to flow.

Therefore, as well as the acute effects of exercise, which may be independent of NO, an exercise regimen may improve endothelial function.

Metabolic effects of exercise The distribution of blood through muscle increases the capacity for nutrient exchange. In exercise, the primary purpose of functional hyperaemia is for oxygen delivery, as the oxygen required by exercising muscle is much higher than resting muscle.37 Recruitment of capillaries can decrease the velocity of blood flow by increasing the cross-sectional area of the capillary bed and the time available for exchange. Recruitment also increases surface area for exchange and decreases perfusion distances to promote oxygen delivery to tissues with exercise34 (Fig. 2). While in exercise the main metabolite required at the working muscle is oxygen, distribution of other nutrients can also be affected, including glucose, fats, other hormones and cytokines. Muscle metabolism can therefore be altered by perfusion of the tissue.48,49 While there can be regulated transport of certain larger hormones across the vasculature,50,51 smaller molecules can diffuse across the endothelium easily, possibly making muscle perfusion a more important player in the delivery of glucose and oxygen to the tissue.

Figure 2. Vasodilation affects delivery, and therefore metabolism. The rate of transfer across the endothelium is dependent on surface area, permeability of the endothelium, diffusion distance, and concentration difference (Fickâ&#x20AC;&#x2122;s first law of diffusion). Vasodilation increases surface area in arterioles for exchange, but will also recruit downstream capillaries, which will reduce diffusion distance and increase surface area for exchange. Working muscle increases oxygen utilisation, increasing the concentration difference from the blood vessel to the tissue.

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Skeletal muscle is the main site of basal glucose uptake, and is the tissue most associated with exercise; therefore the effect of exercise would likely be localised in muscle. A single bout of exercise in sedentary men increases glucose uptake and glucose effectiveness, and it was suggested that the increased blood flow and distribution enhanced glucose delivery to the tissue.52 Capillary recruitment with exercise contributes to glucose uptake, but NO is not required for exercise-mediated capillary recruitment.46 Instead, NO augments glucose uptake in high-intensity exercise,46 but not low-intensity exercise, and may be involved in a partitioning of fuel utilisation.53 Longer-term, mild exercise training improves glucose disposal, even with no change in body composition.54 This sustained effect was independent of the metabolic benefits of a single bout of exercise. Changes in insulin-specific glucose transporter expression have been detected after exercise training,55,56 as have changes in DNA methylation,57 but it is also possible that general improvements in endothelial function increase delivery, and thus metabolism, of glucose.

Fat deposition in muscle is often thought to be associated with insulin resistance,58,59 and selective reduction of intramyocellular lipid restores normal insulin signalling, reverting to a healthy metabolic state.60 Therefore, rather than intramuscular or total body fat, intramyocellular fat is related to muscle insulin resistance.

However a paradox is noted when athletes are considered, as they often have very high levels of intramyocellular lipid, yet high insulin sensitivity.61 Intramyocellular lipid content is increased after exercise intervention and diet change, coinciding with an increase in insulin sensitivity, suggesting that intramyocellular lipid content may not directly impair cellular insulin sensitivity.62 Exercise can prevent lipidinduced insulin resistance,63 and the form the lipid is stored in may contribute to insulin resistance, asceramide or diacylglycerol64-66 are more detrimental to cellular insulin action than triglycerides.

Another component of the divergent effects of intramyocellular lipid on insulin action could be the site of storage of excess fat. Lipid droplets within the muscle cell may regulate insulin action67 and possibly the mitochondria, such that lipid droplet-derived fats can be used as fuel by exercising muscle.68 By contrast, nutrient overload can alter the lipid droplet coat proteins and change the interaction of the lipid droplet with other organelles, causing inflammation and oxidative stress. Therefore, while fat deposition in muscle may not directly affect vascular function, the resulting inflammation69 and oxidative stress70 from intramyocellular lipid can lead to endothelial dysfunction. Further, fat deposition in endothelial cells has not been directly measured, and may occur in a similar fashion as in muscle and directly affect vascular function.

Muscle is composed of oxidative and glycolytic fibre types, with oxidative fibres typically having more mitochondria, and being actively recruited during exercise. The density of capillaries is greater in oxidative muscle; reduced oxidative activity in type 2 diabetes patients is most likely due to a reduction in slow oxidative fibres.71 The decrease in oxidative activity and increase in glycolytic activity in these patients was closely linked to the fraction of each fibre type present in muscle, suggesting that type 2 diabetes patients show both changes in fibre composition and fibre-specific metabolism. Mitochondrial dysfunction has been proposed to be both a cause72 and a consequence73 of insulin resistance, and may contribute to endothelial dysfunction.74 If oxygen delivery is a component of mitochondrial health and biogenesis, it is possible that impaired perfusion may contribute to fibre type switching, where an oxidative fibre, which is typically highly vascularised

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and contains mitochondria, switches to a glycolytic fibre with less vascularity and mitochondria. As exercise can improve oxidative capacity, increase mitochondrial content,75 and also increase muscle perfusion,31,32,34,45,76 the relationship between muscle perfusion, fibre type and mitochondrial function needs to be clarified.

Exercise training may or may not have effects on the basal metabolic rate. In older adults, 26 weeks of training increased resting energy expenditure and also improved lipid oxidation rates.77 Habitually active women were also found to have a higher resting metabolic rate than matched sedentary controls, associated with lower body fat levels.78 However, there are a variety of studies that show no effect of exercise intervention on basal metabolic rate, such as one that used a 26-week training programme investigating a mix of aerobic and resistance training.79 These individuals were previously sedentary and had a history of type 2 diabetes. Many aerobic training studies fail to show an improvement in resting metabolic rate, and Jennings et al.79 note that resistance training intensity or frequency may increase fat-free mass, which is the primary cause of resting metabolic rate changes.80 Therefore, the lack of improvement in basal metabolic rate may be due to no significant change in fat-free mass79 or the reduced exercise capacity of diabetic patients.2

Treating metabolic disease Aside from improvements in endothelial function, exercise can also affect metabolism, and this can be exploited in metabolic disease such as diabetes. Systemic vascular improvement can also improve insulin sensitivity,81 so targeting the endothelium in diabetes is a valid option for treating metabolic disease.82 The relationship between vascular action and metabolism has been previously reviewed,83 and impaired vascular function has been implicated as the link between obesity and diabetes.84 Essentially, without appropriate blood flow, distribution of blood through tissues, or transport from the vessels, metabolic function is limited due to reduced nutrient and hormone availability.

Exercise training improves insulin sensitivity,54 and while this can be due to an increase in insulin-specific glucose transporters after exercise,85 blood flow distribution changes may also indirectly improve metabolism. In rodent models of obesity that show a failure of insulin to increase muscle perfusion, muscle contraction can still cause capillary recruitment and glucose uptake.42 Insulin and exercise have an additive effect on glucose uptake in muscle, and the authors discuss the potential contribution of blood flow and capillary surface area to their results.86 In obese patients, the defect in insulin-mediated skeletal muscle perfusion was restored by exercise, yet cellular insulin resistance was still evident.87 Therefore while exercise does increase the effect of insulin on glucose metabolism in both lean and obese individuals, it does not normalise the cellular deficit due to obesity. The increased insulinmediated glucose uptake observed with exercise training is likely due to improved haemodynamic effects in muscle.76

Complications Insulin resistance per se may underlie the development of other aspects of the metabolic syndrome81 and many of these may have a vascular basis. Targeting endothelial dysfunction is therefore a viable treatment for preventing vascular complications associated with diabetes.70 The vascular component of exercise may well be linked to the reduction of diabetic complications, such as

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retinopathy, peripheral neuropathy and nephropathy, as there is a vascular basis to many of these complications. The endothelium has been implicated in diabetic nephropathy,88 and the blood vessels formed in response to reduced perfusion in retinopathy show abnormal structure and function.89 Endothelial dysfunction is evident in hypertension and cardiovascular disease, and is also noted in many cardiovascular risk factors, including abnormal blood lipid levels, and hyperglycaemia. Treatment of those risk factors typically restores endothelial function. Therefore systemic vascular protection has been proposed as a treatment for type 2 diabetes that would prevent complications, but also improve insulin sensitivity.81 Physical exercise is anti-atherogenic,90 but also confers general vascular protection, and as such could prevent many of the complications associated with diabetes.

Negative or neutral outcomes of exercise Lifestyle interventions such as diet and exercise are the first recommendation for treatment of diabetes and obesity, yet drug treatment is a very common therapy. While diabetic patients have defects in exercise capacity,2 this can be improved by either exercise training or agents that improve insulin sensitivity. Certain hormones can be upregulated in metabolic disease, such as endothelin-1 in hypertension, and excessive levels of endothelin-1 can reduce aerobic capacity of muscle and impair metabolism,91 most likely through impaired blood flow. Investigations are on-going into certain drugs that are designed to mimic exercise. For example, sildenafil92 and AICAR93 have been shown to increase peripheral microcirculation. However, there can be adverse effects of various drugs in combination with exercise. For example, rosiglitazone usage may improve exercise capacity but may contribute to heart failure.94 The Look AHEAD study shows diet and exercise, as part of an intensive lifestyle intervention, had no significant effect on lowering cardiovascular events in overweight or obese individuals, which could suggest that exercise has no long-term cardiovascular benefit,4 and complete remission of type 2 diabetes is rare.95 However, the control group in this study was assigned to diabetes support and education, and no measure of physical activity or dietary changes was performed in this group. Therefore while 6 kg weight loss was achieved by diet and exercise after nearly 10 years, the control group also showed weight loss of 4 kg.4 The use of drugs in the Look AHEAD study may also explain the apparent lack of improvement in cardiovascular outcomes with lifestyle intervention,4 based on potential drug interactions listed above. However, the same study did show partial remission of type 2 diabetes,95 and noted that improvements in glycaemic control by exercise were dependent on the blood glucose level prior to beginning the intervention.96 A similar study investigated lifestyle intervention in overweight people with impaired glucose tolerance, and similarly showed no effect of intervention to decrease cardiovascular morbidity after 10 years. However this study showed a decrease in the incidence of type 2 diabetes in the lifestyle-intervention group, therefore exercise and diet were able to reduce type 2 diabetes incidence.97 Therefore, exercise should be an early intervention to prevent type 2 diabetes and obesity, as it is more effective after a shorter duration of diabetes,96 and can prevent at-risk individuals from progressing to type 2 diabetes.97 Further, short-term exercise interventions have caused weight loss, restored insulin sensitivity, as well as improved cardiometabolic risk factors.98 Therefore, exercise is an

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effective intervention early in the progression of disease, and has some benefits, even in established diabetes. Further, the lifestyle intervention has documented improvements on other quality-of-life measures, including sexual functioning in women and obstructive sleep apnoea, most likely through weight loss.

Perspectives Exercise is an important part of a healthy lifestyle, particularly as part of disease prevention rather than cure. Aerobic activity is recommended by the American Heart Association and the American College of Sports Medicine to promote and maintain health, particularly in respect to cardiovascular disease, stroke, hypertension, type 2 diabetes, obesity, and other common diseases.3 Furthermore, incorporation of resistance training may have additional benefits.80 Exercise has reduced efficiency in established type 2 diabetes patients2 and the duration of diabetes may also be responsible for the lack of improvement in resting energy expenditure in diabetic patients.79 The clinical applicability of exercise in established diabetes will still improve factors discussed above, such as improving atherosclerosis90 and insulin sensitivity.54 In spite of reported negative results,4 exercise may also improve cardiovascular risk factors and prevent the progression to diabetes.97 Early adoption of an exercise regimen will therefore provide best results in cardiovascular and metabolic outcomes.

