Ajd April-June 2013 by IJCP

www.ijcpgroup.com

RNI NO. - 71334/99

ISSN 0972-7043

The Asian Journal of

Diabetology January-March April-June 20132013

VOLUME13, 16,NUMBER NUMBER22 VOLUME

xxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxx Age group

45 40

30-39 40-49 50-59 60-69

38.75

Prevalence

35 30 25 20

18.75

15 10 5 0

13.75

11.25

7.5 6.25 3.75

MS3

6.25

2.5

1.25

MS4

10 6.25 1.25

MS5

Total MS

7.5 3.75 1.25

No MS

A Study of Somatic Status and Complications Among Female Hospitalized and Non-hospitalized xxxxxxxxxxxxxxxxxxxxxxxxx Diabetic Patients from Mysore Urban Area xxxxxxxxxxxxxxxxxxxxxxxx Comparison of Insulin Glargine with Human Premix Insulin in Patients with Type 2 Diabetes xxxxxxxxxxxxxxxxxxxxxxxxx Inadequately Controlled on Oral Hypoglycemic xxxxxxxxxxxxxxxxxxxxxxxx Drugs in a 24-week Randomized Study Among Central Indian Population

xxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxx A Study of Metabolic Syndrome and its Components in Type 2 Diabetes Mellitus Subjects and their Asymptomatic First-degree Relatives

xxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxx

Dr Vijay Viswanathan Editor

Dr Dr KK KK Aggarwal Aggarwal Group Editor-in-Chief Group Editor-in-Chief

The Asian Journal of

DIABETOLOGY

IJCP Group of Publications

Volume 16, Number 2, April-June 2013

Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor Dr Deepak Chopra Chief Editorial Advisor Padma Shri and Dr BC Roy National Awardee

Dr KK Aggarwal

FROM THE DESK OF GROUP EDITOR-IN-CHIEF 5

Pioglitazone Back

KK Aggarwal

Group Editor-in-Chief Dr Veena Aggarwal MD, Group Executive Editor Anand Gopal Bhatnagar Editorial Anchor

IJCP Editorial Board

IJCP Editorial Board Obstetrics and Gynaecology Dr Alka Kriplani Dr Thankam Verma, Dr Kamala Selvaraj Cardiology Dr Praveen Chandra, Dr SK Parashar Paediatrics Dr Swati Y Bhave Diabetology Dr CR Anand Moses, Dr Sidhartha Das Dr A Ramachandran, Dr Samith A Shetty ENT Dr Jasveer Singh Dr Chanchal Pal Dentistry Dr KMK Masthan Dr Rajesh Chandna Gastroenterology Dr Ajay Kumar Dr Rajiv Khosla Dermatology Dr Hasmukh J Shroff Dr Pasricha Dr Koushik Lahiri Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan Dr Vineet Suri Journal of Applied Medicine & Surgery Dr SM Rajendran, Dr Jayakar Thomas Orthopedics Dr J Maheshwari Advisory Bodies Heart Care Foundation of India Non-Resident Indians Chamber of Commerce & Industry World Fellowship of Religions

ORIGINAL STUDY 6

A Study of Somatic Status and Complications Among Female Hospitalized and Non-hospitalized Diabetic Patients from Mysore Urban Area

Prabhavathi SN, Charlotte G Karunakaran, Ashoka HG

CLINICAL STUDY 12 Comparison of Insulin Glargine with Human Premix Insulin in Patients with Type 2 Diabetes Inadequately Controlled on Oral Hypoglycemic Drugs in a 24-week Randomized Study Among Central Indian Population

Abhishek Singhai, Subodh Banzal, Dolly Joseph, Rajesh Kumar Jha

19 A Study of Metabolic Syndrome and its Components in Type 2 Diabetes Mellitus Subjects and their Asymptomatic First-degree Relatives

JL Patel, AM Suthar, VB Dalsaniya, AP Parikh, NN Suthar, KL Patel

PRACTICE GUIDELINES

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

31 ACP Releases Guideline on Intensive Insulin Therapy in Hospitalized Patients

Printed at New Edge Communications Pvt. Ltd., New Delhi E-mail: edgecommunications@gmail.com ÂŠ Copyright 2013 IJCP Publications 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 Ltd. No part of this publication may be published in any form whatsoever without the prior written permission of the publisher.

LIGHTER READING 32 Lighter Side of Medicine

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: 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.

