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The Asian Journal of

Diabetology VOLUME 13, NUMBER 1

Role of î Ą-glucosidase Inhibitors in the Management of Postprandial Hyperglycemia

Vascular Changes Seen in Postprandial Hyperglycemia

Pathogenesis of Postprandial Hyperglycemia

Postprandial Hyperglycemia, Implications and Control

The Use of GLP-1 Agonists in the Treatment of Postprandial Hyperglycemia

Dr Vijay Viswanathan Editor

Dr KK Aggarwal

Group Editor-in-Chief

The Asian Journal of

Diabetology

Volume 13, Number 1

Contents

An IJCP Group Publication Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor

From the Desk of Group Editor-in-Chief

Dr Deepak Chopra Chief Editorial Advisor

Dr KK Aggarwal CMD, Publisher and Group Editor-in-Chief Dr Veena Aggarwal Joint MD & Group Executive Editor Anand Gopal Bhatnagar Editorial Anchor

What’s New in Diabetes?

5

KK Aggarwal

AJD Speciality Panel Editor Dr Vijay Viswanathan Joint Editor Dr G Vijaya Kumar Associate Editors Dr V Mohan (Chennai) Dr PG Talwalkar (Mumbai) Assistant Editors Dr Shashank R Joshi (Mumbai) Dr Manisha Talim (Mumbai) Dr Deven V Parmar (Mumbai) Regional Co-ordinators Dr AK Das (South) Dr D Maji (East) Dr PG Raman (Central) Editorial Advisors Dr JK Agrawal (Varanasi) Dr HB Chandalia (Mumbai) Dr DK Hazra (Agra) Dr SD Mehtalia (Mumbai) Dr CV Krishnaswamy (Chennai) Dr C Moonichoodappa (Bangalore) Dr Sam GP Moses (Chennai) Dr KD Nihalani (Mumbai) Dr Sharad Pendsey (Nagpur) Dr BS Raheja (Mumbai) Dr D Rama Rao (Bangalore) Dr BK Sahay (Hyderabad) Dr BB Tripathy (Cuttack)

Dr V Seshiah Mrs. Rupa Assar (Mumbai) Dr JS Ajmera (Mumbai) Dr Prabha Arora (Delhi) Dr Anil Bhoraskar (Mumbai) Dr Archana Bhate (Mumbai) Dr Arun Bal (Mumbai) Dr Jayshree Barua (Mumbai) Dr SM Munirathnum Chetty (Coimbatore) Dr Siddharth Das (Cuttack) Dr Sanjay Gupta (Nagpur) Dr Sunil Gupta (Nagpur) Dr Avi Hakim (Mumbai) Dr Aspi Irani (Mumbai) Dr Lily John (Bangalore) Dr K Kannan (Madurai) Dr KM Prasanna Kumar (Bangalore) Dr Sandhya Kamath (Mumbai) Dr PSN Menon (Delhi) Dr Anant Nigam (Jaipur) Dr HS Patel (Jabalpur) Dr RB Phatak (Mumbai) Dr SK Rajan (Chennai) Dr Shrenik V Shah (Mumbai) Dr SR Sathe (Mumbai) Dr CB Sridhar (Bangalore) Dr BT Shah (Mumbai) Dr Bharat B Trivedi (Ahmedabad) Dr CS Yajnik (Pune)

FROM THE ISSUE EDITOR

Vijay Viswanathan, G vijaya Kumar

6

Research Article

Role of α-glucosidase Inhibitors in the Management of Postprandial Hyperglycemia

9

Vijay Viswanathan

IJCP Editorial Board Dr Alka Kriplani, Asian Journal of Obs & Gynae Practice Dr VP Sood, Asian Journal of Ear, Nose and Throat Dr Praveen Chandra, Asian Journal of Clinical Cardiology

review Article

Dr Swati Y Bhave, Asian Journal of Paediatric Practice Dr Vijay Viswanathan, The Asian Journal of Diabetology Dr KMK Masthan, Indian Journal of Multidisciplinary Dentistry Dr M Paul Anand, Dr SK Parashar, Cardiology Dr CR Anand Moses, Dr Sidhartha Das, Dr Ramachandran, Dr Samith A Shetty, Diabetology Dr Ajay Kumar, Gastroenterology Dr Koushik Lahiri, Dermatology

Vascular Changes Seen in Postprandial Hyperglycemia

14

Vijay Viswanathan, Dhivya Muthukumar

Dr Georgi Abraham, Nephrology Dr Sidharth Kumar Das, Rheumatology Dr V Nagarajan, Neurology Dr Thankam Verma, Dr Kamala Selvaraj, Obs and Gyne

Advisory Body Heart Care Foundation of India Non-Resident Indians Chamber of Commerce & Industry World Fellowship of Religions

Pathogenesis of Postprandial Hyperglycemia Neeta R Deshpande

19

The Asian Journal of

Diabetology

Volume 13, Number 1

Contents

Published, Printed and Edited by Dr KK Aggarwal, on behalf of IJCP Publications Pvt. Ltd. and Published at E - 219, Greater Kailash, Part - 1, New Delhi - 110 048 E-mail: editorial@ijcp.com

review Article

Printed at IG Printers Pvt. Ltd., New Delhi E-mail: igprinter@rediffmail.com, printer_ig@yahoo.com Š Copyright 2011 IJCP Publications Pvt. Ltd. All rights reserved.

The copyright for all the editorial material contained in this journal, in the form of layout, content including images and design, is held by IJCP Publications Pvt. Ltd. No part of this publication may be published in any form whatsoever without the prior written permission of the publisher.

Postprandial Hyperglycemia, Implications and Control

23

SR Aravind

The Use of GLP-1 Agonists in the Treatment

Editorial Policies The purpose of IJCP Academy of CME is to serve the medical profession and provide print continuing medical education as a part of their social commitment. The information and opinions presented in IJCP group publications reflect the views of the authors, not those of the journal, unless so stated. Advertising is accepted only if judged to be in harmony with the purpose of the journal; however, IJCP group reserves the right to reject any advertising at its sole discretion. Neither acceptance nor rejection constitutes an endorsement by IJCP group of a particular policy, product or procedure. We believe that readers need to be aware of any affiliation or financial relationship (employment, consultancies, stock ownership, honoraria, etc.) between an author and any organization or entity that has a direct financial interest in the subject matter or materials the author is writing about. We inform the reader of any pertinent relationships disclosed. A disclosure statement, where appropriate, is published at the end of the relevant article.

Note: The Asian Journal of Diabetology does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature in this issue.

of Postprandial Hyperglycemia

28

MC Deepak

Emedinews Section

From eMedinewS

38

Editorial & Business Offices Delhi

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From the Desk of Group editor-In-chief

What’s New in Diabetes?

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

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The ACCORD trial evaluated intensive or standard glycemic control in patients with long-standing diabetes.1 There was no difference in the number of patients experiencing the two composite microvascular outcomes. However, there was a significant decrease in the incidence of microalbuminuria in the intensive therapy group.

In a substudy, ACCORD Eye study, the effect of intensive glycemic, blood pressure, and lipid control on progression Dr KK Aggarwal of diabetic retinopathy was evaluated in a subset of 2856 Padma Shri and Dr BC Roy National Awardee 2 adults. After four years, there was a reduction in the Sr Physician and Cardiologist, Moolchand Medcity proportion of patients with progression of retinopathy in President, Heart Care Foundation of India the intensive glycemic therapy group and the fenofibrate Group Editor-in-Chief, IJCP Group Editor-in-Chief, eMedinewS group, but not in the intensive blood pressure control Chairman Ethical Committee, Delhi Medical group.

Council The European Medicines Agency suspended sales of Director, IMA AKN Sinha Institute (08-09) rosiglitazone.3 At the same time, the US FDA restricted Hony. Finance Secretary, IMA (07-08) its use to patients with type 2 diabetes who cannot Chairman, IMA AMS (06-07) President, Delhi Medical Association (05-06) achieve adequate glycemic control with other medications, emedinews@gmail.com including pioglitazone.4 http://twitter.com/DrKKAggarwal Two studies using the UKGPRD show conflicting results Krishan Kumar Aggarwal (Facebook) regarding the association between bisphosphonate use and esophageal cancer.5,6 Further research is required to confirm or refute the potential association, particularly the association between esophageal cancer and different types and formulations of bisphosphonates.

In a 2010 report from an international Task Force appointed by the American Society of Bone and Mineral Research, the incidence of atypical fractures associated with bisphosphonate use was acknowledged to be very low.7,8 The group recommended that physicians and patients be educated about the possible association between atypical femur fractures and long-term (>5 years) bisphosphonate use.

Meta-analyses report conflicting results regarding the effect of calcium supplementation on risk of cardiovascular disease, with one reporting an increased risk and another no effect.8,9

References 1. Ismail-Beigi F, Craven T, Banerji MA, et al. Lancet 2010;376:419-30.

2. Chew EY, Ambrosius WT, Davis MD, et al. N Engl J Med 2010;363:233-44.

3. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2010/09/news_detail_001119. jsp&murl=menus/news_and_events/news_and_events.jsp&mid=WC0b01ac058004d5c1&jsenabled=true (Accessed on September 24, 2010).

4. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm226976.htm (Accessed on September 24, 2010).

5. Cardwell CR, Abnet CC, Cantwell MM, Murray LJ. JAMA 2010;304:657-63.

6. Green J, Czanner G, Reeves G, et al. BMJ 2010;341:c4444.

7. Shane E, Burr D, Ebeling PR, et al. J Bone Miner Res 2010;25(11):2267-94.

8. Bolland MJ, Avenell A, Baron JA, et al. BMJ 2010;341:c3691.

9. Wang L, Manson JE, Song Y, Sesso HD. Ann Intern Med 2010;152:315-23.

n Asian Journal of Diabetology, Vol. 13, No. 1

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FROM THE ISSUE EDITOR

Editor

Joint Editor

Dr Vijay Viswanathan

Dr G Vijaya Kumar

Managing Director MV Hospital for Diabetes & Diabetes Research Centre (WHO Collaborating Centre for Research, Education and Training in Diabetes), Chennai

Diabetologist Diabetes Medicare Centre Consultant in Diabetology Apollo Hospital, Chennai Hony. Consultant, Dept. of Diabetes VHS Medical Centre, Chennai

Dear Colleague,

The target of a diabetic patient, in simple words can be defined as maintaining A1C<7%. However, the target is incomplete unless the premeal and postmeal levels are maintained. Fasting hyperglycemia and postprandial hyperglycemia have their own effect on the system.

Postprandial hyperglycemia (PPH) is associated with greater macrovascular complications. Therefore, the need to control it is mandatory. This edition comes as a ‘Postprandial hyperglycemia’ special, where its pathogenesis, effects and management are discussed in detail. The application of newer agents such as glucagon-like peptide-1 (GLP-1) agonist in reducing PPH is detailed. The vascular injury due to PPH and its consequences leading to complication needs a mention to stress the importance of controlling it.

Administering antihyperglycemic agents with regard to the timing of meal greatly influence the PPG levels. Every patient must be told about the importance of this condition before they leave the physician’s office. n

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Asian Journal of Diabetology, Vol. 13, No. 1

Dr KMK Masthan IJCP Publications Pvt. Ltd. E - 219, Greater Kailash, Part - 1, New Delhi - 110 048 Tel.: 40587513 E-mail: editorial@ijcp.com, emedinews@gmail.com, drveena@ijcp.com Subscription Office: Flat 5E, Merin Estate, Geetanjali, 25/8 diamond Harbour Road, Kolkata - 700 008 Mob.: 9831363901, E-mail: subscribe@ijcp.com, Website: www.ijcpgroup.com

Research Article

Role of α-glucosidase Inhibitors in the Management of Postprandial Hyperglycemia Vijay Viswanathan

Abstract Type 2 diabetes mellitus (T2DM) is a common metabolic disorder characterized by hyperglycemia due to defects in both insulin secretion and insulin resistance. The management of T2DM entails the attenuation of hyperglycemia and therefore its associated complications. However, treatment of T2DM - whether by diet alone or with additional monotherapy with sulfonylurea or metformin - frequently cannot induce or maintain normal plasma glucose levels in face of progressive β-cell failure and are also associated with serious adverse effects. Competitive α-glucosidase enzyme inhibitors, such as miglitol diminish postprandial blood glucose (PPG) excursions despite decrease in insulin levels, thereby offering an alternative therapeutic approach to improving blood glucose control while preserving β-cell function.

Key words: Type 2 diabetes mellitus, postprandial hyperglycemia, miglitol

M

etabolic diseases such as hypertension, diabetes, atherosclerosis, thrombosis and stroke are making galloping strides in terms of morbidity and mortality especially in context of South Asian countries including India. India has the dubious distinction of being labeled as ‘Twin Capital’ for hypertension and diabetes despite the tremendous advances made in their management. The need of the hour therefore is to create increased awareness on early diagnosis and better management of these risk factors including Type 2 diabetes mellitus (T2DM). This is absolutely pertinent since it is projected that cases of diabetes in India will increase from 31.7 millions in 2000 to 79.4 millions in 2030.1 To complicate the matter further, the progressive nature of the disease with insulin resistance and declining insulin levels often leads to elevated plasma glucose levels along with pancreatic β-cell fatigue, as shown in Figure 1.