Conclusion Due to the rising incidence of diabetes and the associated metabolic diseases such as obesity, cardiovascular disease and hypertension, lifestyle interventions including diet and exercise are the first line of defence. The benefits are typically thought of in terms of weight loss, improved body composition and reduced fat mass, but exercise can have many other beneficial effects independent of this. Exercise can affect the vasculature, improving endothelial health. Further, insulin sensitivity is improved, and the treatment of endothelial dysfunction may also reduce complications associated with both diabetes and other metabolic diseases. While the use of drugs to improve microvascular function in diabetes has previously been reviewed,83 exercise can also provide many of the same benefits on endothelial function, and should remain an early intervention and the first prescription in combination with diet when treating insulin resistance and diabetes.

Acknowledgement This work was supported by two National Institutes of Health grants, DK27619 and DK29867. Thanks to Josiane Broussard for editing assistance.

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79. Jennings AE, Alberga A, Sigal RJ, Jay O, Boulé NG, et al. The effect of exercise training on resting metabolic rate in type 2 diabetes mellitus. Med Sci Sports Exerc 2009; 41: 1558–1565.

80. Stiegler P, Cunliffe A. The role of diet and exercise for the maintenance of fat-free mass and resting metabolic rate during weight loss. Sports Med 2006; 36: 239– 262.

81. Utsunomiya K. Treatment strategy for type 2 diabetes from the perspective of systemic vascular protection and insulin resistance. Vasc Health Risk Manag 2012; 8: 429–436.

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82. Mather KJ. The vascular endothelium in diabetes – a therapeutic target? Rev Endocr Metab Disord 2013; 14: 87–99.

83. Kolka CM, Bergman RN. The endothelium in diabetes: its role in insulin access and diabetic complications. Rev Endocr Metab Disord 2013; 14: 13–19.

84. Jonk AM, Houben AJ, de Jongh RT, Serné EH, Schaper NC, et al. Microvascular dysfunction in obesity: a potential mechanism in the pathogenesis of obesityassociated insulin resistance and hypertension. Physiology (Bethesda) 2007; 22: 252–260.

85. Hansen PA, Nolte LA, Chen MM, Holloszy JO. Increased GLUT-4 translocation mediates enhanced insulin sensitivity of muscle glucose transport after exercise. J Appl Physiol 1998; 85: 1218–1222.

86. DeFronzo RA, Ferrannini E, Sato Y, Felig P, Wahren J. Synergistic interaction between exercise and insulin on peripheral glucose uptake. J Clin Invest 1981; 68: 1468–1474.

87. Slimani L, Oikonen V, Hällsten K, Savisto N, Knuuti J, et al. Exercise restores skeletal muscle glucose delivery but not insulin-mediated glucose transport and phosphorylation in obese subjects. J Clin Endocrinol Metab 2006; 91: 3394– 3403.

88. Satchell SC. The glomerular endothelium emerges as a key player in diabetic nephropathy. Kidney Int 2012; 82: 949–951.

89. Tremolada G, Del Turco C, Lattanzio R, Maestroni S, Maestroni A, et al. The role of angiogenesis in the development of proliferative diabetic retinopathy: impact of intravitreal anti-VEGF treatment. Exp Diabetes Res 2012: 728325.

90. Szostak J, Laurant P. The forgotten face of regular physical exercise: a ‘natural’ anti-atherogenic activity. Clin Sci (Lond) 2011; 121: 91–106.

91. Kolka CM, Rattigan S, Richards SM, Clark MG. Potential for endothelin-1mediated impairment of contractile activity in hypertension. Clin Exp Pharmacol Physiol 2007; 34: 217–222.

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92. Sperandio PA, Oliveira MF, Rodrigues MK, Berton DC, Treptow E, et al. Sildenafil improves microvascular O2 delivery-to-utilization matching and accelerates exercise O2 uptake kinetics in chronic heart failure. Am J Physiol Heart Circ Physiol 2012; 303: H1474–1480.

93. Bradley EA, Eringa EC, Stehouwer CD, Korstjens I, NieuwAmerongen GP, et al.

Activation of AMP-activated protein kinase by 5-aminoimidazole-4-carboxamide1-beta-D-ribofuranoside in the muscle microcirculation increases nitric oxide synthesis and microvascular perfusion. Arterioscler Thromb Vasc Biol 2010; 30: 1137–1142.

94. McGuire DK, Abdullah SM, See R, Snell PG, McGavock J, et al Randomized comparison of the effects of rosiglitazone vs. placebo on peak integrated cardiovascular performance, cardiac structure, and function. Eur Heart J 2010; 31: 2262–2270.

95. Gregg EW, Chen H, Wagenknecht LE, Clark JM, Delahanty LM, et al. Association of an intensive lifestyle intervention with remission of type 2 diabetes. J Am Med Assoc 2012; 308: 2489–2496.

96. Solomon TP, Malin SK, Karstoft K, Haus JM, Kirwan JP. The influence of hyperglycemia on the therapeutic effect of exercise on glycemic control in patients with type 2 diabetes mellitus. J Am Med Assoc Intern Med 2013; 173: 1834–1836.

97. Uusitupa M, Peltonen M, Lindström J, Aunola S, Ilanne-Parikka P, et al. Ten-year mortality and cardiovascular morbidity in the Finnish Diabetes Prevention Study-secondary analysis of the randomized trial. PLoS One 2009; 4: e5656.

98. Goodpaster BH, Delany JP, Otto AD, Kuller L, Vockley J, et al. Effects of diet and physical activity interventions on weight loss and cardiometabolic risk factors in severely obese adults: a randomized trial. J Am Med Assoc 2010; 304: 1795– 1802.

Conference calendar 2014 Date

Location

Conference

8–10 August

Birchwood Hotel and OR Tambo Conference Centre, Gauteng, SA

The 16th annual CDE Postgraduate Forum in Diabetes Management

21–24 November

Bangkok, Thailand

5th international conference of fixed combination in the treatment of hypertension, dyslipidaemia and diabetes mellitus www.fixedcombination.com/2013

2–6 December

Melbourne, Australia

World diabetes congress (IDF) http://www.worlddiabetescongress.org

To advertise your conference/meeting, e-mail details and a half-page PDF advert to info@clinicscardive.com.

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Diabetes mellitus and the brain: special emphasis on cognitive function SHERIFA A HAMED Abstract

Introduction

Diabetes mellitus (DM) is a major public health problem.

Cognitive deficits are common with DM which range from subclinical or subtle to severe deficits such as dementia.

Both hypoglycaemia and hyperglycaemia are causes of cognitive impairment with DM. In patients with DM, not only severe hypoglycaemia but also recurrent mild or moderate hypoglyacemia have deleterious effect on the brain. Recurrent mild/moderate hypoglycaemia is associated with intellectual decline, reduced attention, impaired mental abilities and memory deficits. Hypoglycaemia may result in abnormalities of neuronal plasticity, synaptic weakening and scattered neuronal death in the cerebral cortex and hippocampus.

Chronic hyperglycaemia in type 1 and type 2 DM is associated with low IQ (verbal, performance and total) and abnormalities in testing for different domains of cognitive function such as verbal relations, comprehension, visual reasoning, pattern analysis, quantitation, memory, learning, mental control, psychomotor efficiency, mental and motor processing speed and executive function. The suggested mechanisms incriminated in the pathogenesis of hyperglycaemia-related cognitive dysfunction include, macro- and microvascular disease or vasculopathy, hyperlipidaemia, hypertension, insulin resistance and hyperinsulinaemia, stress response, direct toxic effect of chronic hyperglycaemia on the brain, advanced glycation end-products, inflammatory cytokines and oxidative stress. Hyperglycaemia causes oxidative stress, amyloidosis, angiopathy, abnormal lipid peroxidation, accumulation of β-amyloid and tau phosphorylation, neuroinflammation, mitochondrial pathology, apoptosis and neuronal degeneration in the cortex and hippocampus.

Depression has been identified as a risk for accelerated cognitive decline with DM. The knowledge that diagnosis at an early age, frequency of hypoglycaemia, poor glycaemic control and presence of risk factors negatively affect cognitive functions in DM will have important implications for treatment and research purposes.

Diabetes mellitus (DM) is one of the most common and most important metabolic diseases worldwide. The incidence and prevalence of DM are increasing rapidly due to industrialisation, inappropriate diet, sedentary lifestyle and increased obesity.1 Hypoglycaemia, hyperlipidaemia and vascular diseases (such as angiopathy, nephropathy and cardiovascular, cerebrovascular and peripheral vascular diseases) are common complications of DM.2 Cognitive deficits are common with DM, which range from subclinical or subtle to severe deficits such as dementia. Cognition refers to the set of integrated and inter-related mental processes and systems involved in acquiring knowledge and comprehending, storing, retrieving and using this knowledge to perform day-to-day activities. Both hypoglycaemia and hyperglycaemia are causes of cognitive impairment with DM.3-39 Intellectual decline, impaired mental abilities and memory deficits are common with recurrent hypoglycaemic episodes.3-10 Studies indicate that repetitive mild and moderate hypoglycaemia cause impairment in synaptic plasticity with inability to induce longterm potentiation (LTP), which plays a crucial role in memory and this contributes to cognitive impairment.11,12 Recurrent moderate hypoglycaemia results in scattered neuronal death in the cerebral cortex13,14 and hippocampus.15 While severe hypoglycaemia results in oxidative stress and widespread neuronal death in the cerebral cortex and hippocampus.16,17 With hyperglycaemia, low IQ and reduced performance on various domains of cognitive function, including verbal relations, comprehension, visual reasoning, pattern analysis, quantitation, digit forward, digit backward, memory, mental control, associative learning, psychomotor efficiency, problem solving, mental and motor processing speed, eye–hand coordination and executive function, are common.18-26 Metabolic derangement, macro- and microvascular complications,27,28 oxidative stress29,30 and diabetesrelated depression also occur.31-35 Chronic hyperglycaemia causes oxidative stress, amyloidosis, angiopathy, abnormal lipid peroxidation, increase in the formation of advanced glycation end-products, accumulation of β-amyloid and tau phosphorylation, neuro-inflammation, mitochondrial pathology, apoptosis, neurodegeneration in the cortex and hippocampus and brain atrophy.36-39 This review was performed through a comprehensive search in the PubMed, ISI web of science, Science Direct and Scopus databases from 1990 to 2013, using the following search terms: cognitive function in diabetes, hypoglycemia and cognition, type 1 DM (T1DM) and cognition and type 2 DM (T2DM) and cognition.

Data from epidemiological, longitudinal, prospective, doubleblinded and clinical trial studies and case reports were considered.

We also checked the reference lists of the retrieved studies for additional reports.

In this review, we summarised the experimental and clinical evidence of cognitive dysfunction with DM, the possible mechanisms underlying cognitive dysfunction in DM, the relationship between

Keywords: diabetes mellitus, hypoglycaemia, insulin resistance, cognition, vascular disease

Correspondence to: Sherifa A Hamed Department of Neurology and Psychiatry, Assiut University, Assiut, Egypt Tel: +2 088 2371820 Fax: +2 088 2333327/+2 088 2332278 e-mail: hamed_sherifa@yahoo.com Originally published in Int J Diabetol Vasc Dis Res 2013; 1(8): 803.