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FROM THE DESK OF GROUP EDITOR-IN-CHIEF Dr KK Aggarwal

Padma Shri and Dr BC Roy National Awardee Sr. Physician and Cardiologist, Moolchand Medcity, New Delhi President, Heart Care Foundation of India Group Editor-in-Chief, IJCP Group and eMedinewS National Vice President Elect, IMA Member, Ethics Committee, MCI Chairman, Ethics Committee, Delhi Medical Council Director, IMA AKN Sinha Institute (08-09) Hony. Finance Secretary, IMA (07-08) Chairman, IMA AMS (06-07) President, Delhi Medical Association (05-06) emedinews@gmail.com http://twitter.com/DrKKAggarwal Krishan Kumar Aggarwal (Facebook)

Pioglitazone Back As expected, the Indian government has revoked its suspension of the type 2 diabetes drug pioglitazone. However, it has stipulated that the agent should not be used as first-line treatment for diabetes and that it should carry a boxed warning relating to bladder cancer. The decision to suspend the manufacture, sale and distribution of pioglitazone in India, citing concerns over adverse effects, particularly bladder cancer, came out of the blue in June and was widely criticized by doctors and others there. In mid-July, however, a meeting of the Drug Technical Advisory Board (DTAB) recommended that pioglitazone be put back on the market. Now, the Ministry of Health and Family Welfare has announced that all formulations containing pioglitazone for human use are allowed to be manufactured, sold and distributed once again, albeit with warnings on the package insert. The new warnings, which must be listed on pioglitazone formulations in India, will state that patients with active bladder cancer or with a history of bladder cancer and those with uninvestigated hematuria should not receive pioglitazone. And before starting the drug, individuals should be assessed for known risk factors for bladder cancer, including age, smoking history, exposure to occupational or chemotherapy agents or previous irradiation of the pelvic region. Prescribers should also review the use of the agent after 3-6 months to ensure that only patients who are deriving benefit from it continue to be treated. Pioglitazone should be stopped in patients who do not respond adequately to treatment. There is also special advice for the use of pioglitazone in elderly patients, which “should be considered carefully before and during treatment because the risk of bladder cancer increases with age.” Elderly patients should start on the lowest possible dose “and be regularly monitored because of the risks of bladder cancer and heart failure associated with pioglitazone.” (Medscape) ■■■■

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

ORIGINAL STUDY

A Study of Somatic Status and Complications Among Female Hospitalized and Non-hospitalized Diabetic Patients from Mysore Urban Area PRABHAVATHI SN*, CHARLOTTE G KARUNAKARAN**, ASHOKA HGâ&#x20AC;

ABSTRACT In recent years, India has undergone rapid urbanization and socioeconomic development. Changes in time trends have resulted in erratic lifestyle, characterized by physical inactivity, unhealthy eating habits and resultant increase in obesity and diabetes. Diabetes is a major cause of mortality and morbidity in India and its prevalence is increasing at an alarming rate. Chronic complications of diabetes, especially coronary artery diseases and chronic renal diseases results in frequent hospitalization. The main aim of the investigation was to study the somatic status and diabetic complications among the female hospitalized and non-hospitalized patients. A total of 80 female volunteers (40 hospitalized and 40 non-hospitalized) of a private hospital in Mysore, with known history of type 2 diabetes mellitus for more than two years, were recruited for the study. The tools were developed to collect information on personal history, demography, socioeconomic status, dietary habits and anthropometric measurements. Suitable statistical analysis was applied to the data. The results projected that majority of the patients were hospitalized on an average of at least three times a year. More than 90% of the subjects exhibited blood sugar >300 mg on admission. The reason for high morbidity status included poor dietary habits and erratic lifestyle practices among the female hospitalized patients as compared to nonhospitalized patients. Adapting a healthy lifestyle and maintenance of normal blood sugar level can reduce the incidence of complications and hospitalization among the subjects. Keywords: Urbanization, socioeconomic development, obesity, diabetes, somatic status, diabetic complications, hospitalized and non-hospitalized patients

iabetes is a multifactorial disease that combines hereditary and environmental factors. The prevalence of diabetes is increasing globally. Diabetes is pandemic in both developed and developing countries. In the year 2000, it was estimated that there are 175 million diabetics worldwide and expected to increase to 354 million by the year 2030.

lifestyle - physical inactivity, unhealthy eating habits is one of the major causes for increase of diabetes in India. The prevalence of type 2 diabetes is found to be 4-6 times higher in the urban areas as compared to rural areas.