Postprandial Hyperglycemia and α-glucosidase Inhibitors Postprandial hyperglycemia has been associated independently with increased risk of microvascular and macrovascular complications. The Honolulu Heart Study demonstrated an increased risk of fatal coronary heart disease events alone and in combination with

Managing Director MV Hospital for Diabetes and Research Centre Chennai, Tamil Nadu

Asian Journal of Diabetology, Vol. 13, No. 1

Obesity

Diabetes

Uncontrolled hyperglycemia

Postmeal glucose

Plasma glucose 120 (mg/dl) Relative b-cell function

IGT*

Fasting glucose Insulin resistance

100 (%)

Progressive reduction in b-cell mass

-20 -10 0 10 20 Years of diabetes

Insulin level 30

Figure 1. Natural history of type 2 diabetes mellitus.

nonfatal myocardial infarction that was independently related to increased postchallenge glucose levels.2 Furthermore, the Diabetes Intervention Study demonstrated that postprandial blood glucose was an independent risk factor for mortality in patients with newly diagnosed T2DM, but fasting blood glucose (FBG) was not.3 The Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe/ASIA (DECODE/DECODA) study too demonstrated that blood sugar levels at two hours after glucose loading have a superior predictive value for cardiovascular morbidity and overall mortality comparing to fasting blood sugar levels.4,5 Several oral antihyperglycemic agents (OHAs) are available for managing T2DM; however, they differ in their ability to control postprandial glucose (PPG) or fasting plasma glucose (FPG), as well as their risk for hypoglycemia, weight gain, bone fracture and congestive heart failure6

research article Table 1. Summary of Glucose-lowering Interventions Intervention

Mechanism

Fasting and/or postprandial Weight (±) glucose reduction

Risk of hypoglycemia

Metformin

Decrease hepatic glucose output

Fasting > Postprandial

Neutral

N/A

Sulfonylureas

Enhance insulin secretion

Fasting and Postprandial

↑

+

Thiazolidinediones Increase muscle, fat and liver sensitivity to endogenous and exogenous insulin

Fasting > Postprandial

↑

N/A

GLP-1 receptor agonists

Potentiate glucose-stimulated insulin secretion

Postprandial > Fasting

↓

N/A

AGIs

Prevent conversion and absorption of carbohydrates, enhancing GLP-1 while decreasing GIP levels

Postprandial

Neutral

N/A

Glinides

Enhance insulin secretion

Postprandial > Fasting

↑

+

DPP-4 inhibitors

Enhance the effects of GLP-1 and GIP Increase glucose-mediated insulin secretion Suppress glucagon secretion

Postprandial > Fasting

Neutral

N/A

GLP-1: Glucagon-like peptide-1; AGIs: α-glucosidase inhibitors; GIP: Glucose-dependent insulinotropic polypeptide; DPP-4: Dipeptidyl peptidase-4; N/A: Not applicable.

as shown in Table 1. Treatment is often individualized for each patient with T2DM to achieve control of blood glucose and co-morbid conditions. However, it is well-documented that patients with glycosylated hemoglobin (A1C) in the lower range (<8.4%) tend to have postprandial hyperglycemia and should therefore be treated with pharmacotherapy designed to lower PPG. Conversely, patients with A1C in the higher range (>8.4%) tend to have fasting hyperglycemia and should be treated with pharmacotherapy designed to lower FPG.7 Secondly, the choice of the drug is also dependent on the safety and tolerability profile since the patients often have concomitant co-morbid conditions or risk factors.

Miglitol – Differentiated AGI Alpha-glucosidase inhibitors (AGIs) including acarbose, voglibose and miglitol are widely used in the treatment of patients with T2DM. They inhibit the conversion of oligosaccharides into monosaccharides at the intestinal brush border and thus lower postprandial blood glucose and insulin levels after ingestion of complex carbohydrates. The American Association of Clinical Endocrinologists (AACE) therefore recommends their use as monotherapy or in combination with metformin in patients with postprandial hyperglycemia and an A1C between 6.5% and 7.5%.

They are effective as monotherapy or in combination 10

with other antidiabetic agents, particularly if the diet contains at least 50% carbohydrate.8 The major side effects of AGIs are gastrointestinal (GI) and include abdominal discomfort, increased formation of intestinal gas and diarrhea. These adverse GI effects are due to excessive amounts of carbohydrate reaching the large intestine and undergoing bacterial fermentation. To complicate matters further, these AGIs including acarbose and voglibose are poorly absorbed from the GI tract.

Miglitol, on the other hand, is absorbed rapidly and completely from the small intestine when administered in doses less than 50 mg. This reduces flow of carbohydrate to colon leading to fewer side effects in the digestive system such as abdominal bloating and diarrhea.9,10 These pharmacokinetics enable consequent strong and early suppression of PPG since there is greater stimulus for glucagonlike peptide-1 (GLP-1) release compared to other AGIs11 as shown in Figure 2. Miglitol is the first pseudomonosaccharide AGI that has been found to give comparable glycemic control to sulfonylureas in T2DM of recent onset.12 Available literature shows that miglitol induces a larger decrease in HbA1C than voglibose.13 Similarly, it has been shown to activate secretion of GLP-1 and decrease gastric inhibitory polypeptide (GIP) to a greater extent as compared to voglibose10 as shown in Figure 3. This modulation of GLP-1 and GIP levels result in improvement of insulin Asian Journal of Diabetology, Vol. 13, No. 1

research article secreting function, preservation of pancreatic β-cell mass and appetite suppression. These effects were earlier shown

by Narita et al11 in a noncomparative study where miglitol was administered for two weeks in patients with T2DM. The results are shown in Figure 4.

Active GLP-1 (pmol/l)

14

Acarbose and voglibose: Not absorbed: #AGl efficacy is continued at lower portion of intestine

GIP

Glucose absorption at intestine

GLP-1

Miglitol: Absorbed in intestine; #AGl efficacy is decreased at lower portion of intestine #Greater amount of glucose absorption at lower intestine leading to higher GLP-1 secretion and reduced GI side effects

Figure 2. Differences in glucose absorption and secretion of incretins at lower portion of intestine among AGIs

N=9 mean ± SEM

+

4 2 0

30

10.0 8.0

**

6.0

*

** *p < 0.05 vs before miglitol **p < 0.01 vs before miglitol

4.0 0.0

0

30

60 120 Time (min)

60 40

250.0

90.0

10

60

Time (min)

120

180

before miglitol after miglitol

*

80.0

0

*p < 0.05 vs before miglitol **p < 0.01 vs before miglitol

**

* 30

60

Time (min)

120

180

Changes in Plasma Total GIP Responses after a Mixed Meal N=9 Two-factor (time x treatment) repeated mean ± SEM measures ANOVA: p = 0.0001 before miglitol after miglitol

70.0 60.0 50.0 40.0

**

30.0

0.0

**

*

*p < 0.05 vs before miglitol **p < 0.01 vs before miglitol

10.0

30

120

N=9 mean ± SEM

20.0

0

90

Changes in Plasma Glucose Insulin Responses after a Mixed Meal Two-factor (time x treatment) repeated measures ANOVA: p = 0.0004

100.0

0.0

*

60 Time (min)

150.0

N=9 mean ± SEM

*

30

200.0

180

before miglitol after miglitol

**

+ 0

++

† ++

p< 0.05 vs voglibose

GIP (pmoI/l)

20

†

+

Changes in Plasma Active Forms of GLP-1 Responses after a Mixed Meal Two-factor (time x treatment) repeated measures ANOVA: p = 0.0033 *p < 0.05 vs before miglitol **p < 0.01 vs before miglitol

120

80

50.0

Two-factor (time x treatment) repeated measures ANOVA: p < 0.0001

2.0

90

Figure 3. Effect of miglitol and voglibose on GLP-1 and GIP levels.

before miglitol after miglitol

12.0

0

60 Time (min)

0

IRI (pmol/l)

14.0 Plasma glucose (mmol/l)

6

20

Changes in Plasma Glucose Responses after a Mixed Meal

16.0

†

+

100 Total GIP (pmol/l)

Miglitol

Active GLP-1 (pmol/l)

8

120 Colon

Stomach

30

10

0

Acarbose Voglibose

40

Miglitol Voglibose Placebo

12

0

30

60

Time (min)

120

180

Figure 4. Effect of two weeks therapy with miglitol on GLP-1 and GIP levels.

Asian Journal of Diabetology, Vol. 13, No. 1

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research article The results showed significant increase in GLP-1 levels while decreasing GIP and insulin. These responses were observed within 0.5-1.5 hours after meals. The authors concluded that miglitol would be a useful agent in treating or preventing progressive β-cell dysfunction, obesity and insulin resistance.11 AGIs and Cardiovascular Disease Risk T2DM is a strong risk factor for coronary artery disease (CAD). Similarly, postprandial hyperglycemia has been often associated with endothelial dysfunction, increased free radical generation, increase in free fatty acids, triglycerides and remnant lipoproteins with increased risk of coagulation. All these factors contribute to the risk and pathogenesis of micro- and macrovascular complications including cardiovascular disease (CVD).

AGIs have been shown to have beneficial and protective effects against atherosclerosis. In the Study to Prevent Non-Insulin Dependent Diabetes Mellitus (STOP-NIDDM), administration of acarbose reduced the incidence of diabetes and the risk of developing cardiovascular events in patients with impaired glucose tolerance.14,15 These results suggest the possibility that AGIs might exert suppressive effects on CVD by favorably affecting endothelial dysfunction observed due to fluctuating PPG levels.

This was further suggested in a preclinical setting where administration of miglitol was demonstrated to suppress the progression of atherosclerosis associated with controlling fluctuations of blood sugar levels.16 Similarly, in a randomized, double-blind, placebocontrolled, crossover study, miglitol administration successfully modulated vascular endothelial dysfunction in patients with history of CAD.11 AGIs in Combination Therapy The normalization of PPG peaks in clinical practice is recognized as more problematic than the overall management of FPG levels. In patients with an A1C <8.4%, since postprandial hyperglycemia is the predominant abnormality, combination therapy targeting PPG is usually advocated.7 Miglitol in combination with metformin offers an advantage in achieving the important goal of PPG 12

management in these cases. Unlike the other OHAs such as sulfonylureas or dipeptidyl peptidase-4 (DPP4) inhibitors, the combination offers overall glycemic control without the pertinent issues of hypoglycemia, or insulin rise and therefore pancreatic β-cell fatigue. Two studies conducted on this combination by Chaisson et al17 and Van Gaal et al18 showed that significantly greater reductions in HbA1C and PPG levels were obtained than metformin alone, with a good safety profile.

Summary AGIs, including miglitol have been shown to lower PPG peaks without the deleterious rise in insulin levels since they modulate favorably GLP-1 and GIP levels thereby contributing to pancreatic β-cell preservation. Miglitol administration has also been shown to successfully modulate vascular endothelial dysfunction in patients with history of CAD along with improvement in lipid parameters thereby contributing to its ancillary actions.

Postprandial hyperglycemia is well-documented to be an important risk factor for microvascular and macrovascular complications including CVD. Since patients with A1C in the lower range (<8.4%) tend to have postprandial hyperglycemia, pharmacotherapy designed to lower PPG including Miglitol would be useful as initial-line therapy either as monotherapy or in combination especially for those patients in whom carbohydrates is the predominant diet.

References 1. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27(5):1047-53.

2. Donahue RP, Abbott RD, Reed DM, Yano K. Postchallenge glucose concentration and coronary heart disease in men of Japanese ancestry. Honolulu Heart Program. Diabetes 1987;36(6):689-92.

3. Coutinho M, Gerstein HC, Wang Y, Yusuf S. The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care 1999;22(2):233-40.

4. DECODE Study Group, the European Diabetes Epidemiology Group. Glucose tolerance and cardiovascular mortality: comparison of fasting and 2hour diagnostic criteria. Arch Intern Med 2001;161(3): 397-405.

Asian Journal of Diabetology, Vol. 13, No. 1

research article 5. Nakagami T, Qiao Q, Tuomilehto J, Balkau B, Tajima N, Hu G, et al. Screen-detected diabetes, hypertension and hypercholesterolemia as predictors of cardiovascular mortality in five populations of Asian origin: the DECODA study. Eur J Cardiovasc Prev Rehabil 2006;13(4):555-61.

6. Blevins T. Therapeutic options that provide glycemic control and weight loss for patients with type 2 diabetes.

Postgrad Med 2010;122(1):172-83.

7. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c).

Diabetes Care 2003;26(3):881-5.

8. Rodbard HW, Jellinger PS, Davidson JA, Einhorn D, Garber AJ, Grunberger G, et al. Statement by an American College of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes: an algorithm for glycemic control. Endocr Pract 2009;15(6):540-59.

9. Arakawa M, Ebato C, Mita T, Fujitani Y, Shimizu T, Watada H, et al. Miglitol suppresses the postprandial increase in interleukin 6 and enhances active glucagonlike peptide 1 secretion in viscerally obese subjects.

Metabolism 2008;57(9):1299-306.

10. Hiki M, Shimada K, Kiyanagi T, Fukao K, Hirose K, Ohsaka H, et al. Single administration of alphaglucosidase inhibitors on endothelial function and incretin secretion in diabetic patients with coronary artery disease - Juntendo University trial: effects of miglitol on endothelial vascular reactivity in type 2 diabetic patients with coronary heart disease (J-MACH).

Circ J 2010;74(7):1471-8.