S Afr J Diabetes Vasc Dis 2014; 11(2): 82–86

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DM and neurodegeneration and the clinical and research approaches with the aim to prevent and treat cognitive dysfunction with DM.

Cognitive dysfunction with hypoglycaemia The brain is an energy-intensive organ. Glucose is the primary fuel of brain cells. Approximately 25% of total body glucose is required for proper brain function.40 The normal range for human blood glucose concentration is 3.9 to 7.1 mM (1 mM = approximately 18 mg/dl). Hypoglycaemia is defined as blood glucose level below which brain function deteriorates in most patients (i.e. less than 3 mmol/l or 54 mg/l00 ml).41 In patients with DM, not only severe hypoglycaemia (blood glucose level below 2 mM) but also recurrent mild (blood glucose level 3.2 to 3.6 mM) or moderate (blood glucose level 2.3 to less than 3.2 mM) hypoglycaemia has deleterious effect on the brain.311,13-17 Hypoglycaemia is common with intensive insulin therapy. It has been indicated that the oscillations in glycaemia, owing to the nature of subcutaneous insulin administration, are more common and result in increases in the frequency of hypoglycaemia in those treated for DM.42 Recurrent mild and moderate hypoglycaemia is more common than severe hypoglycaemia.7,10,43 It has been reported that most hypoglycaemic events were found to be asymptomatic in 90% of children treated with insulin, 98% of those occurring at night, and the majority of untreated hypoglycaemic events were associated with a relapse into hypoglycaemia within three hours.44 Attention, associative learning and mental flexibility are affected with acute hypoglycaemia.5 Recurrent mild and moderate hypoglycaemia is associated with intellectual decline, particularly performance IQ, impaired mental abilities and memory deficits.3,45 It was reported that recurrent mild and moderate hypoglycaemia in children younger than five years old with T1DM may commonly develop reduced attention, spatial memory and intelligence in adolescence.6,8,46 Experimental and clinical studies indicate that severe hypoglycaemia for a least 10 minutes results in microglial activation and oxidative stress with the release of several neurotoxic substances, including superoxide, nitric oxide and metalloproteinase, and widespread neuronal death in the cerebral cortex and hippocampus. Recurrent moderate hypoglycaemia results in scattered neuronal death in the second and third cerebral cortex layers and hippocampal CA1 dendritic region, and hippocampal thinning.14-16,47,48 It has been suggested that cognitive impairment in children and adults with repetitive mild and moderate hypoglycaemia is due to deterioration of synaptic injury with an inability to induce or persistent inhibition of long-term potentiation (LTP) and facilitation of LTD at the hippocampal CA1 (which plays a crucial role in memory) in the absence of apparent neuronal somatic injuries.

This in turn results in activity-dependent synapse weakening and contributes to cognitive impairment.11,12

Cognitive dysfunction with hyperglycaemia DM is defined by the presence of symptoms of hyperglycaemia and fasting plasma glucose (FBG) levels ≥ 7.0 mmol/l or 126 mg/dl or post-prandial blood glucose (PBG) ≥ 11.1 mmol/l or 200 mg/dl or a random plasma glucose level ≥ 11.1 mmol/l or 200 mg/dl or glycated haemoglobin (HbA1c) ≥ 6.5%.49 At the experimental level, detrimental effects on learning and memory were observed in streptozotocin (STZ) (rodent model of T1DM) and GK rats,50 db/db mice and Zucker rats51 (genetic models

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of T2DM), as seen by impaired performance in the Morris water maze spatial test,51,52 and inhibitory53 or active avoidance tasks,54 and object-discrimination task tests,22 all being indicative of impairment in the hippocampus and related structures.

At the clinical level, children and adults with DM demonstrate low IQ and reduced performance on various domains of cognitive function, including verbal relations, comprehension, visual reasoning, pattern analysis, quantitation, digit forward, digit backward, shortterm memory, memory for sentences, verbal memory, logical memory, mental control, associative learning, psychomotor efficiency, problem solving, mental and motor processing speed, eye–hand coordination and executive functions.18-26,55-57 Many authors have reported that cognitive deficits were correlated with the degree of chronic hyperglycaemia and improvements in performance of cognitive testing occurred with improvement in glucose tolerance.58,59 Wu et al.23 observed that, compared to treated patients, untreated patients with DM had two points of decline over two years on the mini mental state examination test (MMSE) with duration of illness < five years and six points of decline on the MMSE with duration of illness ≥ five years. Cox et al.24 observed that the increase in blood glucose concentrations to > 15mmol/l was associated with a marked decline in cognition and poor performance in arithmetic tasks. The research showed that those with DM had a 1.2- to 1.5fold greater rate of decline in cognitive function compared to those without diabetes.60 At the neurophysiological level, studies also reported abnormalities in the P300 component of event-related potentials (ERPs), a physiological analogue of cognitive testing25,61,62 and prolongation in I–III and I–V inter-peak latencies of the auditory brainstem response (ABR), an indication of central auditory pathway function52,63 in patients with T1DM and T2DM, regardless of the recent metabolic derangement and disease duration.

At the neuroimaging level, structural brain atrophy, particularly in the limbic structures, such the hippocampus and amygdala, smaller total brain volume, smaller gray matter volume, larger ventricular volume, larger white matter lesion volume and accelerated increase in ventricular volume over time and increased risk for incident brain infarcts were seen in magnetic resonance imaging (MRI) of the brain of patients with T2DM and also in patients with early manifestation of impaired glucose tolerance (i.e. PBG ≥ 140 mg/dl or 7.8 mmol/l but not over 200 mg/dl or 11.1 mmol/l).28,38,39,64-66 Studies also reported that well-controlled middle-aged individuals with T2DM,20 and nondiabetic individuals with insulin resistance (IR) (a prediabetic state)67 had declarative memory deficits and specific hippocampal volume reduction and deficits in hippocampal synaptic plasticity,52 which were correlated with the present deficits in declarative memory.

The aetiology of cognitive impairment in people with hyperglycaemia is multifactorial. Vascular27,28 as well as neurodegenation65,66 contribute to cognitive dysfunction with chronic hyperglycaemia. The following have been suggested as causes of hyperglycaemia-induced cognitive impairment: chronic complications such as macro- and microvascular complications (diabetic vasculopathy),20,27,28 hyperlipidaemia,68,69 hypertension,70,71 insulin resistance (IR) and hyperinsulinaemia,67 dysregulation of the limbic–hypothalamic–adrenal pituitary axis (LHPA) with chronic hypercortisolaemia and impairment in hippocampal neurogenesis, synaptic plasticity and learning,72-74 direct toxic effects of chronic hyperglycaemia on the brain,25,55 advanced glycation end-products, inflammatory cytokines, oxidative stress,29,30 and diabetes-related depression.32-35

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DM is a risk for arterial stiffness, and atherosclerotic and cerebrovascular diseases.27,28 Experimental and human studies also indicate that chronic hyperglycaemia results in brain injury with specific vulnerability to memory and learning processing, regardless of the vascular pathology. In experimental models, it was observed that chronic hyperglycaemia and the spontaneous onset of T2DM caused blood–brain barrier (BBB) disruption, alterations in insulin transporters and decreases in insulin receptors, which are expressed in discrete neuronal populations in the CNS, including the hippocampus.

Impairment of insulin function results in reduction in uptake of glucose into the neurons, impairment of energy metabolism and impairment of the brain’s capacity to generate the connections vital to memory and learning.3 Reductions in insulin-like growth factor 1 (ILGF-1)75,76 and brain-derived neurotrophic factor (BDNF) were observed in rat models of T2DM.77 IGFs regulate adult brain mass by maintaining brain protein content, and they support synapses and are required for learning and memory. It was observed that replacement doses of insulin and IGFs in diabetic rats could cross the blood–brain barrier, improve brain atrophy and prevent hippocampus-dependent memory impairment.75-77 Researchers found that insulin and IGF-I were significantly reduced in the frontal cortex, hippocampus and hypothalamus but not the cerebellum in post mortem brain tissue from people with DM.45 It has been indicated that hyperglycaemia causes oxidative stress, amyloidosis, angiopathy, abnormal lipid peroxidation, it increases the formation of advanced glycation end-products, the accumulation of β-amyloid and tau phosphorylation, neuroinflammation, mitochondrial pathology, an increase in Bax expression (pro-apoptotic protein) and caspase-3 (apoptotic element) levels, reduction in Bcl-2 protein levels (antiapoptotic protein), an increase in the ratio of Bax to Bcl-2, DNA fragmentation in the cortex and hippocampus, neuronal degeneration and brain atrophy.36,37 Recently, it was reported that adults and middle-aged patients with T2DM had higher concentrations of serum NSE (a marker of neuronal cell damage), which was significantly correlated with cognitive deficits, regardless of the level of glycaemic control and after adjustment of confounders,25 indicating direct brain injury due to chronic hyperglycaemia. Several studies have shown higher serum and cerebrospinal fluid (CSF) levels of NSE and also their over-expression increases the vulnerability to neurodegeneration, cerebral hypoxic–ischaemic injury and traumatic brain injury.78,79

Cognitive dysfunction with hyperinslinaemia Insulin is a key protein in the control of intermediary metabolism.

It organises the use of fuels for either storage or oxidation. It influences carbohydrate, lipid, protein and mineral metabolism.40 Binding of insulin to its receptors phosphorylates many intracellular proteins and generates a biological response. Insulin acts on cells thoughout the body to stimulate uptake, utilisation and storage of glucose.

In the brain, as with peripheral insulin, insulin is in part responsible for the uptake of glucose into the neurons, which is important for energy metabolism. Most of the brain’s insulin originates from systemic blood circulation but to a lesser extent, it is produced in the brain.80 Insulin crosses the blood–brain barrier (BBB) using a saturable transporter.81 Insulin-sensitive glucose transporters, insulin receptors and insulin downstream signaling molecules are distributed throughout the human brain on both neurons and astrocytes.82

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Insulin receptors are densely expressed in the medial temporal lobe, hippocampus and prefrontal cortex, which mediate longterm memory and working memory.83 Insulin affects a wide range of normal brain functions, such as reward, motivation, cognition, attention and memory formation. Insulin’s anabolic effect in the brain includes stimulation of growth, neuronal differentiation, survival (neurotropism) and remodelling (neuromodulation).82 The synapses (which transmit information between neurons) contain insulin receptors. Insulin serves as a vital element for normal synaptic structure and function and subsequently for the strength of connections between neurons. Insulin binds to receptors on the synapse and together with proper inulin signalling, both contribute to brain plasticity and the formation of new brain circuitries essential for learning and memory.84 Insulin in the brain is degraded by insulin degrading enzyme (IDE). IDE regulates the generation and clearance of amyloid β (Aβ) from the brain.85,86 Hyperinsulinaemia is the most common consequence of IR, which is the main defect in T2DM. It has been indicated that prolonged exposure of the brain to higher than physiological levels of insulin may alter signalling and metabolic pathways in a manner that is deleterious to cognitive circuitry, which mainly depends on proper metabolic processes.84 Chronic elevation of insulin concentrations in the periphery may paradoxically causes a relative hypo-insulinised state in the brain and the resultant hyper-insulinaemia could actually impair cognition by disturbing insulin-mediated utilisation of glucose by cells in the brain. particularly the hippocampus, which is enriched with insulin receptors. Central hypo-insulinaemia may promote central inflammation, β-amyloid generation and reduced neuroplasticity.85 Decrease in levels of insulin degrading enzyme (IDE) was observed in rat models of T2DM. IDE, an enzyme responsible for insulin degradation in the brain, also degrades amyloid plaque. As insulin has a very similar molecular structure to amyloid plaque, the latter might compete for the benefits of IDE in the presence of hyper-insulinaemia.86 Elevated insulin levels are implicated in the brain cells’ failure to clear β-amyloid, the formation of senile plaques and tau protein phosphorylation.87-89