Based on a compilation of studies from different parts of the world, World Health Organization (WHO) has projected that the maximum increase in diabetes would occur in India.1 Presently, India is facing a major healthcare burden due to the high prevalence of type 2 diabetes as it is a major cause of mortality and morbidity in India, and is increasing at an alarming rate. Genetic predisposition superimposed by erratic

The onset of diabetes among Indians is about a decade earlier than their western counterparts and this has been noted in Asian Indians in several studies. Studies show that among urban Asian Indians even minor changes in body mass index (BMI) central adiposity tilts the metabolic balance towards hyperglycemia/insulinemia. Asian Indians are said to have higher upper body adiposity measured as waist-hip ratio (WHR). The cut-off values for normal waist circumference were 80 cm and 0.8 for WHR among women.2

*Dept. of Studies in Food Science and Nutrition Manasagangothri, Mysore, Karnataka **Clinical Nutritionist Aaditya Hospital, Mysore, Karnataka â&#x20AC; Assistant Professor Dept. of General Medicine JSS Medical College and Hospital, JSS University, Mysore, Karnataka Address for correspondence E-mail: pprabhavathisn@gmail.com

The cardiometabolic risk associated with abdominal obesity is attributed to the presence of visceral adipose tissue (VAT), which promotes insulin resistance, dyslipidemia and hypertension.3-5 A national survey of diabetes in the year 2000 conducted in six major cities in India reported 54.1% of diabetes developed in most productive years of life and had higher risk of developing complications of diabetes.6,7

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

ORIGINAL STUDY Asian dyslipidemia is characterized by high serum levels of triglycerides (TG) and lipoprotein a {Lp(a)}, borderline high levels of low-density lipoprotein (LDL) and low levels of high-density lipoprotein (HDL) cholesterol. Asian Indians have high ratio of total cholesterol (TC) to HDL, TG/HDL and apoB/apoA.8-10 These ratios are highly correlated with premature incidence and severity of coronary artery disease (CAD) as well as acute myocardial infraction among Asian Indians. On an average, diabetic patients stay in the hospital 1-3 days longer than patients without diabetes. The prevalence of micro- and macrovascular complications were more in Asians when compared to Europeans. Acute and chronic complications of diabetes, especially cardiovascular diseases (CVDs), results in hospitalization of many patients with diabetes.11 The projections of the present study throw light on the Mysore female diabetic subjects and can be used to develop prevention strategies by consulting physicians. METHODOLOGY A total of 80 volunteers (40 non-hospitalized and 40 hospitalized) with known history of type 2 diabetes mellitus for more than two years were recruited for the study. Volunteers willing to participate and belonging to the age group of 30-70 years with no history of hormonal therapy or hyperthyroidism were included as subjects. Anthropometric measurements like height, weight, mid-upper-arm circumference (MUAC), triceps skin fold (TSF), were recorded using standard procedures.12 Indices viz. BMI, WHR were calculated as an index of obesity. Biochemical assessment included fasting blood sugar (FBS), postprandial blood sugar (PPBS) and lipid profile. The values were recorded from the medical record of the patients. A pre-tested questionnaire was applied to elicit information. Description of the methods applied to collect the data is given below.

Anthropometric Measurements ÂÂ

ÂÂ

Height (cm) was measured with the subject standing, back to a stadiometer in the base feet. Feet were kept parallel with the heels together. The moving arm of the stadiometer was lowered to touch the top of the head and height was measured to the nearest 1.0 mm. Weight (kg) was measured to the nearest 0.005 kg with a weighing machine, which was calibrated daily by using known 5 kg weights.

ÂÂ

MUAC (cm) was measured on the right arm at the point between the tip of olecranon, elbow bent at 90°.

ÂÂ

Skin fold thickness (mm) was measured according to the protocol described by Durmin and Womersley (1) using skin fold calipers (beta-technology incorporated; USA).

ÂÂ

Triceps skin fold (mm) was measured at mid-point of right arm elbow, bent at 90° on the lateral side.

ÂÂ

Waist circumference (cm) was measured midway between the lateral ribs and iliac crests. The subjects were asked not to tuck their stomach in, and the measurement was taken in gentle expiration. Their clothes were loosened around the waist area.

ÂÂ

Hip circumference (cm) was measured at the widest part over the trochanters with the feet kept 25-30 cm apart.