11. Narita T, Katsuura Y, Sato T, Hosoba M, Fujita H, Morii T, et al. Miglitol induces prolonged and enhanced glucagon-like peptide-1 and reduced gastric inhibitory

polypeptide responses after ingestion of a mixed meal in Japanese Type 2 diabetic patients. Diabet Med 2009;26(2):187-8.

12. Segal P, Feig PU, Schernthaner G, Ratzmann KP, Rybka J, Petzinna D, et al. The efficacy and safety of miglitol therapy compared with glibenclamide in patients with type 2 diabetes inadequately controlled by diet alone. Diabetes Care 1997;20(5):687-91.

13. van de Laar FA, Lucassen PL, Akkermans RP, van de Lisdonk EH, Rutten GE, van Weel C. Alpha-glucosidase inhibitors for patients with type 2 diabetes: results from a Cochrane systematic review and meta-analysis.

Diabetes Care 2005;28(1):154-63.

14. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trail Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002;359(9323):2072-7.

15. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trial Research Group. Acarbose treatment and the risk of CVD and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA 2003;290(4):486-94.

16. Mita T, Otsuka A, Azuma K, Uchida T, Ogihara T, Fujitani Y, et al. Swings in blood glucose levels accelerate atherogenesis in apolipoprotein E-deficient mice.

Biochem Biophys Res Commun 2007;358(3):679-85.

17. Chiasson JL, Naditch L; Miglitol Canadian University Investigator Group. The synergistic effect of miglitol plus metformin combination therapy in the treatment of type 2 diabetes. Diabetes Care 2001;24(6):989-94.

18. Van Gaal L, Maislos M, Schernthaner G, Rybka J, Segal P. Miglitol combined with metformin improves glycaemic control in type 2 diabetes. Diabetes Obes Metab 2001;3(5):326-31.

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Review Article

Vascular Changes Seen in Postprandial Hyperglycemia Vijay Viswanathan*, Dhivya Muthukumar**

Abstract Transient increases in blood glucose levels represent an additional and independent risk for endothelial dysfunction, an important fact for the development of diabetic vascular complications. Substantial evidence has accumulated indicating that chronic hyperglycemia is a risk factor for micro- and macrovascular complications of diabetes.

Key words: Hyperglycemia, endothelial dysfunction, vascular complications

T

here is now a global epidemic of diabetes and obesity affecting more than 300 million people worldwide with Asia in the forefront.1 Diabetes is associated with approximately two-fold increased mortality in most populations, with the risks decreasing with increasing age.

Diabetic hyperglycemia is the result of an increase in daily glycemic profiles as compared with that observed in persons with normal carbohydrate metabolism. Transient increases in blood glucose levels represent an additional and independent risk for endothelial dysfunction, an important fact for the development of diabetic vascular complications. Hyperglycemia is a major risk factor for both the micro- and macrovascular complications in patients with type 2 diabetes.

Hyperglycemia and CVD Cardiovascular disease (CVD) is 76% more prevalent in subjects with diabetes. In people with type 2 diabetes, macrovascular disease, in particular CVD is the major source of morbidity and mortality. Acute hyperglycemia is linked to endothelial dysfunction.

*Managing Director **Research Associate MV Hospital for Diabetes and Prof. M. Viswanathan Diabetes Research Centre, [WHO Collaborating Centre for Research Education and Training in Diabetes], Chennai No.4, West Mada Church Street, Royapuram Chennai - 600013, Tamil Nadu Address for correspondence Dr Vijay Viswanathan Managing Director No. 4, West Mada Church Street, Royapuram Chennai - 600 013, Tamil Nadu E-mail: drvijay@mvdiabetes.com

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Epidemiological data suggest a strong link between cardiovascular (CV) risk and glucose control. Recent evidence strongly suggests that control of postprandial hyperglycemia reduces the risk of CVD. Considerable data have accumulated over the past five years, which indicate that elevated postprandial plasma glucose (PPG) levels in the nondiabetic range increases the risk for CVD. Fasting vs Postprandial Hyperglycemia and CV Risk Postprandial hyperglycemia contributes to increased CV risk. PPG levels are more strongly associated with all-cause mortality and CV risks than fasting glucose values.2 The UK Prospective Diabetes Study (UKPDS) showed that lowering of fasting plasma glucose (FPG) levels was associated with significant reductions in microvascular complications. However, such interventions were less effective in reducing the risk of macrovascular complications. In contrast, population studies showed that postprandial hyperglycemia was a risk factor for CV and all-cause mortality in different ethnic groups.2-6 Numerous epidemiological studies have demonstrated a correlation between risk for CVD and plasma glucose levels (both fasting and postprandial) or HbA1C values.7 The relationship between PPG and CV events persists even in the context of HbA1C levels in the nondiabetic range.7,8 Pathogenesis of CVD The pathogenesis of CVD is complex and multifactorial.

Smoking, obesity, dyslipidemia and hypertension were Asian Journal of Diabetology, Vol. 13, No. 1

Review Article considered the major ‘traditional’ risk factors. Now diabetes itself is considered an important independent risk factor.9 Diabetes increases the risk for CVD mortality more than two-fold.10 Mechanisms for Adverse Cardiovascular Effects of Hyperglycemia

Postprandial fluctuations, in addition to absolute increases in glycemia, contribute to oxidative stress and endothelial dysfunction.11-13 Generation of free radicals by hyperglycemia may promote atherogenesis: 



Through peroxidation of low-density lipoprotein (LDL) leading to a more atherogenic molecule By oxidation of fibrinogen leading to products that enhance coagulation



By increasing platelet activation by collagen



By decreasing production of nitric oxide (NO)

Several underlying mechanisms have been proposed to be involved in hyperglycemia-induced vascular damage. These include activation of protein kinase C (PKC) signaling pathway, oxidative stress and glycosylation of protein. Glucotoxicity plays a key part in the development of generalized vascular dysfunction leading to retinopathy, albuminuria and accelerated atherosclerosis.

Hyperglycemia-induced Mechanisms Endothelium-derived NO causes vasodilation and also inhibits platelet aggregation and adhesion of inflammatory cells to endothelium.14 It has been shown that endothelium-dependent vasodilation is reduced in healthy volunteers after six hours of a hyperglycemic clamp.15 A similar impairment in endothelium-dependent vasodilation is seen in healthy individuals after oral glucose intake.16 Many of the above processes are thought to be mediated to a large extent by activation of PKC and generation of diacylglycerol (DAG). Hyperglycemia itself may directly increase PKC and DAG, since tissues incubated with high glucose concentrations have increased levels of DAG and PKC. Activation of PKC and increased DAG promotes expression, formation and enhanced activity of transforming growth factor B, type IV collagen, fibronectin, vascular endothelial growth factor, endothelin-1, caldesmon, Asian Journal of Diabetology, Vol. 13, No. 1

plasminogen-activator inhibitor-1, phospholipase A2, prostaglandin-E2 and intercellular adhesion molecules.

These have been identified to play a role in basement membrane thickness, extracellular matrix formation, angiogenesis, increased vascular permeability, smooth muscle cell proliferation, increased inflammatory cell adhesion and decreased fibrinolysis.17 Hyperglycemia-induced CV Damage After acute hyperglycemia endothelial dysfunction is affected via the vascular glycocalyx (an extracellular matrix of endothelial cell-derived proteoglycans, glycoproteins and absorbed plasma proteins that act as a mechanosensor/mechanotransducer of blood flow and vascular shear stress) in a predominantly NOdependent manner that promotes endothelial response to stimuli.18-20 Nieuwdorp et al20 utilized several techniques (e.g., hyperglycemic clamp, flow-mediated dilation, glycocalyx tracers and laboratory analytical tests) to assess endothelial function and coagulation parameters after hyperglycemic challenge in 10 healthy males. After glucose infusion, glycocalyx volume was decreased, mechanotransduction of flowdependent arterial dilation was attenuated and levels of prothrombin activation fragment F1 + 2, a factor that initiates coagulation cascades, were increased during hyperglycemia. Oxidative stress caused by acute PPG spikes can contribute to macrovascular damage through oxidation of LDL, exacerbation of endothelial dysfunction and other proatherogenic mechanisms.

Hyperglycemia and Oxidative Stress Oxidative stress is the imbalance between the production of oxidative products and antioxidant defenses. Highly reactive and oxidative substances derived from oxygen are termed reactive oxygen species (ROS). In the presence of an excess production of ROS, oxidative stress is related with the progression or development of atherosclerosis.

Free Radicals and Oxidative Stress Oxidative damage modifies the structure and function of proteins through a process associated to nonenzymatic glycation. Oxidative stress can neutralize the vasodilator effect of NO produced by endothelial 15

Review Article cells. This gas, is a free radical, it rapidly reacts with superoxide radical to produce peroxynitrite anion (ONOO-). ONOO- anion reacts with tyrosine residues from proteins producing nitrated compounds. This mechanism is seen in the early stages of vascular damage-related with increased adhesion of monocytes to vascular endothelium and their transendothelial migration produced by ROS.

reduced risk for type 2 diabetes and heart disease. The most recent and notable example of the advantages of weight loss, conferred by increased physical activity and low-calorie/low-fat diets,26 are results from the 10-year follow-up of the Diabetes Prevention Program (DPP) Outcomes Study.

Overload of Mitochondrial Metabolism

Obesity, superimposed on a genetic β-cell defect, is the main cause for the increased prevalence of type 2 diabetes.27 Bariatric surgery has dramatic effects on glycemic control which in turn reduces the comorbidities like type 2 diabetes, coronary artery disease (CAD), hypertension and sleep apnea in morbidly obese patients.

Glucotoxicity is mediated by oxidative stress generated at mitochondrial level.21-23 Superoxide radical (O2) is produced as a result of oxidative processes in the electron transport chain (ETC). Overproduction of O2 is responsible for the integrative processes that explain most hyperglycemic harmful effects on micro- and macrovasculature.

Early Glycation, Autoxidation and Carbonylic Stress One of the main pathophysiological consequences of hyperglycemia is the increased interaction of glucose with proteins. This process - ‘nonenzymatic glycation’takes place without the participation of enzymes and has different stages. Protein glycation is a complex and important pathophysiological process since it modifies the structure, function and biological activity of proteins. According to the kinetics of this nonenzymatic glycation process, the formation of early glycation end products and the development of oxidative stress are more relevant during postprandial hyperglycemia.

Management of Postprandial Hyperglycemia-induced CVD General Considerations

Fasting and PPG concentrations, although due to different pathologic mechanisms, are interrelated.

Manuvers that primarily target postprandial hyperglycemia might fail to achieve satisfactory HbA1C levels if fasting hyperglycemia persists. PPG control is the rate-limiting steep when optimizing blood glucose levels, as demonstrated in a study by Woerle at al.24 Nonpharmacologic Interventions A meta-analysis by Barclay et al25 indicated that low glycemic index and glycemic load diets results in 16

Surgical Interventions

Pharmacologic Interventions Pharmacological agents that specifically target PPG include α-glucosidase inhibitors, glinides (rapidacting, insulin secretagogues) and insulin. New classes of therapies (glucagon-like peptide-1 [GLP-1] derivatives, dipeptidyl peptidase-4 [DPP-4] inhibitors) which address deficiencies in pancreatic and gut hormones also have beneficial effects on controlling postprandial hyperglycemia. GLP-1 and DPP-4 are incretin based therapies. The incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), are released from the small intestine during absorption of meals and increase pancreatic secretion of insulin.28 GLP-1, but not GIP, suppresses glucagon release from pancreatic β-cells. In type 2 diabetes, incretin hormone function is impaired, resulting in less insulin release and more glucagon secretion after meals. More glucose enters circulation, there is decreased glucose removal, higher plasma glucose levels and hence, acute oxidative stress.

Disease-related complications associated with oxidative stress may be reduced with agents that target postprandial hyperglycemia. The new nonsulfonylurea secretagogues (the meglitinides, repaglinide and nateglinide), the α-glucosidase inhibitors (acarbose and miglitol) and rapid-acting insulins specifically target postprandial hyperglycemia.29,30 Randomized controlled trials with agents that primarily target postprandial hyperglycemia have demonstrated CV benefit. The Study to Prevent Non-Insulin Dependent Asian Journal of Diabetology, Vol. 13, No. 1

Review Article Diabetes Mellitus (STOP-NIDDM) trial showed that treating postprandial hyperglycemia with acarbose in patients with impaired glucose tolerance reduced CV events.31 PPG levels in diabetes correlate with carotid intima-media thickness (CIMT), and treatment with antihyperglycemia agents such as nateglinide and acarbose-which target postprandial glycemia-reduces progression of CIMT.

7. Gerich JE. Clinical significance, pathogenesis, and management of postprandial hyperglycemia. Arch Intern Med 2003;163(11):1306-16.

Conclusion

9. Malmberg K, Ryden L, Wedel H. Birkeland K, Bootsma A, Dickstein K, et al; DIGAMI 2 Investigators.

Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J 2005;26(7):650-61.

Substantial evidence has accumulated indicating that chronic hyperglycemia is a risk factor for micro and macrovascular complications of diabetes.

Observational studies indicate that isolated postprandial hyperglycemia increases CV mortality. Controlling and achieving target goals early in the course of diabetes has been shown to provide better outcomes in terms of CV risk. Target levels of glucose control should be individualized by focusing on both FPG and PPG and by optimizing other risk factors of CVD, including high blood pressure, hyperlipidemia, obesity, smoking and poor exercise and dietary habits.

References 1. Tong P. Post-prandial hyperglycemia and cardiovascular disease: an Endocrinologistâ&#x20AC;&#x2122;s perspective. Med Bull 2010;15(6):12-3.