Depression accelerates cognitive decline with DM Epidemiological studies have suggested that diabetic patients are two- to three-fold more likely to develop depressive illness when compared to non-diabetic individuals. On the other hand, individuals with depression have an approximately 60% higher risk of developing T2DM.32-34 In general, the prevalence of depression with DM was estimated to be 31.1%.90 Co-morbid depression has been identified as a risk factor for accelerated cognitive decline among patients with T2DM. Depression has been identified as a risk factor for dementia among patients with T2DM in all domains.35

Clinical and research perspectives The knowledge that diagnosis at an early age, frequency of hypoglycaemic events, poor glycaemic control and the presence of risk factors negatively affect cognitive function in DM, will have important implications for treatment of DM and for research purposes. Preventive strategies include modification of lifestyle, patient education, dietary re-orientation (i.e. eliminating highglycaemic foods, including processed carbohydrates and sweets, would sensitise insulin receptors and correct hyperinsulinaemia91-95), stopping smoking, maintaining a healthy body weight, mental

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and physical exercise, control of hypertension and dyslipidaemia and treatment of brain infarcts, cardiovascular diseases and depression.70,96,97 With hyperglycaemia, it is important to regularly monitor the blood glucose levels and keep glycaemic control, with the aim of an HbA1c level of 6.5%, but no lower than that, and possibly higher.98 Hypoglycaemia should be treated with a defined dose of carbohydrates rather than a mixed meal. Insulin-sensitising drugs are able to slow down, prevent, or perhaps even improve DM-related cognitive decline.

Neuroprotective strategies must be included, aside from the treatment of DM, from the beginning, to prevent long-term diabetic complications. These include: free radical scavengers/antioxidants [as alpha-lipoic acid (ALPA), evening primrose oil (EPO), vitamin C, vitamin E and vitamin B complex),68,99 modifiers of mitochondrial dysfunction, anti-apoptotics, and neurotrophic factors.76 Future studies must be directed to better understanding of the patho-physiological mechanisms underlying cognitive dysfunction in diabetes. There is also a need for construction of longitudinal studies that prospectively assess the relationship of the disease process to cognition over time and randomised clinical trials that compare cognitive function in DM patients receiving memory enhancers and antidepressants, versus a control group of DM patients.

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37. Anarkooli J, Sankian M, Ahmadpour S, Varasteh AR, Haghir H. Evaluation of Bcl-2 family gene expression and Caspase-3 activity in hippocampus STZ-induced diabetic rats. Exp Diabetes Res 2008; 2008: 638467.

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38. Manschot SM, Brands AM, van der GJ, Kessels RP, Algra A, Kappelle LJ, Biessels GJ. Brain magnetic resonance imaging correlates of impaired cognition in patients with type 2 diabetes. Diabetes 2006; 55: 1106–1113.

39. Espeland MA, Bryan RN, Goveas JS, Robinson JG, Siddiqui MS, Liu S, et al; WHIMS-MRI Study Group. Influence of type 2 diabetes on brain volumes and changes in brain volumes: results from the Women’s Health Initiative magnetic resonance imaging studies. Diabetes Care 2013; 36: 90–97.

40. Brüning JC, Gautam, D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W, Müller-Wieland D, Kahn CR. Role of brain insulin receptor in control of body weight and reproduction. Science 2000; 289: 2122–2125.

41. Sucov A, Woolard RH. Ethanol-associated hypoglycemia is uncommon Acad Emerg Med 1995; 2: 185–189.

42. Davis EA, Jones TW. Hypoglycemia in children with diabetes: incidence, counterregulation and cognitive dysfunction. J Pediatr Endocrinol Metab 1998; 11: 177–182.

43. Zammitt NN, Streftaris G, Gibson GJ, Deary IJ, Frier BM. Modeling the consistency of hypoglycemic symptoms: high variability in diabetes. Additional file 1: Figure S1. Experimental protocol for R/M Diabetes. Technol Ther 2011; 13: 571–578.

44. Deiss D, Kordonouri O, Hartmann R, Hopfenmüller W, Lüpke K, Danne T. Treatment with insulin glargine reduces asymptomatic hypoglycemia detected by continuous subcutaneous glucose monitoring in children and adolescents with type 1 diabetes. Pediatr Diabetes 2007; 8: 157–162.

45. Perantie DC, Lim A, Wu J, Weaver P, Warren SL, Sadler M, White NH Hershey T. Effects of prior hypoglycemia and hyperglycemia on cognition in children with type 1 diabetes mellitus. Pediatr Diabetes 2008; 9: 87–95.

46. Bjorgaas M, Gimse R, Vik T, Sand T. Cognitive function in type 1 diabetic children with and without episodes of severe hypoglycaemia. Acta Paediatr 1997; 86: 148–153.

47. Kalimo H, Olsson Y. Effects of severe hypoglycemia on the human brain.

Neuropathological case reports. Acta Neurol Scand 1980; 62: 345–356.

48. Auer RN, Hugh J, Cosgrove E, Curry B. Neuropathologic findings in three cases of profound hypoglycemia. Clin Neuropathol 1989; 8: 63–68.

49. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998; 15: 539–553.

50. Marfaing-Jallat P, Portha B, Penicaud L. Altered conditioned taste aversion and glucose utilization in related brain nuclei of diabetic GK rats. Brain Res Bull 1995; 37: 639–643.

51. Li XL, Aou S, Oomura Y, Hori N, Fukunaga K, Hori T. Impairment of long-term potentiation and spatial memory in leptin receptor deficient rodents. Neuroscience 2002; 113: 607–615.

52. Biessels GJ, Kamal A, Urban IJ, Spruijt BM, Erkelens DW, Gispen WH. Water maze learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: effects of insulin treatment. Brain Res 1998; 800: 125–135.

53. Baydas G, Nedzvetskii VS, Nerush PA, Kirichenko SV, Yoldas T. Altered expression of NCAM in hippocampus and cortex may underlie memory and learning deficits in rats with streptozotocin-induced diabetes mellitus. Life Sci 2003; 73: 1907– 1916.

54. Flood JF, Mooradian AD, Morley JE. Characteristics of learning and memory in streptozocin-induced diabetic mice. Diabetes 1990; 39: 1391–1398.

55. Awad N, Gagnon M, Messier C. The relationship between impaired glucose tolerance, type 2 diabetes, and cognitive function. J Clin Exp Neuropsychol 2004; 26: 1044–1080.

56. Mooradian AD, Perryman K, Fitten J, Kavonian GD, Morley JE. Cortical function in elderly non-insulin dependent diabetic patients: behavioral and electrophysiological studies. Arch Intern Med 1988; 148: 2369–2372.

57. Gradman TJ, Laws A, Thompson LW, Reaven GM. Verbal learning and/or memory improves with glycemic control in older subjects with non-insulin-dependent diabetes mellitus. J Am Geriatr Soc 1993; 41: 1305–1312.

58. Ryan CM, Williams TM. Effects of insulin-dependent diabetes on learning and memory efficiency in adults. J Clin Exp Neuropsychol 1993; 15: 685–700.

59. Biessels GJ, Kappelle AC, Bravenboer B, Erkelens DW, Gispen WH. Cerebral function in diabetes mellitus. Diabetologia 1994; 37: 643–650.

60. Cukierman T, Gerstein HC, Williamson, JD. Cognitive decline and dementia in diabetes – systematic overview of prospective observational studies. Diabetologia 2005; 48: 2460–2469.

61. Pozzessere G, Valle E, de Crignis S, Cordischi VM, Fattapposta F, Rizzo PA, et al.

Abnormalities of cognitive functions in IDDM revealed by P300 event-related potential analysis. Comparison with short-latency evoked potentials and psychometric tests. Diabetes 1991; 40: 952–958.

62. Kurita A, Mochio S, Isogai Y. Changes in auditory P300 event-related potentials and brainstem evoked potentials in diabetes mellitus. Acta Neurol Scand 1995; 92: 319–323.

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63. Dejgaard A, Gade A, Larsson H, Balle V, Parving A, Parving HH. Evidence for diabetic encephalopathy. Diabet Med 1991; 8: 162–167.

64. Alosco ML, Brickman AM, Spitznagel MB, Griffith EY, Narkhede A, Raz N, et al.

The adverse impact of type 2 diabetes on brain volume in heart failure. J Clin Exp Neuropsychol 2013; 35: 309–318.

65. Gold AE, Deary IJ, Jones RW, O’Hare JP, Reckless JPD, Frier BM. Severe deterioration in cognitive function and personality in five patients with long-standing diabetes: a complication of diabetes or a consequence of treatment?. Diabet Med 1994; 11: 499–505.

66. Den Heijer T, Vermeer SE, van Dijk EJ, Prins ND, Koudstaal PJ, Hofman A, Breteler MM. Type 2 diabetes and atrophy of the medial temporal lobe structures.

Diabetologia 2005; 46: 1604–1610.

67. Taylor VH, MacQueen GM. Cognitive dysfunction associated with metabolic syndrome. Obes Rev 2007; 8: 409–418.

68. Van Exel E, de Craen AJ, Gussekloo J, Houx P, Bootsma-van der Wiel A, Macfarlane PW, et al. Association between high-density lipoprotein and cognitive impairment in the oldest old. Ann Neurol 2002; 51: 716–721.

69. Henderson VW, Guthrie JR, Dennerstein L. Serum lipids and memory in a population based cohort of middle age women. J Neurol Neurosurg Psychiatry 2003; 74: 1530–1535.

70. Elias PK, Wilson PW, Elias MF, Silbershatz H, D’Agostino RB, Wolf PA, Cupples LA. NIDDM and blood pressure as risk factors for poor cognitive performance.

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71. Hassing LB, Hofer SM, Nilsson SE, Berg S, Pedersen NL, McClearn G, Johansson B. Comorbid type 2 diabetes mellitus and hypertension exacerbates cognitive decline: evidence from a longitudinal study. Age Ageing 2004; 33: 355–361.

72. Hamed SA, Youssef AH, Elserogy YE, Herdan O, Abd-Elaal RF, Metwaly NA, Hassan MM, Mohamad HO. Cognitive function in patients with Type 2 Diabetes Mellitus: Relationship to stress hormone (Cortisol). J Neurol Neurosci 2013: 4: 3.

73. Rosmond R. Stress induced disturbances of the HPA axis: a pathway to type 2 diabetes?. Med Sci Monit 2003; 9: RA35 – RA9.

74. Bruehl H, Rueger M, Dziobek I, Sweat V, Tirsi A, Javier E, et al. Hypothalamicpituitary-adrenal axis dysregulation and memory impairments in type 2 diabetes.

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75. Chiarelli F, Santilli F, Mohn A. Role of growth factors in the development of diabetic complications. Horm Res 2000; 53: 53–67.

76. Serbedžija P, Ishii DN. Insulin and insulin-like growth factor prevent brain atrophy and cognitive impairment in diabetic rats. Indian J Endocrinol Metab 2012; 16: S601–610.