Statistical Analysis The collected data was compiled for obtaining mean ± SD. Student t-test was used for comparison of groups. All the analysis was done using windowsbased SPSS statistical package (version 11.0). Significant figures used; 0.05 < p < 0.10* Moderately significant, 0.01 < p ≤ 0.05** Strongly significant p ≤ 0.01. RESULTS The baseline characteristics of the subjects are shown in Table 1. From among the 80 subjects, 40 were hospitalized and the other 40 non-hospitalized. The mean age of the subjects was 57 (hospitalized) and 60 (non-hospitalized) years. Majority of the subjects from both the groups (74%) reported to have family history of diabetes. It was observed that majority (32%) of hospitalized subjects developed diabetes at an younger age (35-45 years), while among the non-hospitalized subjects the onset was after 45 years of age (37%). A considerably higher percentage of the subjects were found to have basic primary school education (40%) and 30% were illiterate. High majority (47%) of the subjects were found to be daily wagers and were economically backward and belonged to the among the hospitalized group. Diet history showed that a high percentage (68%) of the subjects were nonvegetarians. It is noteworthy to mention that a significantly higher mean body weight (p = 0.031) and BMI (p = 0.005) was seen among the hospitalized subjects while, TSF (0.038) was significantly higher among the non-hospitalized subjects. Waist circumferences was above the normal

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

ORIGINAL STUDY Table 1. Baseline Characteristics of the Subjects Hospitalized (n = 40)

Nonhospitalized (n = 40)

Total (n = 80) percentage (%)

≥35-<45

4 (10)

3 (7)

≥45-<55

10 (26)

≥55-<65

Table 2. Mean ± SD Anthropometric Measures and Indices Parameters

Hospitalized patients (n = 40)

p value

7 (8.7)

Nonhospitalized patients (n = 40)

Height (cm)

157.4 ± 5.4

157.4 ± 5.8

1.000

9 (23)

19 (23.7)

Weight (kg)

63.2 ± 10.1

58.8 ± 7.5

0.031*

13 (32)

12 (30)

25 (31.3)

BMI

(kg/m2)

25.9 ± 4.2

23.6 ± 2.9

0.005**

13 (32.5)

16 (40)

29 (36.3)

Waist (cm)

88.6 ± 10.5

85.8 ± 6.1

0.219

Age of onset of diabetes

WHR (cm)

0.83 ± 0.04

0.81 ± 0.03

0.204

≥35-<45

13 (32)

07 (18)

25 (20)

MUAC (cm)

28.0 ± 3.7

26.8 ± 2.6

0.093

≥45-<55

08 (20)

15 (37)

29 (23)

TSF (cm)

19.6 ± 2.7

20.9 ± 2.8

0.038

≥55-<65

12 (30)

8 (20)

25 (20)

>65

07 (18)

10 (25)

21 (17)

40 (100)

80 (100)

Ιlliterates

10 (25)

13 (32.5)

24 (30)

1-7th

14 (35)

10 (25)

18 (22.5)

8-10th

8 (20)

10 (25)

15 (18.7)

Age (years)

>65

Marital status Married Unmarried

Table 3. Complications and Duration of Diabetes Hospitalized patients Complications

Duration of diabetes

Myocardial infarction

COPD

CKD

>15

Education

PUC and above

8 (20)

7 (17.5)

23 (28.8)

Family history of diabetes mellitus Yes

30 (75)

29 (73)

59 (74)

10 (25)

11 27)

21 (26)

4 (10)

4 (5)

10-20,000

19 (47.5)

9 (22.5)

28 (35)

20-40,000

8 (20)

11 (27.5)

19 (23.8)

40-60,000

4 (10)

12 (30)

16 (20)

5 (12.5)

8 (20)

13 (16.2)

Vegetarians

14 (35)

12 (30)

26 (32)

Non vegetarians

26 (65)

28 (70)

54 (68)

Income ≥5,000

>60,000 Type of diet

cut-off level (>80 cm) recommended for Asian Indians in both the groups. Protein status as indicated through MUAC was within the normal range (Table 2). Different comorbidity conditions of the subjects are presented in Table 3. Sixty-two percent of the

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

Non-hospitalized patients

hospitalized subjects had myocardial infarction as a major complication. The mean duration of diabetes among these subjects was found to be eight years. Among the non-hospitalized subjects, though the duration of diabetes was longer, complication of myocardial infarction was found only in 22% of the subjects. Among the subjects, chronic obstructive pulmonary disease (COPD) appeared to be a common complication in both the groups. It was observed that subjects having diabetes for more than 15 years developed chronic kidney diseases (CKDs), which accounted for 13% among hospitalized and 7% in non-hospitalized subjects. The correlation of somatic measures with biochemical parameters are presented in Table 4. Significant associations were observed in hospitalized subjects against various body and biochemical parameters. Higher BMI showed significant association with TC and LDL. Hip circumference showed inversely significant relationship with LDL. BMI showed moderately significant association with FBS only in non-hospitalized subjects.