2. Hanefeld M, Fischer S, Julius U, Schulze J, Schwanebeck U, Schmechel H, et al. Risk factors for myocardial infarction and death in newly detected NIDDM: the Diabetes Intervention Study, 11-year follow-up. Diabetologia 1996;39(12):1577-83.

3. Shaw JE, Hodge AM, de Courten M, Chitson P, Zimmet PZ. Isolated post-challenge hyperglycaemia confirmed as a risk factor for motility. Diabetologia 1999;42(9):1050-4.

4. Barrett-Connor E, Ferrara A. Isolated postchallenge hyperglycemia and the risk of fatal cardiovascular disease in older women and men. The Rancho Bernado Study.

Diabetes Care 1998;21(8):1236-9.

5. Tominaga M, Eguchi H, Manaka H, Igarashi K, Kato T, Sekikawa A. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. The Funagata Diabetes Study. Diabetes Care 1999;22(6):920-4.

6. Donahue RP, Abbott RD, Reed DM, Yano K. Postchallenge glucose concentration and coronary heart disease in men of Japanese ancestry. Honolulu Heart Program. Diabetes 1987;36(6):689-92.

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8. Cavalot F, Petrelli A, Traversa M, Bonomo K, Fiora E, Conti M, et al. Postprandial blood glucose is a stronger predictor of cardiovascular events than fasting blood glucose in type 2 diabetes mellitus, particularly in women: lessons from the San Luigi Gonzaga Diabetes Study. J Clin Endocrinol Metab 2006;91(3):813-9.

10. Dale AC, Vatten LJ, Nilsen TI, Midthjell K, Wiseth R. Secular decline in mortality from coronary heart disease in adults with diabetes mellitus: cohort study. BMJ 2008;337:a236.

11. Beckman JA, Goldfine AB, Gordon MB, Creager MA. Ascorbate restores endothelium-dependent vasodilation impaired by acute hyperglycemia in humans. Circulation 2001;103(12):1618-23.

12. Monnier L, Colette C. Glycemic variability: should we and can we prevent it? Diabetes Care 2008;31(Suppl 2):S150-4.

13. Shimabukuro M, Higa N, Yamakawa K, Takasu N. Effects of a single administration of acarbose on postprandial glucose excursion and endothelial dysfunction in type 2 diabetic patients: a randomized crossover study. J Clin Endocrinol Metab 2006;91(3):837-42.

14. Vane JR, Anggard EE, Botting RM, Regulatory functions of the vascular endothelium. N Engl J Med 1990;323(1):27-36.

15. Williams SB, Goldfine AB, Timimi FK, Ting HH, Roddy MA, Simonson DC, et al. Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. Circulation 1998;97(17):1695-701.

16. Title LM, Cummings PM, Giddens K, Nassar BA. Oral glucose loading acutely attenuates endotheliumdependent vasodilation in healthy adults without diabetes: an effect prevented by vitamins C and E. J Am Coll Cardiol 2000;36(7):2185-91.

17. Meier M, King GL. Protein kinase C activation and its pharmacological inhibition in vascular disease. Vasc Med 2000;5(3):173-85.

18. Weinbaum S, Zhang X, Han Y, Vink H, Cowin SC. Mechanotransduction and flow across the endothelial glycocalyx. Proc Natl Acad Sci USA 2003;100(13): 7988-95.

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Review Article 19. Noble MI, Drake-Holland AJ, Vink H. Hypothesis: arterial glycocalyx dysfunction is the first step in the atherothrombotic process. QJM 2008;101(7):513-8.

20. Nieuwdorp M, van Haeften TW, Gouverneur MC, Mooij HL, van Lieshout MH, Levi M, et al. Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo. Diabetes 2006;55(2):480-6.

21. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001;414:813-20.

22. Robertson RP, Harmon J, Tran PO, Tanaka Y, Takahashi H. Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes 2003;52(3):581-7.

23. Krauss S, Zhang CH, Scorrano L, Dalgaard LT, St-Pierre J, Grey ST, et al. Superoxide-mediated activation of uncoupling protein 2 causes pancreatic beta cell dysfunction. J Clin Invest 2003;112(12):1831-42.

24. Woerle HJ, Neumann C, Zschau S, Tenner S, Irsigler A, Schirra J et al. Impact of fasting and postprandial glycemia on overall glycemic control in type 2 diabetes: importance of postprandial glycemia to achieve target HbA1c levels. Diabetes Res Clin Pract 2007;77(2):280-5.

25. Barclay AW, Petocz P, McMillan-Prince J, Food VM, Prvan T, Mitchell P, et al. Glycemic index, glycemic load, and chronic disease risk: a meta-analysis of observational studies. Am J Clin Nutr 2008;87(3):627-37.

26. Diabetes Prevention Program Research Group.

The Diabetes Prevention Program (DPP): description of lifestyle intervention. Diabetes Care 2002;25(12):2165-71.

27. Ramao I, Roth J. Genetic and environmental interactions in obesity and type 2 diabetes. J Am Diet Assoc 2008;108(4 Suppl 1):S24-8.

28. Drucker DJ, Nauck MA. The incretin system: glucagonlike peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006;368:1696-705.

29. Mooradian A, Thurman J. Drug therapy of postprandial hyperglycemia. Drugs 1999;57(1):19-29.

30. Lebovitz H. Insulin secretogogues old and new. Diabet Rev 1999;7:139-53.

31. Chiasson Jl, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trial Research Group.

Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial JAMA 2003;290:486-94.

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Asian Journal of Diabetology, Vol. 13, No. 1

Review Article

Pathogenesis of Postprandial Hyperglycemia Neeta R Deshpande

Abstract Sustained chronic hyperglycemia has two components - fasting and postprandial, both of which contribute to long-term complications in the form of glycation and oxidative stress. There is enough evidence to establish that PPH is a major contributor towards oxidative stress and the ensuing endothelial dysfunction. PPH contributes immensely to glycemic variability. Various mechanisms contribute to PPH. A thorough understanding of these mechanisms could then be therapeutic targets.

Key words: Oxidative stress, glycation, glycemic control

S

ustained chronic hyperglycemia has two components - fasting and postprandial, both of which contribute to long-term complications in the form of glycation and oxidative stress. Indeed, oxidative stress, inflammation and the subsequent endothelial dysfunction caused by acute excursions of glucose levels could well explain the link between postprandial hyperglycemia (PPH) and cardiovascular risk. Oxidant stress is directly proportional to the increase in glucose after a meal. These concepts are receiving wide acceptance as there is a growing body of literature demonstrating the immediate attenuation of oxidative stress and inflammation when postprandial glucose (PPG) and lipids are lowered. Most trials looking to reduce cardiovascular complications by intensive glycemic control have never really achieved this target, probably because only fasting sugar and glycosylated hemoglobin (HbA1C) have been the parameters in these ‘treat to target trials’. Glycemic excursions have not really received the requisite attention in these trials and could thus explain the mostly inconclusive or negative results.

Normal Disposal of Glucose Following intravenous administration of glucose, the insulin secretion is biphasic - an early phase

Consultant Diabetologist and Bariatric Physician, Belgaum Diabetes Centre Professor and Head, Maratha Mandal Institute for Dental Sciences, Belgaum Address for correspondence Neeta R Deshpande Belgaum Diabetes Centre and Weight Watch Weight Management Centre Maruti Galli, Belgaum - 590 001 E-mail: neetarohit@gmail.com, neetadeshpande@hotmail.com

Asian Journal of Diabetology, Vol. 13, No. 1

(or first phase) followed by a slow, prolonged phase.

The first phase of insulin secretion inhibits hepatic glucose production in the early part of the absorptive phase. The second phase promotes the peripheral uptake of glucose thereby reducing the glycemic excursions.1 Both these phases of insulin secretion are important for regulation of prandial glucose.

Relation of Postprandial Hyperglycemia to HbA1C There are three components to consider when evaluating glycemic control - fasting plasma glucose (FPG), PPG and HbA1C. Since, the value of HbA1C in a normal individual is about 6%, the excess of HbA1C above this value is contributed to by the excess glycemia in type 2 diabetes, both fasting and postprandial.2,3 Monnier has also shown that whatever the level of HbA1C, the contribution of PPG to it is 1%. This means that if all excursions were taken care of, we could reduce A1C by 1%.4 The UKPDS has proved the effect of reduction of 1% A1C on micro- and macrovascular complications.5 Pathogenetic Mechanisms of PPH β-cell Dysfunction

Failure of the β-cell to compensate for insulin resistance is the principal underlying defect leading to the development of impaired glucose tolerance (IGT) and eventually overt type 2 diabetes. In fact, it is wellknown that in type 2 diabetes, at least 50% of the β-cell secretory capacity is lost by the time a person 19

Review Article is detected to be diabetic. A calorie dense or high carbohydrate meal would therefore lead to PPH. Hepatic Insulin Resistance

Hepatic insulin resistance is the major contributor towards PPH. Failure of suppression of endogenous glucose production after a meal leads to the additional burden of glucose in the postprandial period. This is one of the earliest defects in type 2 diabetes and it is due to loss of the first phase of insulin secretion.

This accounts for PPH being the earliest abnormality to arise in type 2 diabetes.6,7 With time, the second phase is also impaired.

There is a possibility that the hepatic glucokinase is not sufficiently activated. Therefore, glucose uptake by the liver may be impaired. Consequently, glycogen synthesis is affected and is attenuated.

Incretin Defect

At least half of the insulin response after a meal is mediated by the incretins, the incretin effect. In type 2 diabetes, this incretin effect is significantly attenuated, leading to reduced secretion of the two gastrointestinal incretins namely GLP-1 (glucagon-like peptide-1) and GIP (gastric inhibitory polypeptide). This defect could very well be one of the early defects in the pathogenesis of type 2 diabetes.

Gastric Emptying Dysregulation

Recently, alterations in the rates of gastric emptying have been thought to be one of the factors contributing towards PPH.8 Earlier it was believed that this could result only as a late complication of diabetes. But some studies have shown that acute glycemic excursions could affect gastric motility.9 This could well be a compensatory attempt by the gastrointestinal tract to try and limit the glucose entering the circulation thereby reducing the acute glycemic excursion.

Under normal circumstances, food in the gut triggers neuronal and hormonal signals that try to regulate the rate of gastric emptying. When food reaches the small intestine, incretin hormone secretion is stimulated.

Both GLP-1 and GIP are secreted by the L and K cells. These then act via the vagus nerve and reduce antral motility, while increasing the activity at the pylorus. This effectively retards the gastric emptying.

Additionally, the incretin hormones stimulate the 20

release of human islet amyloid polypeptide (hIAPP), a substance that is co-secreted with insulin, which also has a similar effect, but through the central nervous system. Hyperglycemia could potentiate all these effects in an attempt to attenuate the glycemic excursions. In healthy individuals, insulin itself could partly regulate gastric emptying. Contrary to these mechanisms is the presence of nitric oxide in the gut, which results in relaxation of gastrointestinal smooth muscle. This facilitates gastric emptying. The balance between the incretin hormones, hIAPP and the nitric oxide would decide the ultimate rate of gastric emptying.

This balance is disturbed in type 2 diabetes. Woerle et al showed that in type 1 diabetes, the capacity to delay gastric emptying in response to hyperglycemia, is impaired.10 Secretion of hIAPP in type 2 diabetes may be impaired even before the insulin secretion is impaired.11 Insulin and GLP-1 levels are also impaired in diabetes.

Therefore, these abnormalities could explain PPH via the gastric motility pathway.

Pathogenesis of the Role of PPG in Cardiovascular Disease Two-thirds of the mortality in type 2 diabetes is accounted for by CVD. In diabetes, PPH is responsible for glycemic excursions. It is known that these excursions result in oxidative stress, which in turn has a major role to play in both micro- and macrovascular complications. Mean amplitude of glucose excursions (MAGE) correlates very well with markers of oxidative stress. Certain peptides that are prothrombotic and proinflammatory may be expressed excessively in diabetic patients with PPH.12 The Diabetes Intervention Study demonstrated that PPH was a better predictor of subsequent myocardial infarction and mortality than fasting hyperglycemia.13 This is probably due to the fact that acute excursions of glucose, as happens in the postprandial state, evoke more oxidative stress and subsequent production of superoxide molecules, leading to more glycation of proteins.14 Nitrotyrosine, a derivative of peroxynitrite which is a marker of oxidative stress, is increased in the fasting state in diabetic individuals. There is an additional rise of these levels in the postprandial phase that falls in response to rapid-acting insulin analogs.15 Asian Journal of Diabetology, Vol. 13, No. 1

Review Article The DECODE study showed that the 2-hour PPG excursions had a major role to play in pathogenesis of atherosclerosis and CVD and that PPG was a better predictor for all-cause mortality and cardiovascular death than was FPG.16 Apparently well-controlled type 2 diabetics as seen by HbA1C, still remain at high cardiovascular risk. This could be explained by the fact that HbA1C cannot record glycemic excursions and is only an average. Therefore, mere testing of HbA1C would not accurately predict cardiovascular risk as the glycemic excursions are not delineated with this test. A PPG test, then, would be required, in addition.