77. Rao AA. Views and opinion on BDNF as a target for diabetic cognitive dysfunction.

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78. Skogseid IM, Nordby HK, Urdal P, Paus E, Lileaas F. Increased serum creatine kinase BB and neuron-specific enolase following head injury indicates brain damage.

Acta Neurochir (Wien) 1992; 115: 106–111.

79. Herrmann M, Ehrenreich H. Brain derived proteins as markers of acute stroke: their relation to pathophysiology, outcome prediction and neuroprotective drug monitoring. Restor Neurol Neurosci 2003; 21: 177–190.

80. Clarke DW, Mudd L, Boyd FT, Fields M, Raizada MK. Insulin is released from rat brain neuronal cells in culture. J Neurochem 1986; 47: 831–836.

81. Brant AM, Jess TJ, Milligan G, Brown CM, Gould GW. Immunlogical analysis of glucose transporters expressed in different regionsof the rat brain and central nervous system. Biochem Biophys Res Commun 1993; 192: 1297–1302.

82. Wozniak M, Rydzewski B, Baker P, Raizada MK. The cellular and physiological actions of insulin in the central nervous system. Neurochem Int 1993; 22: 1–40.

83. Hopkins DF, Williams G. Insulin receptors are widely distributed in human brain and bind human and porcine insulin with equal affinity. Diabet Med 1997; 14: 1044–1050.

84. Chiu S, Chen C, Cline H. Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron 2008; 58: 708–719.

85. Fishel MA, Watson GS, Montine TJ, Wang Q, Green PS, Kulstad JJ, et al.

Hyperinsulinemia provokes synchronous increases in central inflammation and β-amyloid in normal adults. Arch Neurol 2005; 62: 1539–1544.

86. Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, et al. Insulindegrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA 2003; 100: 4162–4167.

87. Young SE, Mainous AG 3rd, Carnemolla M. Hyperinsulinemia and cognitive decline in a middle-aged cohort. Diabetes Care 2006; 29: 2688–2693.

88. Exalto LG, Whitmer RA, Kappele LJ, Biessels GJ. An update on type 2 diabetes, vascular dementia and Alzheimer’s disease. Exp Gerontol 2012; 47: 858–864.

89. Alafuzoff I, Aho L, Helisalmi S, Mannermaa A, Soininen H. Beta-amyloid deposition in brains of subjects with diabetes. Neuropathol Appl Neurobiol 2008; 35: 60–68.

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Type 1 diabetes and cardiovascular disease OLIVER SCHNELL, FRANCESCO CAPPUCCIO, STEFANO GENOVESE, EBERHARD STANDL, PAUL VALENSI, ANTONIO CERIELLO Abstract The presence of cardiovascular disease (CVD) in type 1 diabetes largely impairs life expectancy. Hyperglycaemia, leading to an increase in oxidative stress, is considered to be the key pathophysiological factor of both micro- and macrovascular complications. In type 1 diabetes, the presence of coronary calcifications is also related to coronary artery disease. Cardiac autonomic neuropathy, which significantly impairs myocardial function and blood flow, also enhances cardiac abnormalities. Also hypoglycaemic episodes are considered to adversely influence cardiac performance.

Intensive insulin therapy has been demonstrated to reduce the occurrence and progression of both micro- and macrovascular complications. This has been evidenced by the Diabetes Control and Complications Trial (DCCT)/ Epidemiology of Diabetes Interventions and Complications (EDIC) study. The concept of a metabolic memory emerged based on the results of the study, which established that intensified insulin therapy is the standard of treatment of type 1 diabetes. Future therapies may also include glucagonlike peptide (GLP)-based treatment therapies. Pilot studies with GLP-1-analogues have been shown to reduce insulin requirements.

Keywords: type 1 diabetes, cardiovascular disease

Introduction Over the past 40 years, a reduction in mortality rate due to cardiovascular disease (CVD) and coronary heart disease (CHD) by Correspondence to: Oliver Schnell Forschergruppe Diabetes e.V., Helmholtz Center Munich, MunichNeuherberg, Germany e-mail: Oliver.Schnell@lrz.uni-muenchen.de Eberhard Standl Forschergruppe Diabetes e.V., Helmholtz Center Munich, MunichNeuherberg, Germany Francesco Cappuccio University of Warwick, Warwick, UK Stefano Genovese Department of Cardiovascular and Metabolic Diseases, Gruppo Multimedica, Sesto San Giovanni, Milan, Italy Paul Valensi Service d’Endocrinologie-Diabétologie-Nutrition, Hôpital Jean Verdier, Bondy Cedex, France Antonio Ceriello Insititut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Hospital Clínic Barcelona, Barcelona, Spain Originally published in Cardiovasc Diabetol 2013, 12: 156.

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about 70%, both in diabetic and non-diabetic patients, has been observed.1 The cause is presumed to be a substantial progress in CV risk factor management and interventional cardiology.1 Furthermore, in patients with type 1 diabetes, a decrease in mortality and a remarkable improvement in life expectancy has occurred during the past decades.2,3 The comparison of two sub-cohorts of the Pittsburgh Epidemiology of Diabetes Complications (EDC) study based on the period of diabetes diagnosis (1950–1964 vs 1965–1980) found an increase in life expectancy of approximately 14 years.3 Nevertheless, the overall risk of CVD for people with type 1 diabetes compared to people without diabetes is increased two- to three-fold in men, and three- to five-fold in women. A significant increase in CVD mortality related to increasing glycated haemoglobin (HbA1c) levels has been reported in type 1 diabetes.4 The aim of this article was to present an overview on epidemiological and pathophysiological aspects of the relationship between type 1 diabetes and CVD. In addition, the management of risk factors, both with a view on diagnostic and therapeutic approaches, is addressed.

Epidemiology In the EURODIAB IDDM Complications study, including more than 3 200 patients with type 1 diabetes from 16 European countries, the prevalence of CVD was reported to be 9% in men and 10% in women, respectively.5 Related to an increase in duration of diabetes and age, an increase from 6% in the age group of 15–29 years to 25% in the age group of 45–59 years, has been observed.5 In type 1 diabetes compared to type 2 diabetes, the relationship of hyperglycaemia with microangiopathy as well as macroangiopathy seemed to be more significant.6,7 According to the results of a large Finnish database, CVD mortality in patients with type 1 diabetes aged from 45–64 years at baseline increased by about 50% with every 1% increase in HbA1c level.6 In a population-based cohort of 879 individuals with type 1 diabetes from Wisconsin, hyperglycaemia was associated with allcause and cardiovascular mortality.8 At baseline examination (1980– 1982), patients were free of cardiovascular disease and end-stage renal disease. The patients were followed up until December 2001.

The multivariable relative risks comparing the highest quartile of HbA1c (≥ 12.1%) with the lowest quartile (≤ 9.4%) were 2.42 (95% CI: 1.54–3.82; p = 0.0006) for all-cause mortality and 3.28 (95% CI: 1.77–6.08; p < 0.0001) for cardiovascular mortality.8 This association was present among both sexes, and independent of duration of diabetes, smoking, hypertension and proteinuria. The relationship persisted in subgroup analyses by categories of diabetes duration, smoking, body mass index, proteinuria and retinopathy.8 In a Japanese study, which included type 1 diabetes subjects who were diagnosed at an age of < 18 years, between 1965 and 1979, CVD was identified as the leading cause of death in diabetes of more than 20 years of duration.9 Recently, the long-term clinical outcomes and survival in patients with both young-onset type 2 and type 1 diabetes with a similar age of diagnosis were evaluated.10 Compared with type 1, type

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2 diabetes presented with a more lethal phenotype and a higher mortality rate. Also diabetic complications were detected more frequently.10

dehydrogenase (GAPDH) is stimulated. These processes result in acute endothelial dysfunction, which contributes to the genesis of diabetic complications.12,13

Pathophysiology/aetiology

Inflammation An increase in inflammatory cytokines is also proposed to contribute to plaque instability in patients with diabetes.14 Several inflammatory markers including C-reactive protein, interleukin (IL)-6, IL-8, tumour necrosis factor (TNF)-Îą, and endothelin-1 are increased during hypoglycaemia. The accumulation of inflammatory cytokines is assumed to cause endothelial injury and abnormalities in coagulation, resulting in increased risk for CV events.14

Long-term hyperglycaemia, both in type 1 and type 2 diabetes, leads to microvascular and macrovascular complications.11 Microvascular damage affects particularly the retina, kidneys, and both the autonomic and peripheral nervous system, while the heart, brain and lower limbs are affected by both micro- and macrovascular disorders.11 Oxidative stress Hyperglycaemia-induced overproduction of superoxide by the mitochondrial electron transport chain is supposed to be the key element in the activation of all other pathways involved in the pathogenesis of diabetic complications (Fig. 1).12,13 These include an increase in polyol pathway flux and advanced glycation endproduct formation, an activation of protein kinase C, and an increase in hexosamine pathway flux. Superoxide overproduction is accompanied by increased nitric oxide generation, due to an endothelial nitric oxide synthase (NOS) and inducible NOS uncoupled state. Therefore the formation of the strong oxidant peroxynitrite is favoured, which in turn damages the deoxyribonucleic acid (DNA).12,13 Due to this DNA damage, a rapid activation of poly[adenosine diphosphate (ADP)-ribose] polymerase occurs, in turn depleting the intracellular concentration of its substrate nicotinamide adenine dinucleotide (NAD+), and slowing the rate of glycolysis, electron transport, and adenosintriphosphate (ATP) formation. In addition, the ADP-ribosylation of the glyceraldehyde 3-phosphate

Figure 1. Pathogenesis of diabetic complications: hyperglycaemia-induced overproduction of superoxide by the mitochondrial electron transport chain is proposed to be the key element. By activation of different pathways, the formation of the strong oxidant peroxynitrite is favoured, which in turn damages the DNA. Through several intermediate steps, acute endothelial dysfunctioncontributing to the genesis of diabetic complications, is triggered.13

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Hypercoagulability The coagulation system is altered due to changes in clotting factor levels and/or activity. Plasma levels of procoagulant factors are increased while fibrinolytic capacity is decreased.15 Hyperinsulinaemia results in increased hepatic synthesis of prothrombotic factors such as fibrinogen and plasminogen activator inhibitor (PAI)-1, thereby creating a thrombotic milieu. Furthermore, diabetes causes quantitative modifications in clotting factors, including glycation and oxidation which also increase thrombosis risk.15 Autonomic neuropathy Cardiac autonomic neuropathy (CAN) detected by standard tests is a common complication of type 1 diabetes. CAN prevalence is around 20% and increases with age and diabetes duration with about a 2% annual increase.16 Poor glycaemic control is a strong risk factor for CAN as supported by the EURODIAB study.17 In the Diabetes Control and Complications Trial (DCCT), intensive insulin treatment reduced the incidence of CAN by 53% compared to conventional therapy.18 In the Epidemiology of Diabetes Interventions and Complications (EDIC) study, at the 13th to 14th year after DCCT close-out, the prevalence and incidence of CAN remained significantly lower in the former intensive than in the former conventional group.19 Several studies showed the predictive value of CAN on mortality,16 and that CAN is an independent predictor of mortality.

CAN was reported to be a predictor of CV morbidity and mortality in type 1 diabetes.20 Various CV disorders associated with CAN and resulting from vagal impairment and sympathetic predominance were shown mostly in type 2 diabetes and may account for the poor prognosis related to CAN.16 Such disorders have been far less studied in patients with type 1 diabetes.