ORIGINAL STUDY DISCUSSION

Table 4. Mean Biochemical Parameters of the Subjects Biochemical parameters (mg)

NHP

t value

p value

199.5 ± 36.7 198.0 ± 35.8

0.179

0.858

HDL

46.4 ± 13.2

40.4 ± 7.4

2.57

0.012

LDL

119.6 ± 31.2

112.7 ± 30.4

1.00

0.315

TGs

157.1 ± 59.9 146.4 ± 35.8

0.98

0.331

FBS

176.7 ± 68.3 158.0 ± 23.5

1.63

0.107

PPBS

326.2 ± 99.8 267.2 ± 62.7

3.16

0.002

HP = Hospitalized; NHP = Non-hospitalized; TGs = Triglycerides

Table 5. Correlation for Somatic Measures Parameters BMI

Hospitalized patients

Non-hospitalized patients

T. cho

0.016*

LDL

0.015*

FBS

0.041*

PPBS

Hip circumference

LDL

0.018*

WHR

LDL

0.038*

TSF

LDL

0.042*

*Moderately significant; NS = Not significant

Table 6. Correlation of Biochemical Parameters Parameters FBS PPBS Triglyceride

Hospitalized patients TGL

0.016**

PPBS

0.0002**

HDL

Non-hospitalized patients

0.004**

T. cho

0.0001**

LDL

0.001**

**Highly significant

Correlation between various biochemical parameters are shown in Table 6. Significant association was found between FBS and triglycerides only among hospitalized subjects. Those with high FBS also had high PPBS among the hospitalized subjects. While among non-hospitalized subjects PPBS was highly significant with HDL. Triglycerides showed significant correlation with TC and LDL among only the nonhospitalized subjects.

Epidemiological studies conducted in southern India show a steady increase in the prevalence of diabetes in the urban population. The earlier reports from Chennai show a male preponderance in the prevalence of diabetes, which in subsequent years had shifted slightly towards a female excess.6,7,13-16 In India, nearly 75% of the type 2 diabetics have firstdegree family history of diabetes indicating a strong familial aggregation. Risk factors for developing type 2 diabetes, peculiar to the Indian population, are high familial aggregation, central obesity, insulin resistance and lifestyle changes due to urbanization.17 Insulin resistance has been demonstrated to be a characteristic feature of Asian Indians. In the present study, the onset of diabetes was found to be between the age groups of 35-45 years and all the subjects reported family history of diabetes. The mean age of onset of diabetes was found to be 35 years. Several studies on the Asian population reveal that the onset of diabetes is seen before the age of 50 years and at the time of diagnosis of diabetes most of them had developed micro- and macrovascular complications.18 Familial aggregation, a typical feature of the Indian population, could be one of the cause for early onset of diabetes among the subjects. The three urban diabetic surveys conducted in 1989, 1995 and 2000 in randomly collected areas in the city of Madras (now known as Chennai) reported no significant time-related change in the prevalence of obesity as measured by BMI.7,13 Analysis of these surveys showed, that among the diabetic women, a higher percentage had BMI of 23-24.9 kg/m2.19 The normal cut-off values for Asian Indians are below 23 kg/m2. A BMI of ≥25 kg/m2 has been considered to indicate different grades of obesity. In the present study, the hospitalized patients had a mean BMI of 25.9 and 23.6 among the non-hospitalized subjects.7 A peculiar pattern was observed among the study population that, there was no significant association between BMI and PPBS in the hospitalized subjects while, non-hospitalized subjects had significant association with only FBS. Studies show that the factors, which influence the BMI and the WHR have also frequently lacked specificity with respect to women.7,13 Central obesity is common among Indians despite low rates of general obesity and this android pattern of body fat typified by more upper body adiposity measured as WHR was found to be a greater risk factor as compared to general obesity. The cut-off values for

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

ORIGINAL STUDY normal waist circumference are 80 cm and 0.8 for WHR in women.20-22 Asian Indians have higher upper body adiposity measured as WHR. This has been suggested to be a superior predictor of CVD risk because it includes a measurement of hip circumference, which is inversely associated with dysglycemia, dyslipidemia, diabetes, hypertension, CVD and death.23-27 The present study population also exhibited higher WHR as compared to the Asian standards. This could be one of the major causes for dyslipidemia exhibited by the subjects. Increasing evidence suggests that waist and hip circumferences have independent and opposite associations with glucose and lipid levels and risk of diabetes and CVD.28,29 al17