Postprandial dysmetabolism is associated with increased inflammation, endothelial dysfunction, decreased fibrinolysis, plaque instability and cardiac events.17 The risk of macrovascular disease attributable to PPH is present not only in established type 2 diabetes but also in IGT stage.18 In fact, the STOP-NIDDM trial, a prospective study, showed that reduction of postmeal glucose in IGT by means of pharmacotherapy could reduce macrovascular events.19 Optimal Time to Check PPG The usual recommendation of most guidelines is to measure PPG two hours after a meal. However, some studies show that perhaps 1.5 hours after the beginning of a meal may be more appropriate.

Moreover, there is some debate about which meal is to be considered. Theoretically, PPG after any meal should be acceptable. But studies show that PPG after breakfast is perhaps the best and most indicative since they correspond to the highest daytime sugars.

But postprandial sugars after lunch correspond best to HbA1C <7%.20 The best approach is perhaps to check after all meals at different time points since eating patterns are different and also because euglycemia over the entire 24 hours is an idealistic goal. Therapeutic strategies can then be individualized based on these different values.

Conclusion Excessive glycation and oxidative stress are the two major contributors towards diabetic complications, the latter being even more so for CVD. There is enough evidence to establish that PPH is a major contributor towards oxidative stress and the ensuing Asian Journal of Diabetology, Vol. 13, No. 1

endothelial dysfunction. PPH contributes immensely to glycemic variability. Therefore, HbA1C alone as an indicator of good glycemic control may be inadequate.

Various mechanisms contribute to PPH. A thorough understanding of these mechanisms could then be therapeutic targets.

References 1. Pfeifer MA, Halter JB, Porte D Jr. Insulin secretion in diabetes mellitus. Am J Med 1981;70(3):579-88.

2. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c).

Diabetes Care 2003;26(3):881-5.

3. Fowler GC, Vasudevan DA. Type 2 diabetes mellitus: managing hemoglobin A(1c) and beyond. South Med J 2010;103(9):911-6.

4. Monnier L, Colette C, Owens DR. Type 2 diabetes: a well-characterised but suboptimally controlled disease. Can we bridge the divide? Diabetes Metab 2008;34(3):207-16.

5. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321(7258):405-12.

6. Groop L. Pathogenesis of type 2 diabetes: the relative contribution of insulin resistance and impaired insulin secretion. Int J Clin Pract Suppl 2000;(113):3-13.

7. Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 1999;104(6):787-94.

8. Horowitz M, Oâ&#x20AC;&#x2122;Donovan D, Jones KL, Feinle C, Rayner CK, Samsom M. Gastric emptying in diabetes: clinical significance and treatment. Diabet Med 2002;19(3):177-94.

9. Fraser RJ, Horowitz M, Maddox AF, Harding PE, Chatterton BE, Dent J. Hyperglycaemia slows gastric emptying in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1990;33(11):675-80.

10. Woerle HJ, Albrecht M, Linke R, Zschau S, Neumann C, Nicolaus M, et al. Impaired hyperglycemia-induced delay in gastric emptying in patients with type 1 diabetes deficient for islet amyloid polypeptide. Diabetes Care 2008;31(12):2325-31.

11. Ludvik B. Amylin/IAPP (islet amyloid polypeptide): physiology and clinical significance. Wien Klin Wochenschr 1997;109(11):379-83.

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Review Article 12. Crandall JP, Shamoon H, Cohen HW, Reid M, Gajavelli S, Trandafirescu G, et al. Post-challenge hyperglycemia in older adults is associated with increased cardiovascular risk profile. J Clin Endocrinol Metab 2009;94(5):1595-601.

13. Hanefeld M, Fischer S, Julius U, Schulze J, Schwanebeck U, Schmechel H, et al. Risk factors for myocardial infarction and death in newly detected NIDDM: the Diabetes Interventional Study, 11-year follow-up.

Diabetologia 1996;39(12):1577-83.

14. Ceriello A. Postprandial hyperglycemia and diabetes complications: is it time to treat? Diabetes 2005;54(1):1-7.

15. Ceriello A, Quagliaro L, Catone B, Pascon R, Piazzola M, Bais B, et al. Role of hyperglycemia in nitrotyrosine postprandial generation. Diabetes Care 2002;25(8):1439-43.

16. DECODE Study Group, on behalf of the European Diabetes Epidemiology Group. Glucose tolerance and cardiovascular mortality: comparison of fasting

and 2-hour diagnostic criteria. Arch Intern Med 2001;161(3):397-405.

17. Bell DS, O’Keefe JH, Jellinger P. Postprandial dysmetabolism: the missing link between diabetes and cardiovascular events? Endocr Pract 2008;14(1):112-24.

18. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). U.K. Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352(9131):837-53.

19. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trial Research Group.

Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA 2003;290(4):486-94.

20. Monnier L, Colette C, Boniface H. Contribution of postprandial glucose to chronic hyperglycaemia: from the “glucose triad” to the trilogy of “sevens”. Diabetes Metab 2006;32 (Spec No. 2):2S11-6.

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Asian Journal of Diabetology, Vol. 13, No. 1

Review Article

Postprandial Hyperglycemia, Implications and Control SR Aravind

Abstract A growing body of evidence suggests that reducing postmeal plasma glucose excursions is as important, or perhaps more important for achieving HbA1C goals. If tight control has to be achieved, PPG control is mandatory. PPG excursions are linked to endothelial dysfunction and atherogenesis resulting in higher cardiovascular morbidity and mortality.

Key words: HbA1C, fasting plasma glucose, postmeal plasma glucose excursions

Glycemic Targets in Type 2 Diabetes For patients with type 2 diabetes mellitus (T2DM), the American Diabetes Association (ADA) recommends a target A1C level <7.0% and a fasting plasma glucose (FPG) level between 70 and 130 mg/dl.1 In clinical practice, the major focus of treatment has been on lowering glycosylated hemoglobin (HbA1C) levels, with a strong emphasis on FPG. Although control of FPG is necessary, it is often insufficient to obtain optimal glycemic control. A growing body of evidence suggests that reducing postmeal plasma glucose excursions is as important, or perhaps more important for achieving HbA1C goals. To address this issue, the International Diabetes Federation (IDF) has published a guideline that reviews the evidence on the harmful effects of elevated postmeal glucose and makes recommendations on treatment of postmeal glucose.2 Importance of Postprandial Glucose Because T2DM is often diagnosed based on FPG level and patientâ&#x20AC;&#x2122;s A1C at diagnosis is 8%-9% or higher, the initial focus of treatment is on FPG. Research has found that at A1C levels of <8.5%, PPG begins to become the major determinant of the A1C level. In fact, as the A1C level falls to <7.3%, it is estimated that Director, Diacon Hospital Course Director: Certificate course in Diabetology (RGUHS) Visiting Professor, Dept. of Medicine, PESIMSR, Kuppam Past Chairman, Scientific Committee, RSSDI - 2010 Past Chairman, KRSSDI, Vice President, Diabetes India Exe. Committee Member, RSSDI Patron, Diabetes Club, Bangalore E-mail: draravind@hotmail.com/diaconhospital@hotmail.com

Asian Journal of Diabetology, Vol. 13, No. 1

postprandial glucose (PPG) contributes approximately 70% to the magnitude of the A1C level.3 Even in the natural history of type 2 diabetes, PPG is affected initially due to defect in first phase insulin secretion following any glucose challenge. FPG is affected late in the course of pathophysiology when the insulin secretion is considerably low.4 A meta-analysis of the Whitehall, Paris Prospective and Helsinki Policemen studies,5 the Chicago Heart Association Detection Project in Industry Study6 and the Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe (DECODE) study7 all provide evidence for emerging potential correlation of PPG excursions with increased cardiovascular disease (CVD) mortality.7 The mechanism whereby elevated PPG exerts its effects on atherogenesis is still evolving, but it may be through a negative impact on endothelial function.8,9 PPG peaks have been directly associated with increased intima-media thickness, with a reduced endothelial-dependent flow mediated dilation indicating a decrease in nitric oxide production in type 2 diabetic patients indicative of an increased atherosclerotic risk.10 Nonetheless, because of its contribution to glycemia and the A1C level as well as atherogenesis, the importance of achieving PPG targets is clear.

Postprandial Glucose Excursions: Indian Context The higher glucose load, having higher glycemic index, in the Indo-Chinese diets lead to greater prandial glycemic excursion, increased glucosidase and incretin activity in the gut and may need special therapeutic strategies to tackle these glucose peaks. Thus a typical 23

Review Article Indo-Chinese postmeal glucose curve has wider glycemicexcursion as well as greater postprandial load which leads to higher lipemic peaks and has epidemiological links to CVD.11 PPG Excursions and Gestational Diabetes Mellitus The most significant neonatal complication associated with gestational diabetes mellitus (GDM) is macrosomia. The risk of macrosomia increases with increasing postprandial hyperglycemia.12-14 Studies have documented that the peak glucose concentration occurs one hour after eating. Improved fetal outcome and less risk of neonatal hypoglycemia, macrosomia and cesarean delivery occurred in GDM managed by controlling PPG concentration.15 Options for Treating Postprandial Excursions Lifestyle Interventions to Reduce PPG

Lifestyle interventions remain a cornerstone of therapy for lowering PPG in T2DM. In a 3-year randomized controlled study of lifestyle interventions, including dietary modification and exercise, after one year, PPG levels decreased 11 mg/dl in the lifestyle intervention group and increased 7 mg/dl in the control group.

After three years, a sustained reduction of the PPG level was observed, but only in the 72% (106/147) who completed the 3-year study.16 Pharmacologic Options to Reduce PPG

The α-glucosidase inhibitors are effective in lowering PPG because they delay carbohydrate absorption, with one meta-analysis reporting mean reductions of 42 and 49 mg/dl for acarbose and miglitol, respectively.17 They have the added advantage of being weight-neutral; however, gastrointestinal side effects often limit patient acceptance.

The glinides are another option. Repaglinide has been shown to provide a similar reduction in PPG (p = 0.07) compared with glyburide after 14 weeks in 195 patients with T2DM.18 Compared with glimepiride 2 mg oncedaily, repaglinide 1 mg twice-daily has been shown to provide a significantly greater reduction in PPG following a standard meal (n = 14).19 An 8-week study 24

involving 101 patients showed similar reduction of PPG with nateglinide 120 mg thrice-daily and glyburide 10 mg once-daily following a standard meal.20 Direct comparison of repaglinide and nateglinide shows comparable reduction in PPG.21-23 Other options include the oral dipeptidyl peptidase-4 (DPP-4) inhibitors - sitagliptin24 and saxagliptin.25 In addition, injectable agents are also effective in lowering PPG. These include the glucagon-like peptide-1 (GLP-1) agonists - exenatide26 and liraglutide;27 the amylin analogs - pramlintide28 and prandial insulin.13 An advantage of the GLP-1 agonists is that they promote weight loss. Pramlintide is approved only for use in conjunction with prandial insulin.29 Insulin Therapy and PPG Excursions

Basal insulin is a common start insulin. However, it must be recognized that control of PPG is less likely with basal insulin than with prandial insulin. From a physiologic viewpoint, prandial/premixed (mealtime or bolus) insulin would be the best choice if the plan is to target PPG and to continue the oral agents (metformin and pioglitazone).

Short-acting insulins specifically address postprandial hyperglycemia when given in a meal-adapted manner. regular human insulin (RHI) has a maximal action approximately two hours after injection and duration of action of approximately 6-8 hours, depending on the dose injected. The fast-acting insulin analogs like aspart and lispro were developed to mimic the physiological insulin response after a meal with a better action profile than RHI and can also be used for prandial insulin therapy.30,31 Rapid-acting Insulin Analogs

Insulin aspart: It was approved for clinical use in 1999.

Insulin aspart is made by a structural modification wherein proline in B28 position is replaced with negatively charged aspartic acid which offers an ultrashort-acting pharmacokinetic property to it. Efficacy and safety in pregnancy has been proved in several clinical studies across the world including India.32-38 Insulin lispro: In this insulin, amino acids, lysine and proline, respectively at 29th and 28th position in the β chain are swapped. The pharmacokinetic profile of Asian Journal of Diabetology, Vol. 13, No. 1

Review Article lispro is similar to that of aspart. Anecdotal studies of lispro in pregnancy have shown better efficacy and safety than RHI; however, use of insulin lispro in preGDM is still a concern though the teratogenicity has not been conclusively established. Lispro is category B drug in the US FDA list.39 Biphasic Insulins

α-glucosidase inhibitors, glinides, human short-acting insulin, short-acting analogs, DPP-4 inhibitors and GLP-1-based therapies, short-acting sulfonylureas.

Among all the available options, rapid-acting analogs and biphasic insulin analogs provide the best PPG control with least amount of hypoglycemia and weight gain. Its unique formulation and pharmacokinetic actions make this possible.

Rapid-acting premixed insulin analogs such as biphasic insulin aspart 30 (BIAsp 30 [30% soluble insulin aspart and 70% protamine-crystallized insulin aspart] and LisproMix (25% soluble Lispro and 75% protaminated Lispro) have recently been developed to overcome the pharmacokinetic limitations of RHI used in the most commonly prescribed premix, biphasic human insulin 30 (BHI 30, 30% human insulin and 70% neutral protamine Hagedorn [NPH] insulin). One study reported a greater lowering of postprandial triglyceride levels with BIAsp 30 than with BHI 30.40

References

The story of glucose control does not end with insulin, but monitoring control is also of paramount importance. It should include frequent monitoring of blood glucose levels with an aim to achieve normoglycemia without significant hypoglycemia.