In a study on patients with type 1 and type 2 diabetes, the prevalence of hypertension was shown to increase with CAN severity (from 3.6% in the patients without CAN to 36.4% in those with severe CAN), and CAN was an independent risk factor for hypertension.21 This association suggests that vagosympathetic imbalance with a relative sympathetic overdrive may be involved in hypertension. In the Pittsburgh EDC study, CAN was associated with increased arterial stiffness 18 years later.22 There is also strong evidence, based on studies in patients with type 1 or type 2 diabetes, that QT-interval prolongation is an independent predictor of mortality for all-cause and cardiovascular deaths.16 The balance of the activity of the autonomic nervous system is considered to play a key role in the performance of the diabetic heart.23 Advanced single-photon emission computed tomography (SPECT) and positron emission tomography (PET) allow one to directly and sensitively assess cardiac sympathetic innervation,24-29

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coronary blood flow30,31 and myocardial metabolism.32,33 In long-term type 1 diabetes, myocardial blood flow response to sympathetic stimulation is significantly impaired.

Scintigraphically, cardiac sympathetic dysinnervation was identified in 77% of newly diagnosed metabolically stabilised type 1 diabetic patients.27 The pattern of cardiac sympathetic dysinnervation of newly diagnosed type 1 diabetic patients is heterogeneous with a predominant affection of the posterior myocardial region.25,27 More recent publications, however, emphasise that neither impairment of metabolic control nor the presence of CV denervation may be a prerequisite for the development of impaired vasodilatory reserve. Diastolic dysfunction occurring early in the course of type 1 diabetes has been reported to be associated with abnormal cardiac sympathetic function as assessed by cardiac sympathetic imaging.34,35 Neuronal abnormalities are reported to progress with duration of diabetes.36 In parallel, defects of cardiac sympathetic innervation are more enhanced in long-term than in newly diagnosed type 1 diabetes patients.25,27 In patients with a long diabetes history, heterogeneity of cardiac sympathetic dysinnervation, characterised by a more advanced affection of the posterior myocardium in comparison to the anterior, lateral and septal myocardium has been observed.25 In studies on small groups of patients with type 1 diabetes, frequent sympathetic dysinnervation and a predominance in the posterior myocardial region,37 and proximal sympathetic hyperinnervation of the heart38 has been observed with PET. Immunological factors against sympathetic ganglia have been reported to be associated with cardiac sympathetic dysfunction.39-45 Auto-antibodies against sympathetic ganglia have been found in 20–35% of type 1 diabetes patients.39,41,42 The presence of autoantibodies against sympathetic ganglia has been shown to be associated with scintigraphically assessed cardiac sympathetic dysfunction39,41 and electrocardiogram (ECG)-based abnormalities of heart rate variation.41 Auto-antibodies against sympathetic ganglia seem to be rather specific for cardioneuropathy of type 1 diabetes patients.41 Hypoglycaemia Additional haemodynamic changes have been reported to be associated with hypoglycaemia.46 An increase in heart rate and peripheral systolic blood pressure as well as a reduction in central blood pressure and peripheral arterial resistance (causing a widening of pulse pressure) has been described. Furthermore, an increase in myocardial contractility, stroke volume and cardiac output has been observed.47 In healthy people, arteries have been reported to become more elastic during hypoglycaemia, with a decline in wall stiffness.46 In people with a longer history of type 1 diabetes, however, due to an enhanced arterial wall stiffness, hypoglycaemia is followed by a less pronounced fall in central arterial pressure.46,48 As a consequence, a temporary markedly increase in the workload of the heart must be assumed.46 On ECG, hypoglycaemia has been found to elicit ST-wave changes with lengthening of the QT interval49 and cardiac repolarisation.50 Therefor the risk for arrhythmia is assumed to be increased.46 Related to hypoglycaemia, various abnormal heart rhythms, including ventricular tachycardia and atrial fibrillation, have been observed.

In conclusion, hypoglycaemia has been found to potentially cause abnormal electrical activity in the heart and is assumed to provoke sudden death.46 An association between hypoglycaemia

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and sudden death has been detected by various investigators.51-56 In line with the hypothesis, an autopsy study demonstrated that sudden unexpected deaths were four times more frequent in type 1 diabetes patients than in non-diabetic people.56

Cardiovascular risk Risk factors for microvascular complications The risk of microvascular complications is influenced by several factors, such as puberty, blood pressure, dyslipidaemia, gender, diabetes duration, smoking and lifestyle.57-59 Poor metabolic control has been identified as an important factor contributing to microvascular complications.60,61 In addition, familial risk factors related to all microvascular complications of type 1 diabetes have been reported.62 A study performed in type 1 diabetes patients (onset age < 30 years) among 6 707 families revealed a significantly increased risk of retinopathy (odds ratio 9.9; CI 5.6–17.7, p < 0.001), nephropathy (6.2; CI 2.9–13.2, p < 0.001) and neuropathy (2.2; CI 1.0–5.2; p < 0.05) in type 1 diabetes siblings of patients diagnosed with these complications.62 In an analysis of 572 type 1 diabetes participants of the Pittsburgh EDC study (mean follow up: 15 years), baseline HbA1c level was an independent risk factor for fatal CAD, along with duration of diabetes and albuminuria.63 Lower baseline insulin dose, however, was strongly predictive of non-fatal CAD, as was lower renal function, and higher diastolic blood pressure and lipid levels.63 In patients with diabetes onset at age 5–14 years, a higher risk for complications (retinopathy, nephropathy and neuropathy) has been found compared to patients diagnosed either at a very young age or after puberty.62 In adolescents with type 1 diabetes, an elevated blood pressure or body mass index (BMI),64-66 dyslipidaemia and smoking67-69 were associated with an elevated risk of incipient nephropathy, early retinopathy and peripheral neuropathy.

With the onset of diabetic nephropathy, a dramatic increase in the risk for CAD has to be assumed. After 20 years with diabetes, up to 29% of patients with childhood-onset type 1 diabetes and nephropathy will have CAD compared to only 2–3% in similar patients without nephropathy.70 In addition to traditional cardiovascular disease risk factors, elevated mean HbA1c levels and macroalbuminuria were significantly associated with alterations in left ventricular structure and function evaluated by cardiac magnetic resonance imaging (MRI).71 In observational studies, the relationship between blood pressure and the progression of chronic kidney disease (CKD) and incident end-stage renal disease (ESRD) is direct and progressive in diabetes.72 However, most of the evidence is in type 2 diabetes. High blood pressure is a common feature of type 1 diabetes as well, and an increase in blood pressure in type 1 diabetes increases the risk of nephropathy.73,74 Masked hypertension is not infrequent.72 In people with type 1 diabetes an increase in systolic blood pressure, particularly at night, precedes the development of microalbiminuria.75 It has been argued that, unlike in type 2 diabetes, in people with type 1 diabetes, hypertension develops often after the establishment of microalbuminuria. Hence, 24-hour blood pressure monitoring in type 1 diabetes may be a useful diagnostic procedure.

In the DCCT/EDIC study, during a 15.8-year median follow up, 630 of 1 441 participants developed hypertension.76 Intensive therapy during the DCCT reduced the risk of incident hypertension by 24% during the EDIC study follow up. A higher HbA1c level,

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measured at baseline or during follow up, was associated with increased risk for incident hypertension. Older age, male gender, family history of hypertension, greater baseline BMI, weight gain, and greater albumin excretion rate were independently associated with increased risk of hypertension. These data show that hyperglycaemia is a risk factor for incident hypertension in type 1 diabetes and that intensive insulin therapy reduces the long-term risk of developing hypertension.

In a recently published Brazilian study on approximately 1 300 patients with type 1 diabetes, however, body size and blood pressure were not correlated to lipid levels and glycaemic control.77 Correlation of serum lipids with HbA1c level was shown to be heterogeneous across the spectrum of glycaemic control. Several pathophysiological factors were suggested based on the HbA1c level. These results, therefore, do not support a unified explanation for cardiovascular risk in type 1 diabetes patients.77 Cardiovascular risk markers As demonstrated in 144 participants of the Pittsburgh EDC study, pulse-wave analysis (PWA) may contribute to assessment of CV risk in patients with type 1 diabetes.78 Arterial stiffness index, augmentation index, augmentation pressure, sub-endocardial viability ratio (serving as an estimate of myocardial perfusion), electron beam computed tomography-measured coronary artery calcification (CAC) and ankle-brachial index (ABI) were determined.

In the analysis of cross-sectional associations, greater augmentation pressure was independently associated with prevalent CAD and estimated myocardial perfusion with low ABI (< 0.90).78 In the DCCT/EDIC study the stiffness/distensibility of the ascending thoracic aorta was measured with magnetic resonance imaging in 879 patients.79 After adjusting for gender and cohort, aortic distensibility was lower with increasing age, mean systolic blood pressure, lowdensity lipoprotein (LDL) cholesterol and HbA1c level measured over an average of 22 years. Patients with macroalbuminuria had 25% lower aortic distensibility compared with those without, and lower distensibility was also associated with greater ratio of left ventricular mass to volume. This data stand in favour of strong adverse effects of hypertension, chronic hyperglycaemia and macroalbuminuria on aortic stiffness in type 1 diabetes.

After 15 years additional follow up in EDIC, left ventricular indices were measured by cardiac magnetic resonance imaging in 1 017 of the 1 371 members of the DCCT cohort.80 Mean DCCT/EDIC HbA1c level over time was associated with end-diastolic volume, stroke volume, cardiac output, left ventricular mass, LV mass/EDV, and aortic distensibility. These associations persisted after adjustment for CVD risk factors. Therefore cardiac function and remodelling in the EDIC cohort was associated with prior glycaemic exposure (glycaemic memory).

As part of the EDIC study, 1 229 patients with type 1 diabetes underwent ultrasonography of the internal and common carotid arteries from 1994 to 1996 and again from 1998 to 2000.81 At year 1 of the EDIC study, the carotid intima–media thickness (IMT) was similar to that in an age- and gender-matched non-diabetic population. After six years, the IMT was significantly greater in the diabetic patients than in the controls. The mean IMT progression was significantly less in the group that had received intensive therapy during the DCCT than in the group that had received conventional therapy after adjustment for other risk factors. IMT progression was associated with age, and the EDIC baseline systolic blood pressure, smoking, the LDL/HDL ratio, and urinary albumin excretion rate and

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with the mean HbA1c value during the mean duration of the DCCT. Therefore, intensive therapy during the DCCT resulted in decreased progression of IMT six years after the end of the trial, which again stands in favour of the effect of glycaemic memory.

As found by the 10-year follow-up examination of the Pittsburgh EDC study cohort, CAC is related to clinical CAD independent of other risk factors.82 This association, however, was stronger in men than in women.82 In a cohort of patients with type 1 diabetes (aged 22–50 years), progression of CAC, as identified by electron beam computed tomography (EBCT), was strongly associated with suboptimal glycaemic control (HbA1c > 7.5%).83 In a study assessing CAC with multi-slice spiral computed tomography (MSCT), nearly one-third of asymptomatic long-term type 1 diabetes patients presented with coronary calcifications.84 In patients with coronary calcifications, both cardiac autonomic neuropathy and retinopathy were detected more frequently than in those without (64 vs 29%, p < 0.02; 59 vs 31%; p < 0.02).

Additionally, duration of diabetes was longer in patients with than without coronary calcification.84 In a small cohort of adolescent, non-obese type 1 diabetes patients, an increased carotid intima–media thickness was found to be associated with insulin resistance. A causal relationship, however, cannot be concluded.85 According to a prospective longitudinal study in children and adolescents with type 1 diabetes, systolic blood pressure and body mass index are related to increased carotid intima–media thickness. Control of these risk factors is presumed to contribute to prevention of progression of carotid intima–media thickness.86 In patients with long-term type 1 diabetes, sexual dysfunction was demonstrated to be independently associated with CVD and to potentially predict CVD.87 Results on the predictive value of plasminogen activator inhibitor-1 (PAI-1) are inconsistent. One study found PAI-1 levels to be independently related to CAC in younger (< 45 years) patients with type 1 diabetes.88 According to another analysis, neither PAI-1 nor tPA-PAI-1 was an independent predictor of CAD.89

Diagnosis/screening In type 1 diabetes, hypertension is often the result of nephropathy.

Blood pressure measurement is recommended at every routine visit.90 In most adult patients with diabetes, a fasting lipid profile is recommended at least once a year.90 Low-risk lipid values (LDL cholesterol < 100 mg/dl, HDL > 50 mg/dl, triglycerides < 150 mg/dl) provided, assessment may be repeated bi-annually.90 In type 1 diabetes patients with diabetes duration ≥ five years, the screening for nephropathy should include an annual assessment of urine albumin excretion.90 Irrespective of the degree of urine albumin excretion, in all adults with diabetes serum creatinine should be measured at least annually.90 The creatinine value is useful for estimation of glomerular filtration rate (GFR).90 In children and adolescent patients, annual screening both for nephropathy and retinopathy is recommended to start at age 11 years in case of two years’ diabetes duration and at age nine years with five years duration, respectively.91 Screening for signs and symptoms of CV autonomic neuropathy should be started five years after the diagnosis of type 1 diabetes.16,90 CV reflex tests are the gold standard in clinical autonomic testing.

The most widely used tests assessing cardiac parasympathetic function are based on the time-domain heart rate response to deep breathing, Valsalva manoeuvre and postural change. Age is a strong modulator of these tests and needs to be considered when

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interpreting the results. CV sympathetic function is assessed by measuring the blood pressure response to standing.92 PWA may contribute to assessment of CV risk in patients with type 1 diabetes.78 In a study, greater augmentation pressure was independently associated with prevalent CAD and estimated myocardial perfusion with low ABI (< 0.90).78 Screening patients for silent myocardial ischaemia is controversial but seems reasonable in very high-risk patients, in particular in those with long duration of diabetes and proteinuria or evidence of peripheral artery disease, and in those who wish to start a vigorous exercise programme. Measurement of CAC score may be suggested as a first-line investigation, leading to a stress test if the score is higher than 400.93,94

Treatment Gycaemic control Intensive insulin therapy has been strongly demonstrated to reduce the onset as well as progression of all diabetes-related microvascular complications.58,60,95-98 The DCCT/ EDIC study found in approximately 1 200 patients with type 1 diabetes a relative CVD risk reduction of 40%, adjusted for other risk factors including albuminuria, when comparing intensive versus standard treatment (mean HbA1c 7.4 vs 9.1%) for 11 years.58 In adolescent patients, intensive treatment (HbA1c = 8.1%) compared to conventional treatment (HbA1c = 9.8%) has been shown to reduce the risk and progression of background retinopathy by 53%, clinical neuropathy by 60%, and microalbuminuria by 54%.60 A prolonged effect of early intensive approaches was also seen in a four-year follow up of intensively treated adolescent type 1 diabetic patients.99 Several studies confirmed the association between poor glycaemic control and an increasing risk for nephropathy,100-102 retinopathy,95,103,104 and neuropathy.105-109 A large proportion of patients, however, fail to achieve glycaemic targets.110-112 GLP-1-based treatment as an add-on to insulin Due to their action on insulin secretion and glucose regulation, glucagone-like peptide 1 (GLP-1)-based treatment approaches have been established in the treatment of type 2 diabetes. Based on in vitro and animal studies, GLP-1-based drugs additionally may be effective in preserving and even expanding the beta-cell mass.113 In a small study on 15 patients with newly detected type 1 diabetes, the addition of exenatide at onset of diabetes has been shown to decrease insulin requirement.113 Three groups of patients have been formed: group1 (insulin alone), group 2 (insulin and exenatide) and group 3 (insulin and sitagliptin).

After one year, a decrease in insulin requirement of 16.7 ± 12.5, 39.8 ± 17.2, 21.2 ± 9.6 units in groups 1, 2 and 3, respectively (p = 0.0431) was detected. A mean stimulated c-peptide secretion of 0.34 ± 0.12, 0.45 ± 0.34, 0.44 ± 0.5 ng/ml was found (p = 0.8656).

The maximum percentage preservation in c-peptide was observed in the patients of group 2.113 Of relevance is the evidence that GLP-1 can protect type 1 diabetes patients from both acute hyperglycaemiaor hypoglycaemia-induced endothelial dysfunction, oxidative stress and inflammation.114 Approaches beyond glycaemic control In contrast to DCCT/EDIC, some trials did not confirm the association between glycaemic control and CVD risk.115-117 Discrepancies are suggested to be based on differences between the study populations.118 With a view to prevention and treatment of CAD,

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it is recommended to focus not only on glycaemic control.118 Traditional risk factors such as albuminuria, the metabolic syndrome and inflammatory markers should also be addressed.118 International guidelines recommend lowering blood pressure in diabetes to prevent macro- and microvascular outcomes. However, most evidence from randomised clinical trials refers to type 2 diabetes. A goal of blood pressure < 130 and < 80 mmHg has been recommended.90,119 The most recent recommendations of the American Diabetes Association (ADA) set a blood pressure goal of < 140/< 80 mmHg for persons with diabetes and hypertension; lower targets (such as < 130 mmHg) may be appropriate in patients if the specific target can be achieved without an additional burden of treatment.90 Pharmacological therapy in people with diabetes and hypertension should be with a regimen that includes either an angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB).90 Generally, two or more drugs are required to achieve blood pressure targets in diabetics. Preferred combinations are either ACE inhibitors or ARBs (not together) with a calciumchannel blocker or a diuretic. For the latter, both thiazide90and, more recently, thiazide-like diuretics120 are recommended. However, more recent appraisal of the evidence indicates lack of evidence to support systolic blood pressure targets < 130 mmHg and suggests optimal diastolic blood pressure between 80 and 85 mmHg.72 In studies among patients with diabetes, regular physical activity has been demonstrated to reduce CVD-related and total mortality.11 Early treatment of hypertension has been reported to prevent end-stage kidney disease in patients with type 1 diabetes.121 ACE inhibitors have been demonstrated to be effective and safe in in reducing microalbuminuria.122 In adolescent patients with persistent microalbuminuria, the use of ACE inhibitors91,100,123 or angiotensin II receptor blockers91 is recommended to prevent the progression to macroalbuminuria. Furthermore, in order to reduce progression of microalbuminuria, cessation of smoking is strongly recommended.117,124,125 Lifestyle modification is recommended for the improvement of lipid profile. In diabetic patients with overt CVD, statins should be added irrespective of lipid levels.90 Statin therapy is also recommended in diabetic patients without CVD aged > 40 years and ≥ one other CVD risk factor (family history of CVD, hypertension, smoking, dyslipidaemia, albuminuria).90 In patients with lower CV risk, statin therapy should be considered if LDL cholesterol remains above 100 mg/dl.90 In diabetic patients without overt CVD, the goal for LDL cholesterol is 100 mg/dl (2.6 mmol/l). In patients with overt CVD, an LDL cholesterol goal of 70 mg/dl (1.8 mmol/l) using a high dose of statin may be considered.90

Discussion Despite a remarkable improvement in life expectancy, type 1 diabetes patients are confronted with an increased risk of CV mortality, often under-recognised evidence. Further improvement may base on consequent risk assessment and management of risk factors. Estimation of CV risk including the role of surrogate markers deserves more attention in the future. Currently, optimised glycaemic control is considered to be the most promising approach.

Recent research on a small group of patients suggests the addition of exenatide at onset of diabetes to decrease insulin requirement.

These results, however, need to be confirmed by further investigation on larger groups of patients.

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107. Solders G, Thalme B, Aguirre-Aquino M, et al. Nerve conduction and autonomic nerve function in diabetic children. A 10-year follow-up study. Acta Paediatr 1997; 86: 361–366.

108. Craig ME, Handelsman P, Donaghue KC, et al. Predictors of glycaemic control and hypoglycaemia in children and adolescents with type 1 diabetes from NSW and the ACT. Med J Aust 2002; 177: 235–238.

109. Vanelli M, Chiarelli F, Chiari G, Tumini S. Relationship between metabolic control and quality of life in adolescents with type 1 diabetes. Report from two Italian centres for the management of diabetes in childhood. Acta Biomed 2003; 74(Suppl 1): 13–17.

110. Holl RW, Swift PG, Mortensen HB, et al. Insulin injection regimens and metabolic control in an international survey of adolescents with type 1 diabetes over 3 years: results from the Hvidore study group. Eur J Pediatr 2003; 162: 22–29.

111. Hari Kumar KV, Shaikh A, Prusty P. Addition of exenatide or sitagliptin to insulin

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in new onset type 1 diabetes: A randomized, open label study. Diabetes Res Clin Pract 2013. doi: 10.1016/j.diabres.2013.1001.1020.

112. Ceriello A, Novials A, Ortega E, et al. Glucagon-like peptide 1 reduces endothelial dysfunction, inflammation, and oxidative stress induced by both hyperglycemia and hypoglycemia in type 1 diabetes. Diabetes Care 2013; 36(8): 2346–2350.

113. Klein R, Klein BE, Moss SE. The Wisconsin epidemiological study of diabetic retinopathy: a review. Diabetes Metab Rev 1989; 5: 559–570.

114. van Hecke MV, Dekker JM, Stehouwer CD, et al. Diabetic retinopathy is associated with mortality and cardiovascular disease incidence: the EURODIAB prospective complications study. Diabetes Care 2005; 28: 1383–1389.

115. Rossing P, Hougaard P, Parving HH. Risk factors for development of incipient and overt diabetic nephropathy in type 1 diabetic patients: a 10-year prospective observational study. Diabetes Care 2002; 25: 859–864.

116. Wajchenberg BL, Feitosa AC, Rassi N, Lerario AC, Betti RT. Glycemia and cardiovascular disease in type 1 diabetes mellitus. Endocr Pract 2008; 14: 912– 923.

117. American Diabetes Association. Hypertension management in adults with diabetes. Diabetes Care 2004; 27: s65–s67.

118. NICE. Hypertension. The clinical management of primary hypertension in adults.

NICE Clinical Guideline 127. 2011. Available at http://publications.nice.org.uk/ hypertension-cg127 webcite [last accessed: 02-07-2013]. 2011.

119. Rossing P, Hougaard P, Borch-Johnsen K, Parving HH. Predictors of mortality in insulin dependent diabetes: 10 year observational follow up study. Br Med J 1996; 313: 779–784.

120. Cook J, Daneman D, Spino M, et al. Angiotensin converting enzyme inhibitor therapy to decrease microalbuminuria in normotensive children with insulindependent diabetes mellitus. J Pediatr 1990; 117: 39–45. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents Pediatrics 2004; 114: 555–576.

121. Couper JJ, Staples AJ, Cocciolone R, et al. Relationship of smoking and albuminuria in children with insulin-dependent diabetes. Diabet Med 1994; 11: 666–669.