In all these cases, FPG and PPG levels should be measured regularly and self-monitoring of blood glucose (SMBG) should be emphasized upon. Careful monitoring and dose adjustments are required towards the end of pregnancy, labor and after delivery as during this time insulin requirements undergo several changes.

4. Das AK, Varma RS. Monitoring and natural history of post-prandial hyperglycemia. J Assoc Physicians India 2001;49(Spec No):7-10.

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7. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria.

The DECODE study group. European Diabetes Epidemiology Group.

Diabetes Epidemiology: Collaborative analysis of Diagnostic criteria in Europe.

Lancet 1999;354(9179):617-21.

Contribution of PPG is important for HbA1C values <8.5. If tight control has to be achieved, PPG control is mandatory. PPG excursions are linked to endothelial dysfunction and atherogenesis resulting in higher cardiovascular morbidity and mortality. Traditional South East Asian diet has a high carbohydrate load, which results in higher PPG excursions. PPG excursions are linked to higher fetal abnormalities in pregnancies complicated by impaired glucose tolerance.

Lifestyle modification is a must in all patients. This includes dietary and exercise advice on an individual basis. Among the drugs available for PPG control, following can be chosen based on the evidence: Asian Journal of Diabetology, Vol. 13, No. 1

1. American Diabetes Association. Standards of medical care in diabetes - 2010. Diabetes Care 2010;33 (Suppl 1):S11-61.

2. Guideline for management of postmeal glucose.

International Diabetes Federation 2007.

3. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c).

Diabetes Care 2003;26(3):881-5.

5. Balkau B, Shipley M, Jarrett RJ, Pyörälä K, Pyörälä M, Forhan A, et al. High blood glucose concentration is a risk factor for mortality in middle-aged nondiabetic men. 20-year follow-up in the Whitehall Study, the Paris Prospective Study, and the Helsinki Policemen Study.

Diabetes Care 1998;21(3):360-7.

6. Lowe LP, Liu K, Greenland P, Metzger BE, Dyer AR, Stamler J. Diabetes, asymptomatic hyperglycemia, and 22-year mortality in black and white men. The Chicago Heart Association Detection Project in Industry Study.

Diabetes Care 1997;20(2):163-9.

8. Esposito K, Giugliano D, Nappo F, Marfella R; Companion Postprandial Hyperglycemia Study Group.

Regression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus.

Circulation 2004;110(2):214-9.

9. Iijima R, Nakajima R, Sugi K, Nakamura M. Improvement of postprandial hyperglycemia has a positive impact on epicardial flow of entire coronary tree in acute coronary syndromes patients. Circ J 2007;71(7):1079-85.

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Review Article 10. Siervo M, Corander M, Stranges S, Bluck L. Postchallenge hyperglycaemia, nitric oxide production and endothelial dysfunction: the putative role of asymmetric dimethylarginine (ADMA). Nutr Metab Cardiovasc Dis 2011;21(1):1-10.

11. Joshi SR, Karne R. Pre-diabetes, dysglycaemia and early glucose intolerance and vascular health. J Assoc Physicians India 2007;55:829-31.

12. Langer O, Mazze R. The relationship between largefor-gestational age infants and glycemic control in women with gestational diabetes. Am J Obstet Gynecol 1988;159(6):1478-83.

13. Jovanovic-Peterson L, Peterson CM, Reed GF, Metzger BE, Mills JL, Knopp RH, et al. Maternal postprandial glucose levels and infant birth weight: the Diabetes in Early Pregnancy Study. The National Institute of Child Health and Human Development – Diabetes in Early Pregnancy Study. Am J Obstet Gynecol 1991;164 (1 Pt 1):103-11.

14. Combs CA, Gunderson E, Kitzmiller JL, Gavin LA, Main EK. Relationship of fetal macrosomia to maternal postprandial glucose control during pregnancy. Diabetes Care 1992;15(10):1251-7.

15. de Veciana M, Major CA, Morgan MA, Asrat T, Toohey JS, Lien JM, et al. Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy. N Engl J Med 1995;333(19):1237-41.

16. Roumen C, Corpeleijn E, Feskens EJ, Mensink M, Saris WH, Blaak EE. Impact of 3-year lifestyle intervention on postprandial glucose metabolism: the SLIM study.

Diabet Med 2008;25(5):597-605.

17. Van de Laar FA, Lucassen PL, Akkermans RP, Van de Lisdonk EH, Rutten GE, Van Weel C. Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev 2005;(2):CD003639.

18. Landgraf R, Bilo HJ, Müller PG. A comparison of repaglinide and glibenclamide in the treatment of type 2 diabetic patients previously treated with sulphonylureas.

Eur J Clin Pharmacol 1999;55(3):165-71.

19. Rizzo MR, Barbieri M, Grella R, Passariello N, Barone M, Paolisso G. Repaglinide is more efficient than glimepiride on insulin secretion and post-prandial glucose excursions in patients with type 2 diabetes. A short term study.

Diabetes Metab 2004;30(1):81-9.

20. Hollander PA, Schwartz SL, Gatlin MR, Haas SJ, Zheng H, Foley JE, et al. Importance of early insulin secretion: comparison of nateglinide and glyburide in previously diet-treated patients with type 2 diabetes.

Diabetes Care 2001;24(6):983-8.

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21. Li J, Tian H, Li Q, Wang N, Wu T, Liu Y, et al.

Improvement of insulin sensitivity and beta-cell function by nateglinide and repaglinide in type 2 diabetic patients: a randomized controlled double-blind and doubledummy multicentre clinical trial. Diabetes Obes Metab 2007;9(4):558-65.

22. Rosenstock J, Hassman DR, Madder RD, Brazinsky SA, Farrell J, Khutoryansky N, et al; Repaglinide Versus Nateglinide Comparison Study Group. Repaglinide versus nateglinide monotherapy: a randomized, multicenter study. Diabetes Care 2004;27(6):1265-70.

23. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G; Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone.

Diabetes Care 2006;2(12):2638-43.

24. Rosenstock J, Sankoh S, List JF. Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes. Diabetes Obes Metab 2008;10(5):376-86.

25. Linnebjerg H, Park S, Kothare PA, Trautmann ME, Mace K, Fineman M, et al. Effect of exenatide on gastric emptying and relationship to postprandial glycemia in type 2 diabetes. Regul Pept 2008;151(1-3):123-9.

26. Schwartz SL, Ratner RE, Kim DD, Qu Y, Fechner LL, Lenox SM, et al. Effect of exenatide on 24-hour blood glucose profile compared with placebo in patients with type 2 diabetes: a randomized, double-blind, two-arm, parallel-group, placebo-controlled, 2-week study. Clin Ther 2008;30(5):858-67.

27. Marre M, Shaw J, Brändle M, Bebakar WM, Kamaruddin NA, Strand J, et al; LEAD-1 SU study group. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU).

Diabet Med 2009;26(3):268-78.

28. Thompson RG, Gottlieb A, Organ K, Koda J, Kisicki J, Kolterman OG. Pramlintide: a human amylin analogue reduced postprandial plasma glucose, insulin, and C-peptide concentrations in patients with type 2 diabetes. Diabet Med 1997;14(7):547-55.

29. Symlin prescribing information. San Diego, CA: Amylin Pharmaceuticals, Inc.; 2008.

30. Lindholm A, McEwen J, Riis AP. Improved postprandial glycemic control with insulin aspart: a randomized double-blind crossover trial in type 1 diabetes. Diabetes Care 1999;22(5):801-5.

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Review Article 31. Anderson JH Jr, Brunelle RL, Keohane P, Koivisto VA, Trautmann ME, Vignati L, et al. Mealtime treatment with insulin analog improves postprandial hyperglycemia with hypoglycemia in patients with non-insulin dependent diabetes mellitus. Multicenter Insulin Lispro Study Group. Arch Intern Med 1997;157(11):1249-55.

32. Seshiah V, Balaji V, Balaji MS. Insulin aspart - safe during pregnancy. Diabetes Care 2006;54(Suppl 1):A133.

33. Prasad S, Prasad GM. Maternal and perinatal outcome in using insulin aspart versus regular insulin in gestational diabetes mellitus. Diab Care 2008;57(Suppl 1):A581.

34. Hod M, Visser G, Damm P, et al. Safety and perinatal outcome in pregnancy: a randomized trial comparing insulin aspart with human insulin and 322 subjects with type 1 diabetes. Diabetes 2006;55(1):A417.

35. Mathiesen ER, Kinsley B, Amiel SA, et al. Maternal hypoglycemia and glycemic control in pregnancy: a randomized trial comparing insulin aspart with human insulin and 322 subjects with type 1 diabetes. Diabetes 2006;55(Suppl 1):A40.

36. Pettitt DJ, Ospina P, KolaczynskI JW, Jovanovic L. Comparison of an insulin analog, insulin aspart, and regular human insulin with no insulin in gestational diabetes mellitus. Diabetes Care 2003;26(1):183-6.

37. Jovanovic L, Pettitt DJ. Treatment with insulin and its analogs in pregnancies complicated by diabetes. Diabetes Care 2007;30(2):S220-4.

38. Haruo N, Mitsuyo S, Koji M, Makoto O, Ikuko H, Hideshi K. Does multiple injection therapy (MIT) with an ultrarapid-acting insulin analogue prevent cardiovascular disease in type 2 diabetes? The NICEStudy: a prospective, randomised, open-label, blinded endpoint study. ADA 68th Scientific Sessions 2008, Abstract Number: 163-OR. 39. Diamond T, Kormas N. Possible adverse fetal effects of insulin lispro. N Engl J Med 1997;337(14):1009; author reply 1010.

40. Halimi S, Raskin P, Liebl A, Kawamori R, Fulcher G, Yan G. Efficacy of biphasic insulin aspart in patients with type 2 diabetes. Clin Ther 2005;27(Suppl B): S57-74.

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Review Article

The Use of GLP-1 Agonists in the Treatment of Postprandial Hyperglycemia MC Deepak

Abstract Current therapies for type 2 diabetes mellitus (T2DM) are frequently associated with inadequate control of postprandial hyperglycemia, weight gain and, in the case of oral agents, loss of efficacy over time. Incretinbased therapies slow gastric emptying, stimulate insulin and inhibit glucagon secretion, thereby lead to improved control of postprandial hyperglycemia and control of body weight. Amylin, GIP, GLP-1, dipeptidyl peptidase IV (DPP-IV) inhibitors are the commonly used gastrointestinal peptide therapies, but we shall concentrate on GLP-1 and its analogs in this article.

Key words: Type 2 diabetes, incretin-based therapies, GLP-1 agonists

C

urrent therapies for type 2 diabetes mellitus (T2DM) are frequently associated with inadequate control of postprandial hyperglycemia, weight gain and, in the case of oral agents, loss of efficacy over time. Incretin-based therapies are associated with slowing of gastric emptying, stimulation of insulin and inhibition of glucagon secretion, thereby leading to improved control of postprandial hyperglycemia and control of body weight.

Barriers to Achieving the Desired A1C Value of <7% in Type 2 Diabetes Prandial Hyperglycemia

In most of the clinical trials mentioned below,1-3 the achievement of good control of hyperglycemia in the fed state has been quite dismal. Alpha-glucosidase inhibitors (AGIs) reduce postprandial hyperglycemia.

Use of AGIs is associated with increased secretion of (GLP-1),4,5 which may contribute to their therapeutic effects. The nonsulfonylurea secretagogues (repaglinide and nateglinide) provoke rapid secretion of endogenous insulin with meals but the need for repeated doses (with each meal) is a major limiting factor.6-9 The advent of rapid-acting insulin analogs has somewhat improved the scenario but nevertheless neither of these agents consistently

Dept. of Diabetology Madhav Diabetes Centre AA2, Anna Nagar Chennai 600 040 E-mail: diabdeepak@gmail.com

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eliminate postprandial glycemic excursions by >50%.10 As the A1C goes <7.3%, the contribution of prandial hyperglycemia to the overall A1C becomes paramount.11 Hypoglycemia

Hypoglycemia is a major barrier to achieving A1C <7%. It is more pronounced with the use of any insulin or oral secretagogue, especially when glycemic control approaches near normal levels. In the DCCT (Diabetes Control and Complications Trial) and the UK Prospective Diabetes Study (UKPDS), the risk of hypoglycemia increased as the A1C approached 7. The fear of hypoglycemia and its effects on cognitive function make it as a barrier to patient compliance.12-14 Weight Gain

Weight gain with improvement of glycemic control can be minimized by using metformin but insulin, secretagogues and thiazolidinediones are all associated with variable degrees of weight gain. In the UKPDS, treatment with insulin or a sulfonylurea was associated with significantly more weight gain over 10 years than treatment with metformin or diet alone.15,16 Weight gain with thiazolidinediones is known to be in the range of 2-5 kg.17-19 Hypoglycemic episodes can compel patients to eat defensively to avoid or treat symptoms of hypoglycemia, leading to some of the weight gain that occurs during insulin treatment.

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Review Article Physiology of Prandial versus Fasting Glucose Homeostasis

gastrointestinal peptide therapies, but we shall concentrate on GLP-1 and its analogs in this article.

The pathophysiology of hyperglycemia in T2DM is known to be abnormalities in insulin secretion and action. This model is most accurate in the fasting state wherein plasma glucose levels are determined mainly by insulin concentrations and hepatic sensitivity to insulin.

Modest increases of systemic insulin concentrations can suppress free fatty acid (FFA) mobilization from adipose tissue and thereby increase hepatic sensitivity to portal insulin.20-22 Modulation of insulin secretion during fasting consequently regulates hepatic glucose output (HGO); small changes in plasma glucagon also modulate HGO, in effect by altering hepatic responses at given levels of insulin.23,24 It is a well known fact that to control the fasting sugars in people with type 2 diabetes is not a very big task. It is well known that small doses of basal insulin say <10 Units/day is all that is required to control the fasting glucose;25,26 this becomes even more evident if insulin therapy is initiated early. The logic behind this is that the quantum of insulin required to suppress HGO and thereafter neoglucogenesis/glycogenolysis is less than the amount of insulin required to permit peripheral glucose uptake. Metformin if added helps to regulate the HGO making control of fasting hyperglycemia a relatively simple task. The same does not hold true for control of postprandial sugar since there are a multitude of factors involved.

GLP-1: Physiological Role

The mechanisms regulating plasma glucose after eating are however more complicated. An ordinary meal contains 50-100 g of carbohydrate, which is 10-20 times the amount of glucose in the blood. Several factors beyond increasing insulin secretion in response hyperglycemia prevent the dramatic hyperglycemia that would otherwise occur after meals. They include: 1) The incretin effect through two specific peptides from the gut, i.e., glucose-dependent insulinotropic polypeptide (GIP) and GLP-1, 2) suppression of glucagon secretion and, 3) Neural mechanisms that influence the secretion of both insulin and glucagon.27-29 Gastrointestinal Peptides Used in the Management of Postprandial Hyperglycemia Amylin, GIP, GLP-1, dipeptidyl peptidase IV (DPP-IV) inhibitors are the commonly used Asian Journal of Diabetology, Vol. 13, No. 1

GLP-1 is a 30-amino acid gut peptide produced in enteroendocrine L cells located in the distal ileum and colon. GLP-1 is rapidly secreted from the distal gut within minutes of ingestion of food. GLP-1 also contains an NH2-terminal alanine at position 2, rendering it a substrate for cleavage by DPP-IV.30 Both enzymatic inactivation and renal clearance contribute to a very short circulating t1/2 of several minutes for native GLP-1. GLP-1 controls blood glucose via multiple actions, principally by stimulation of insulin secretion and inhibition of both glucagon secretion and gastric emptying.31,32 GLP-1 also activates regions in the CNS important associated with control of satiety.33-35 GLP-1 also promotes increase in β-cell mass via stimulation of β-cell proliferation and inhibition of apoptosis in multiple preclinical models of experimental diabetes. The cytoprotective actions of GLP-1 receptor agonists have also been observed in human islets cultured in vitro.36-38 GLP-1 exerts extrapancreatic actions independent of its effects on glucoregulation, including activation of the hypothalamic pituitary axis and induction of an aversive stress response in rodents. Moreover, GLP-1 receptor agonists enhance learning and memory and promote neuronal survival in experimental models of neurotoxicity in rat models.39 Furthermore, it has been shown that short-term GLP-1 administration activates cytoprotective pathways in vulnerable cardiomyocytes40-42 and improves myocardial contractility in preclinical studies and in human subjects after myocardial infarction and revascularization.42 GLP-1 Action in Subjects with Normal Glucose Homeostasis and Diabetes

Acute infusion or subcutaneous administration of GLP-1 lowers meal-related glucose excursions in human subjects via inhibition of g.43 GLP-1 has also been found in short-term studies of normal and diabetic subjects to enhance satiety and reduce food intake.44,45 Repeated daily injections of GLP-1 lowers blood glucose in subjects with T2DM with significant improvements in fasting and postprandial glucose and A1C in association with increases in insulin sensitivity 29

Review Article and a reduction in body weight.46 There are two forms of commercially available GLP-1 form, a synthetic GLP-1 agonist i.e., exenatide and an analog form called liraglutide.

Exenatide

Exenatide (Exendin-4) is a 39-amino acid synthetic GLP-1 agonist that has been shown in preclinical and clinical studies to mimic the entire spectrum of GLP-1dependent actions. Exendin-4 was originally isolated from the venom of a lizard, Heloderma suspectum.47 Exendin-4 contains a glycine at position 2, is resistant to DPP-IV cleavage and is considerably more potent than native GLP-1 in vivo due in large part to less rapid inactivation and clearance. Dosing range studies have identified an optimal glucose-lowering dose range of 0.05-0.2 μg/kg for exenatide when injected subcutaneously in human diabetic subjects. Current antidiabetic regimens for exenatide administration involve twice-daily dosing.

Exenatide slows gastric emptying, suppresses glucagon, and promotes satiety. In addition, it potentiates glucosemediated insulin secretion.48-52 Nausea and vomiting can occur, especially at the beginning of treatment, but this is less frequent when treatment is started with the 5 μg dose. Published results from three large 6-month trials testing the addition of exenatide to metformin alone sulfonylurea alone, or metformin and a sulfonylurea together are available. The placebo-adjusted decline of A1C from baseline levels of 8.2-8.6% was ~1.0% in each trial. A mean placebo-adjusted weight loss of 2.5 kg occurred when exenatide was added to metformin, 1.0 kg when the drug was added to a sulfonylurea and 0.9 kg when it was added to metformin plus a sulfonylurea.52,53 Exenatide is less likely to cause hypoglycemia if used by patients taking metformin, but the risk of hypoglycemia is significantly increased in patients treated with both exenatide and a sulfonylurea. Exenatide is approved for use by T2DM patients not yet requiring insulin, so that the addition of exenatide to prior oral therapies promises a lower rate of hypoglycemia than that achieved with the addition of insulin.

Exenatide lowered the prandial glucose excursions by as much as 2.5 mmol which sustained over a 16-week trial.50 In yet another study published in Diabetes Care,54 subjects who underwent a standardized meal tolerance 30

test, baseline data at Week 0 (all arms received placebo) showed a similar rise in postprandial plasma glucose concentrations across treatment arms. At Week 4, postprandial plasma glucose concentrations were reduced in both exenatide arms compared with placebo (p = 0.006). Postprandial plasma glucose geometric mean area under the curve 15-180 minutes values averaged 34% lower than baseline in each exenatide arm, compared with only 9% lower than baseline in the placebo arm. This pattern was sustained to Week 30 with a robust lowering of postprandial glucose concentrations in the 10 μg (p = 0.004) and 5 μg exenatide arms (p = 0.03).

In a current trial by David Kendall, Julio Rosenstock and coworkers,52 the observation of a modest reduction in fasting plasma glucose, in keeping with the pharmacokinetic profile of exenatide, and yet a significant drop in A1C strongly suggests a robust effect of exenatide on postprandial plasma glucose concentrations. This is confirmed by the sustained reductions in postprandial glucose concentrations observed in the meal challenge test at Weeks 4 and 30.

Incremental plasma glucose AUC and average concentration during the postprandial period were reduced by ~60% (5 μg arm) and 90% (10 μg arm) by exenatide treatment.

Exenatide once-weekly preparations were studied in the DURATION-1 trial, wherein patients on twicedaily exenatide were switched on to once-weekly and showed similar improvements in metabolic profile and cardiovascular risk factors at the end of 32 weeks; more studies in this regard need to be done. If proven to show similar effects, it will go a long way in improving patient compliance to weekly injections.55 One-year exenatide treatment in a separate trials,56,57 showed reduced body fat mass and improved the profile of circulating biomarkers of cardiovascular risk in comparison to the long-acting basal analog glargine.

No significant changes were seen with insulin glargine except a trend for reduced endothelin-1 levels. A recent paper has shown that exenatide ameliorates postprandial endothelial dysfunction after a high-fat meal.58 Liraglutide

Liraglutide is a GLP-1 receptor agonist that is administered by a single daily injection. As with Asian Journal of Diabetology, Vol. 13, No. 1

Review Article exenatide, nausea is the most common associated adverse effect with liraglutide administration. Although the optimal dose has not yet been identified, a 12week trial including 193 patients with T2DM showed that 0.75 mg liraglutide daily caused equivalent placebo-adjusted reductions of A1C compared with the sulfonylurea glimepiride (0.75 and 0.74%) from mean baseline values of 7.4-7.9%.59,60 However, liraglutide treatment was associated with a placebo-adjusted weight reduction of 0.39 kg, whereas patients treated with glimepiride experienced a mean weight gain of 0.94 kg. A significant reduction of the glucagon profile occurred as well, but insulin levels were not different between treatments.

Liraglutide is an acylated human GLP-1 analog that binds noncovalently to albumin, and may be administered once-daily and exhibits a more prolonged pharmacokinetic profile relative to native GLP-1 or exenatide. It is slowly absorbed, with maximal concentration after 9-14 hours and a half-life of 12.6 ± 1.1 hours. Its absolute bioavailability is ~55%.

Once-daily administration of liraglutide is attributable to its sustained glucose-lowering activity at 24 hours postadministration at steady state concentration. It has an elimination half-life of 11-15 hours. No clinically significant drug-drug interaction related to inhibition or induction of cytochrome P450 are expected during treatment with liraglutide.60 In rodent studies, both GLP-1 and liraglutide promote the maintenance of β-cell mass in diabetes, presumably by inhibiting both cytokine and free fatty acid induced apoptosis.60,61 In addition to animal studies, clinical studies indicate improved β-cell function as measured by the homeostasis model assessment for β-cell function (HOMA-B), secretion of C-peptide and proinsulin to insulin ratio.60,61 Extrapancreatic effects on the cardiovascular system: A reduction in systolic blood pressure has also been observed with liraglutide. The mechanism for this is not well-understood but appears to be independent of a reduction in body weight. Like native GLP-1, liraglutide inhibits tumor necrosis factor-alpha (TNF-a)-mediated plasminogen activator inhibitor type-1 (PAI-1) activation in human vascular endothelial cells.62 These observations suggest that a beneficial effect of liraglutide on endothelial dysfunction associated Asian Journal of Diabetology, Vol. 13, No. 1

with premature atherosclerosis observed in T2DM. Evidence from randomized control studies is yet to establish whether such improvement in biomarkers has an impact on long-term micro- and macrovascular disease.

Risk of Pancreatitis with GLP-1 Based Therapies

Three cases of pancreatitis (one patient in Liraglutide Effect and Action in Diabetes (LEAD)-1 and 2 patients in LEAD-3) have been reported during clinical trials with liraglutide. Compared to general population, patients with T2DM have a 3-fold risk of acute pancreatitis.59,63 Therefore, it is difficult to establish whether these reported cases are due to liraglutide therapy or to pre-existing increased risk. In view of confounding factors, a causal relationship between liraglutide and pancreatitis may be difficult to establish.

However, a weak association cannot be excluded based on available clinical data.59,63 A similar view has been expressed for exenatide.63 The Phase III LEAD Studies64

The LEAD program is composed of six randomized, controlled, double-blind, Phase III clinical studies, which includes around 6,500 people worldwide, of which ~4,200 received liraglutide. The program was designed to obtain the indication of use of liraglutide to treat people with T2DM in monotherapy and in combination therapy with commonly used antidiabetic medications. The LEAD program has compared the efficacy and safety of liraglutide with sulfonylurea, glitazone, insulin and exenatide. The LEAD program includes six studies. In all studies, the initial dose of liraglutide was escalated weekly in a stepwise manner from 0.6 to 1.8 mg/day.

Meta-analysis of LEAD Studies

Participants from LEAD 1, 2 and 5 were stratified by baseline HbA1C quartiles. Treatment with liraglutide resulted in a reduction of HbA1C of about 0.6-1.0% point in quartile 1 (mean HbA1C about 7.3%) to a reduction of 1.4-1.8% point in quartile 4 (mean HbA1C of about 9.7%). The greatest decrease in body weight occurred in subjects with BMI >35 kg/m2. The weight reduction in subjects with BMI <25 kg/m2 was from 0 to 2 kg increasing to 1 to 4.5 kg in subjects with a BMI >35 kg/m2.

31

Review Article Table. Comparison of Liraglutide and Exenatide Parameter assessed

Liraglutide (Daily)

Exenatide (Twice-daily)

-1.12b

-0.79

FPG reduction (mg/dl)

29b

11

Achievement of A1C < 7% (%)

54

c

43

Change in body weight (kg)

-3.2

-2.9

Effect on glycemic parameters A1C (%)

A1C: Hemoglobin, FBG: Fasting plasma glucose. a 26-week data b p < 0.0001 versus exenatide c p = 0.0015 versus exenatide

Comparison of Liraglutide and Exenatide

The greatest weight loss was observed with the combination of liraglutide and metformin. The highest dose of liraglutide (1.8 mg/day) reduced systolic blood pressure with 2.7-4.5 mmHg versus comparator treatment. No change in the diastolic blood pressure was observed. Lastly, liraglutide improved β-cell function evaluated from HOMA β-cell function and the proinsulin/insulin ratio.

Liraglutide has been well-tolerated with a low risk of hypoglycemia, primarily in participants also treated with sulfonylurea. The incidence of nausea has been acceptable and mostly observed during the first weeks of treatment and has thereafter been minimal or completely absent.

Fears and Concerns  It is still unclear to what extent the various effects of GLP-1 are mediated through actions directly on islet cells, the brain or peripheral sites (e.g., intestinal mucosa, portal vein) and whether the differing effects of exenatide, liraglutide and the gliptins are due to differences in pharmacokinetics or mechanisms of action.  What is the potential for long-term benefits or risks independent of glucose control and body weight with these new agents? Can the weight-loss benefits of exenatide and liraglutide be sustained over time?  Will these injectable peptides be associated with immunogenicity and the development of neutralizing antibodies that may diminish the efficacy of therapy over time in selected patients?