122. Astrup AS, Tarnow L, Rossing P, et al. Improved prognosis in type 1 diabetic patients with nephropathy: a prospective follow-up study. Kidney Int 2005; 68: 1250–1257.

Continued from page 86 90. Lustman PJ, Clouse RE. Depression in diabetic patients: the relationship between mood and glycemic control. J Diabetes Complications 2005; 19: 113–122.

91. Solfrizzi V, Panza F, Capurso A. The role of diet in cognitive decline. J Neural Transm 2003; 110: 95–110.

92. Witte AV, Fobker M, Gellner R, Knecht S, Flöel A. Caloric restriction improves memory in elderly humans. Proc Natl Acad Sci USA 2009; 106: 1255–1260.

93. Malik VS, Popkin BM, Bray GA, Després JP, Willett WC, Hu FB. Sugarsweetened beverages and risk of metabolic syndrome and type 2 diabetes: a meta-analysis. Diabetes Care 2010; 33: 2477–2483.

94. Hu EA, Pan A, Malik V, Sun Q. White rice consumption and risk of type 2 diabetes: meta-analysis and systematic review. Br Med J (Clinical research ed.)

2012; 344: e1454.

95. Lee IM, Shiroma EJ, Lobelo F, Puska P, Blair SN, Katzmarzyk PT, Lancet Physical

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Activity Series Working Group. Effect of physical inactivity on major noncommunicable diseases worldwide: an analysis of burden of disease and life expectancy. Lancet 2012; 380: 219–229.

96. Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, et al.

Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study.

Br Med J 2000; 321: 412–419.

97. Risérus U, Willet W. Dietary fats and prevention of type 2 diabetes. Prog Lipid Res 2009; 48: 44–51.

98. National Institute for Health and Clinical Excellence. Clinical guideline 66: Type 2 diabetes. London, 2008.

99. Kahler W, Kuklinski B, Ruhlmann C. Diabetes mellitus – a free radical associated disease. Results of adjuvant antioxidant supplementation. Z Gesamte Inn Med 1993; 48: 223–232.

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SA JOURNAL OF DIABETES & VASCULAR DISEASE

BEST PRACTICE

Best Practice

New guidelines address problems associated with suboptimal injection technique

T

he incorrect administration of insulin injections contributes to complications associated with South Africa’s growing diabetes burden and makes problems worse.1 But this is about to change. Earlier this year, South Africa became the sixth country worldwide and the first in Africa to benefit from the introduction of guidelines for optimal injection technique for diabetes control. ‘Needles have come a long way and are shorter and thinner than in the past, which has helped us to work around doctor and patient reluctance to initiate insulin’, says paediatric endocrinologist, Dr David Segal. ‘These guidelines are important to ensure uniformity in respect of how patients administer insulin and how healthcare professionals advise them with regard to correct techniques.’

The guidelines were made public at an official launch on 10 April 2014 prior to the annual SEMDSA conference and are specifically tailored to South Africa and its needs. They were created by the South African Forum for Injection Technique (FIT), made up of experienced specialist diabetes nurses, whose chairperson, Hester Davel, underlines the need for action. ‘Reliable statistics are not readily available but data held by companies that supply insulin and other injectable therapies suggest that some 200 000 people in South Africa currently use injectable therapies to treat their diabetes.

We intend making life easier by guiding those who are injecting on the best injection techniques available.’

Razana Allie, a diabetes nurse educator and member of the FIT steering committee, adds: ‘Education is key to the effective management of diabetes and this includes education on how to use medication.

Simplifying and improving diabetes control for patients and caregivers will have huge benefits in the longer term. It will improve overall quality of care, minimise individual complications and increase the costeffectiveness of diabetes control resources.’

Incorrect injection technique on its own complicates the management of diabetes.1,2

VOLUME 11 NUMBER 2 • JUNE 2014

When insulin is prescribed, the appropriate administration devices and needles frequently aren’t given. In addition, consistent education on correct technique is lacking. Allie explains that incorrect technique, including use of TEN BEST-PRACTICE RECOMMENDATIONS Needle length 1. For all children and adolescents a 4-, 5- or 6-mm needle should be used.

2. Adults, including obese patients, can use 4-, 5- and 6-mm needles.

Site rotation 3. An easy-to-follow injection site rotation scheme should be taught to patients from the initiation of injection therapy.

Needle/syringe hygiene 4. Ideally do not reuse needles.

Lipohypertrophy 5. The injection site should be inspected at every visit. Patients should be taught to inspect their own sites and should also be given training on how to detect lipohypertrophy.

6. The best current strategies to prevent and treat lipohypertrophy are to rotate the injection site with each injection, using larger injection areas and with non-reuse of needles.

Injection sites 7. Injection should be given at a clean site with clean hands.

8. Prior to the injection, the site has to be palpated for lipohypertrophy and inspected for wounds, bruises or blisters. If the injection site shows any signs of these, then a different site should be selected until the problem has been resolved.

Safety issues 9. Safety needles should be recommended whenever there is risk of a contaminated needle-stick injury.

10. Correct safe disposal of needles/syringes is essential.

inappropriate needle lengths, failure to rotate injection sites and reuse of needles can lead to unpredictable absorption of insulin.3 Injecting insulin into muscle where it is absorbed at a faster rate may cause hypoglycaemia. If the insulin is injected into an area where it is poorly absorbed, it may lead to hyperglycaemia.3-5 ‘The health scene in the country has shifted.

The StatsSA report on the causes of mortality in the country released in March confirms the trend showing that the incidence of noncommunicable diseases is strongly upward – the four main types are cardiovascular disease, cancer, chronic respiratory diseases and most definitely diabetes. We intend helping people with diabetes help themselves’, says Peter Mehlape, general manager of Becton, Dickinson and Company (BD), a global medical devices manufacturer and supporter of the initiative. ‘As a technology partner we support the continuing education of both healthcare workers and patients to ensure successful disease management and make life easier for those with diabetes.’

Davel concludes: ‘Knowing what to do and how to do it will now make a powerful combination in the efforts to improve diabetes control.’

For more information, visit www.fit4diabetes.com/ south-africa/

P Wagenaar 1.

2.

3.

4.

5.

Strauss K, De Gols H, Hannet I, et al. A panEuropean epidemiologic study of injectable therapy injection technique in patients with diabetes. Pract Diabetes Int 2002; 19: 71–76.

Blanco M, Hernandez MT, Strauss KW, Amaya M. Prevalence and risk factors of lipohypertrophy in insulin-injecting patients with diabetes. Diabetes Metab 2013; 39(5): 445–453.

Frid A, Hirsch L, Gaspar R, et al. New injection recommendations for patients with diabetes.

Diabetes Metab 2010; 36(Suppl 2): S3–S18.

Gibney MA, Arce C, Byron K, Hirsch L. Skin and subcutaneous adipose layer thickness in adults with diabetes at sites used for insulin injections: implications for needle length recommendations.

Curr Med Res Opin 2010; 26(6): 1519–1530.

Vardar B, Kizilci S. Incidence of lipohypertrophy in diabetic patients and a study of influencing factors.

Diabetes Res Clin Pract 2007; 77(2): 231–236.

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DIABETES NEWS

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The South African diabetic retinopathy screening programme launches STEPHEN COOK

S

outh Africa has not had a screening programme until recently. The Ophthalmological Society of South Africa (OSSA) has launched a diabetic retinopathy screening programme for South Africa. This has been administered and funded by the African Eye Foundation.

The key component of the system is the patient-held record titled ‘What is the score?’. This serves a combined function as a patient information sheet for patients, their families and caregivers and as a ‘cheat-sheet’ for healthcare practitioners to learn the grading system. The Scottish diabetic retinopathy grading system for screening has been chosen for use in South Africa.

This system is a simple hierachical system for grading features of retinopathy. The system allocates grades for retinopathy (R1–4) and maculopathy (M1–2). A key objective is to encourage access to screening close to the point of primary care to help encourage skills development at a local level. This is particularly important with increased appreciation of the systemic importance of diabetic retinopathy detection.

Systemic risk has been incorporated into the system utilising the risk calculator developed by Prof Einar Steffanson (www.risk.is). A subsidiary site has been established at www.riskafrica.co.za. This is used as a counselling tool for patients and to modify the follow-up algorithm.

Correspondence to: Stephen Cook Director Opthalmologist, The Eye Centre and East London Eye Hospital, East London, South Africa Tel: +27 824535987/+43 7434334 Fax: +27 43 7430359 e-mail: scook@eyecentre.co.za/steve@eyecentre.co.za Originally published in Diabetes Metab 2014; 5(4): 359.

S Afr J Diabetes Vasc Dis 2014; 11: 96

96

An internet-based patient-tracking database has been established to enable common record keeping and look up by non-screening practitioners (www.diabeticregister.co.za). This is accessed with the patient’s consent utilising his/her database number.

A concerted effort has been made to increase access to screening opportunities by enlisting optometrists and general practitioners.

The Scottish external quality assurance (EQA) has been utilised as a means of establishing an accreditation process. This internet-based system involves grading 100 fundus images. The individual sensitivity and specificity is then plotted on a receiver operating characteristic curve (ROC). The results are fed back to the individual with his/her position marked in relation to the (anonymous) peer group. The Scottish experience has been that the system encourages learning over time and their experience shows a greater conformity over time; 282 healthcare practitioners have completed the EQA process.

A directory has been established at www.diabeticretinopathy.co.za to allow patients to find accredited screening services.

The diverse range of healthcare scenarios and levels of practice have necessitated an innovative approach to the programme. This needs to be suited to public and private-sector needs. The system is now ready to provide patients with access to screening. This will enable people living with diabetes to access retinopathy screening and to ‘know their score’ in the fight against the complications of diabetes.

The next step will be to raise awareness regarding the need for screening of the general public. This will be marketed on the basis of the need for screening as a blindness-prevention strategy and emphasising the importance of retinopathy as a biomarker for systemic vascular complications of diabetes mellitus. Healthcare practitioners are being educated to ‘screen for life’ as the detection of any retinopathy is critical to inform of risk of coronary artery disease and stroke (twice the risk). The system can be used more generally in other countries at low cost. It is highly suited to situations where healthcare is in evolution.

VOLUME 11 NUMBER 2 • JUNE 2014

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Malone JK et al. L ispro Mixture-Glargine Study Group. Combined therapy with insulin lispro Mix 75/25 plus metformin or insulin glargine plus metformin: 30% a 16 week randomized, open-label, crossover study in patients with type 2 diabetes beginning insulin therapy. Clin Ther 2004 Dec; 26(12): 2034-44. 3.

Malone JK et al. Twice-daily premixed insulin rather than basal insulin therapy alone results in better overall glycaemic control in patients with Type70% 2 diabetes. Diabet Med 2005 Apr 22(4): 374-81. 4. Niskanen L, Jensen LE, RĂĽstam J, et al. Randomized, Multinational, Open-Label, 2-Period, Crossover Comparison of Biphasic Insulin Aspart 30 and Biphasic Insulin Lispro 25 and Pen Devices in Adult Patients with Type 2 Diabetes Mellitus. Clin Ther, 2004; 26: 531-540. Product information: S3 HumalogÂŽ Mix25â&#x201E;˘ Suspension for injection. Insulin lispro (rDNA origin) 25% Insulin lispro, 75% Insulin lispro protamine suspension (NPL) 100 IU/ml. Reg. No. 33/21.1/0073. For full prescribing information please refer to the package insert currently approved by the Medicine Regulatory Authority.

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