32







Will there be cardiovascular benefits independent of the improvement in glycemic control with some or all of these agents?

Will exenatide, liraglutide and vildagliptin protect β-cells or promote their regeneration in clinical use, as appears to be the case in animal studies?

Conversely, the recent description of hyperinsulinemic hypoglycemia and nesidioblastosis together with increased circulating levels of GLP-1 in a few patients after gastric bypass surgery further emphasizes the importance of understanding the long-term consequences of prolonged activation of the GLP-1 receptor in human subjects. The answers to these questions will determine, to a large extent, the future role of these agents in the treatment of type 2 diabetes.

References 1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.

N Engl J Med 1993;329(14):977-86.

2. Shichiri M, Kishikawa H, Ohkubo Y, Wake N. Longterm results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care 2000;23(Suppl 2):B21-9.

3. Riddle MC, Rosenstock J, Gerich J; Insulin Glargine 4002 Study Investigators. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003;26(11):3080-6.

4. Lebovitz HE. Alpha-glucosidase inhibitors. Endocrinol Metab Clin North Am 1997;26(3):539-51.

5. van de Laar FA, Lucassen PL, Akkermans RP, van de Lisdonk EH, Rutten GE, van Weel C. Alpha-glucosidase inhibitors for patients with type 2 diabetes: results from a Cochrane systematic review and meta-analysis. Diabetes Care 2005;28(1):154-63.

6. Schmitz O, Lund S, Andersen PH, Jonler M, Porksen N. Optimizing insulin secretagogue therapy in patients with type 2 diabetes: a randomized double-blind study with repaglinide. Diabetes Care 2002;25(2):342-6.

7. Hollander PA, Schwartz SL, Gatlin MR, Haas SJ, Zheng H, Foley JE, et al. Importance of early insulin secretion: comparison of nateglinide and glyburide in previously diet-treated patients with type 2 diabetes.

Diabetes Care 2001;24(6):983-8.

8. Carroll MF, Izard A, Riboni K, Burge MR, Schade DS. Control of postprandial hyperglycemia: optimal use Cont’d on page 35...

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Review Article ...Cont’d from page 32 of short-acting insulin secretagogues. Diabetes Care 2002;25(12):2147-52.

9. Carroll MF, Gutierrez A, Castro M, Tsewang D, Schade DS. Targeting postprandial hyperglycemia: a comparative study of insulinotropic agents in type 2 diabetes. J Clin Endocrinol Metab 2003;88(11):5248-54.

10. Anderson JH Jr, Brunelle RL, Keohane P, Koivisto VA, Trautmann ME, Vignati L, et al. Mealtime treatment with insulin analog improves postprandial hyperglycemia and hypoglycemia in patients with non-insulin-dependent diabetes mellitus. Multicenter Insulin Lispro Study Group. Arch Intern Med 1997;157(11):1249-55.

11. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of Hb(A1c).

Diabetes Care 2003;26(3):881-5.

12. Hypoglycemia in the Diabetes Control and Complications Trial. The Diabetes Control and Complications Trial Research Group. Diabetes 1997;46(2):271-86.

13. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352(9131):837-53.

14. Cryer PE. Hypoglycemia is the limiting factor in the management of diabetes. Diabetes Metab Res Rev 1999;15(1):42-6.

15. Influence of intensive diabetes treatment on body weight and composition of adults with type 1 diabetes in the Diabetes Control and Complications Trial. Diabetes Care 2001;24(10):1711-21.

16. Purnell JQ, Hokanson JE, Marcovina SM, Steffes MW, Cleary PA, Brunzell JD. Effect of excessive weight gain with intensive therapy of type 1 diabetes on lipid levels and blood pressure: results from the DCCT. Diabetes Control and Complications Trial. JAMA 1998;280(2):140-6.

17. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352(9131):854-65.

18. Yki-Järvinen H. Thiazolidinediones. N Engl J Med 2004;351(11):1106-18.

19. Vasudevan AR, Balasubramanyam A. Thiazolidinediones: a review of their mechanisms of insulin sensitization, therapeutic potential, clinical efficacy, and tolerability.

Diabetes Technol Ther 2004;6(6):850-63.

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is regulated by the portal vein insulin concentration.

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30. Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ. Both subcutaneously and intravenously administered glucagon-like peptide 1 are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes 1995;44(9):1126-31.

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32. Vahl TP, Paty BW, Fuller BD, Prigeon RL, D’Alessio DA. Effects of GLP-1-(7-36)NH(2), GLP-1-(7-37), and GLP-1-(9-36)NH(2) on intravenous glucose tolerance and glucose-induced insulin secretion in healthy humans.

J Clin Endocrinol Metab 2003;88(4):1772-9.

33. Turton MD, O’Shea D, Gunn I, Beak SA, Edwards CM, Meeran K, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 1996;379(6560):69-72.

35

Review Article 34. Young AA, Gedulin BR, Bhavsar S, Bodkin N, Jodka C, Hansen B, et al. Glucose-lowering and insulinsensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta).

Diabetes 1999;48(5):1026-34.

35. Baggio LL, Huang Q, Brown TJ, Drucker DJ. A recombinant human glucagon-like peptide (GLP)-1 albumin protein (albugon) mimics peptidergic activation of GLP-1 receptor-dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis.

Diabetes 2004;53(9):2492-500.

36. Xu G, Stoffers DA, Habener JF, Bonner-Weir S. Exendin4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes 1999;48(12):2270-6.

37. Li Y, Hansotia T, Yusta B, Ris F, Halban PA, Drucker DJ. Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis. J Biol Chem 2003;278(1):471-8.

38. Farilla L, Bulotta A, Hirshberg B, Li Calzi S, Khoury N, Noushmehr H, et al. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology 2003;144(12):5149-58.

39. During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, et al. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med 2003;9(9):1173-9.

40. Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM. Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes 2005;54(1):146-51.

41. Gros R, You X, Baggio LL, Kabir MG, Sadi AM, Mungrue IN, et al. Cardiac function in mice lacking the glucagon-like peptide-1 receptor. Endocrinology 2003;144(6):2242-52.

42. Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D, et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion.

Circulation 2004;109(8):962-5.

47. Eng J, Kleinman WA, Singh L, Singh G, Raufman JP. Isolation and characterization of exendin-4, an exendin3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem 1992;267(11):7402-5.

48. Kim JG, Baggio LL, Bridon DP, Castaigne JP, Robitaille MF, Jette L, et al. Development and characterization of a glucagon-like peptide 1 albumin conjugate: the ability to activate the glucagon-like peptide 1 receptor in vivo.

Diabetes 2003;52(3):751-9.

49. Poon T, Nelson P, Shen L, Mihm M, Taylor K, Fineman M, et al. Exenatide improves glycemic control and reduces body weight in subjects with type 2 diabetes: a doseranging study. Diabetes Technol Ther 2005;7(3):467-7.

50. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformintreated patients with type 2 diabetes. Diabetes Care 2005;28(5):1092-100.

51. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD; Exenatide-113 Clinical Study Group. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 2004;27(11):2628-35.

52. Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea.

Diabetes Care 2005;28(5):1083-91.

53. Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG; GWAA Study Group. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med 2005;143(8):559-69.

44. Deacon CF. Therapeutic strategies based on glucagonlike peptide 1. Diabetes 2004;53(9):2181-9.

54. Davis SN, Johns D, Maggs D, Xu H, Northrup JH, Brodows RG. Exploring the substitution of exenatide for insulin in patients with type 2 diabetes treated with insulin in combination with oral antidiabetes agents.

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45. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 2002;359(9309):824-30.

55. Buse JB, Drucker DJ, Taylor KL, Kim T, Walsh B, Hu H, et al; DURATION-1 Study Group. DURATION1: exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks. Diabetes Care 2010;33(6):1255-61.

43. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003;26(10):2929-40.

36

46. Meneilly GS, Greig N, Tildesley H, Habener JF, Egan JM, Elahi D. Effects of 3 months of continuous subcutaneous administration of glucagon-like peptide 1 in elderly patients with type 2 diabetes. Diabetes Care 2003;26(10):2835-41.

Asian Journal of Diabetology, Vol. 13, No. 1

Review Article 56. Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR; NN2211-1310 International Study Group. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, doubleblind, randomized, controlled trial. Diabetes Care 2004;27(6):1335-42.

57. Bunck MC, Diamant M, Eliasson B, CornĂŠr A, Shaginian RM, Heine RJ, et al. Exenatide affects circulating cardiovascular risk biomarkers independently of changes in body composition. Diabetes Care 2010;33(8):1734-7.

58. Koska J, Schwartz EA, Mullin MP, Schwenke DC, Reaven PD. Improvement of postprandial endothelial function after a single dose of exenatide in individuals with impaired glucose tolerance and recent-onset type 2 diabetes. Diabetes Care 2010;33(5):1028-30.

59. Mari A, Degn K, Brock B, Rungby J, Ferrannini E, Schmitz O. Effects of the long-acting human glucagon-like peptide-1 analog liraglutide on beta-cell function in normal living conditions. Diabetes Care 2007;30(8):2032-3.

60. Marre M, Shaw J, Brandle M, Bebakar WM, Kamaruddin NA, Strand J, et al; LEAD-1 SU Study

Group. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU).

Diabet Med 2009;26(3):268-78.

61. Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, et al; LEAD-2 Study Group. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 2009;32(1):84-90.

62. Liu H, Dear AE, Knudsen LB, Simpson RW. A long-acting glucagonlike peptide-1 analogue attenuates induction of plasminogen activator inhibitor type-1 and vascular adhesion molecules. J Endocrinol 2009;201(1):59-66.

63. Bain SC, Stephens JW. Exenatide and pancreatitis: an update. Expert Opin Drug Saf 2008;7(6):643-4.

64. Buse JB, Sesti G, Schmidt WE, Montanya E, Chang CT, Xu Y, et al; Liraglutide Effect Action in Diabetes-6 Study Group. Switching to once-daily liraglutide from twicedaily exenatide further improves glycemic control in patients with type 2 diabetes using oral agents. Diabetes Care 2010;33(6):1300-3.

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Emedinews Section

From eMedinewS Gestational Diabetes may Portend Fullfledged Type 2 Diabetes Later Despite the fact that “roughly half of women who’ve had gestational diabetes…go on to develop full-fledged type 2 diabetes in the months to years after their child’s birth,” a new study involving some 9,00,000 pregnant women and published in the journal Obstetrics and Gynecology reveals that “fewer than one in five of those women returns for a crucial diabetes test within six months of delivery.

Women with Pcos may have Four Times the Prevalence of Type 2 Diabetes According to a review and meta-analysis published online in the journal Human Reproduction Update, women with polycystic ovary syndrome (PCOS) have a four-fold increased prevalence of type 2 diabetes, independent of body mass index (BMI). After including 35 studies in the systematic review and 30 in the metaanalysis, the study found that women with PCOS had a 4.48-, 2.48- and 2.88-fold increased prevalence of type 2 diabetes, impaired glucose tolerance (IGT) and the metabolic syndrome, respectively, compared with controls. And, in BMI-matched studies, the corresponding prevalence’s were increased a respective 4.00-, 2.54- and 2.20-fold.

—Dr Monica and Brahm Vasudev

Silent Myocardial Ischemia may be more Common in Asymptomatic Type 2 Diabetics than Nondiabetics According to a study published Jan. 21 in the journal Cardiovascular Diabetology, true silent myocardial ischemia is significantly more common in asymptomatic type 2 diabetics than nondiabetics.

Increasing Step Counts Linked to Improved Insulin Sensitivity A study reported in the British Medical Journal that middle-aged Australian men and women (mean age 50 years) who increased their daily step count over 5 years’ follow-up showed significant improvements in insulin sensitivity and adiposity. The daily step count

decreased during follow-up in almost two-thirds of study subjects. Individuals whose step count increased between the two evaluations had a much lower BMI: Mean change 0.08/1,000 steps. An increase in step count was also associated with a lower waist-to-hip ratio, 0.15/1,000 steps; and greater insulin sensitivity, 1.38 HOMA units.

Type 1 Diabetes Linked to Viruses Australian researchers looked at a number of studies, and concluded there is a strong association between enteroviruses and the development of type 1 diabetes.

In fact, children with diabetes were 10 times more likely to have had an enterovirus infection than children without the disease. (Dr. Maria Craig, an associate professor at Children’s Hospital at Westmead’s Institute of Endocrinology and Diabetes in Sydney.)

An Inspirational Story Migrating Geese

The next season, when you see the geese migrating, going to a warmer place, to sort the winter…

Pay attention that they fly in a “V” formation. Maybe you will be interested in knowing why they do it this way. By flying in a “V” formation…The whole flock increases the flight efficiency by 71% compared to just one bird flying alone.

Laugh a While Three Vampires Walk into a Bar

Three vampires walk into a bar and sit down at a table.

The waitress comes over and asks the first vampire what he would like. The first vampire responds, “I vould like some blood.” The waitress turns to the second vampire and asks what he would like. The vampire responds, “I vould like some blood.” The waitress turns to the third vampire and asks what he would like. The vampire responds, “I vould like some plasma.”

The waitress looks up and says, “Let me see if I have this order correct. You want two bloods and a blood light?” n

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Asian Journal of Diabetology, Vol. 13, No. 1