Study by Ramachandran et has reported that Asian Indians require higher levels of plasma insulin to maintain normoglycemia; they also have other features of insulin resistance such as central obesity and high percentage of body fat in comparison to many other populations. Significant association was found between various lipid profile parameters and blood sugar levels in hospitalized subjects, while for non-hospitalized subjects PPBS was strongly associated with HDL and triglycerides with TC and LDL. Based on the available published data there is a paucity of reliable data on diabetes related complications among people worldwide. A common complication of diabetes and the most common cause of mortality in people with diabetes is CVD.18 This was prominently seen among hospitalized subjects who had blood sugar levels of >300 mg% on admission. The most common complications seen was myocardial infarction followed by COPD and CKD. Among the subjects majority were hospitalized on an average of at least 3 times a year. The reason for hospitalization included; myocardial infraction, COPD and/or nephropathy. More than 90% of the subjects exhibited blood sugar >300 mg on admission despite being on oral hypoglycemic agents. Evaluation of elevated blood sugar revealed-poor dietary habits, irregular meal timings, festive occasions, physical inactivity and poor morbidity status. CONCLUSION The main findings of the study were that, majority of the subjects had onset of diabetes mellitus at the mean age of 35 years. This early onset of diabetes will result in higher diabetes related complications at an earlier age, which can lead to increased mortality in the productive years of life. There is an urgent need to prevent diabetes and its complications rather than

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

simply treat it once established. Patients should be educated for lifestyle changes such as weight control, increased physical exercise and smoking cessation, which are potentially beneficial in preventing diabetes mellitus and CAD. The limited data available on gender-wise, region-wise diabetes complication rates highlight the need for nation-specific and populationspecific studies. Furthermore, the morbidity and mortality caused by diabetes mellitus can be reduced by secondary prevention through regular screening, early detection and appropriate treatment of chronic complications. 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. Must A, Jacques PF, Dallal GE, Bajema CJ, Dietz WH. Long-term morbidity and mortality of overweight adolescents. A follow-up of the Harvard Growth Study of 1922 to 1935. N Engl J Med 1992;327(19):1350-5. 3. Tchernof A, Lamarche B, Prud’Homme D, Nadeau A, Moorjani S, Labrie F, et al. The dense LDL phenotype. Association with plasma lipoprotein levels, visceral obesity, and hyperinsulinemia in men. Diabetes Care 1996;19(6):629-37. 4. Pouliot MC, Després JP, Nadeau A, Moorjani S, Prud’Homme D, Lupien PJ, et al. Visceral obesity in men. Associations with glucose tolerance, plasma insulin, and lipoprotein levels. Diabetes 1992;41(7):826-34. 5. Després JP, Moorjani S, Lupien PJ, Tremblay A, Nadeau A, Bouchard C. Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease. Arteriosclerosis 1990;10(4):497-511. 6. Ramaiya KL, Kodali VR, Alberti KG. Epidemiology of diabetes in Asians of the Indian subcontinent. Diabetes Metab Rev 1990;6(3):125-46. 7. Ramachandran A, Snehalatha C, Dharmaraj D, Viswanathan M. Prevalence of glucose intolerance in Asian Indians. Urban-rural difference and significance of upper body adiposity. Diabetes Care 1992;15(10):1348-55. 8. Enas EA. How to beat the heart disease epidemic among south Asians; a prevention and management guide for asian Indians and their doctors. Downers Grove IL; Advanced Heart Lipid Clinic USA; 2007. 9. Smith J, Cianflone K, Al-Amri M, Sniderman A. Body composition and the apoB/apoA-I ratio in migrant Asian Indians and white Caucasians in Canada. Clin Sci (Lond) 2006;111(3):201-7. 10. Sierra-Johnson J, Somers VK, Kuniyoshi FH, Garza CA, Isley WL, Gami AS, et al. Comparison of apolipoprotein-B/ apolipoprotein-AI in subjects with versus without the metabolic syndrome. Am J Cardiol 2006;98(10):1369-73.

ORIGINAL STUDY 11. Chowdhury TA, Lasker SS. Complications and cardiovascular risk factors in South Asians and Europeans with early-onset type 2 diabetes. QJM 2002;95(4):241-6. 12. Jelliffee DB. The Assessment of the Nutritional Status of the Community. WHO Monograph Series no. 53. Geneva: World Health Organization, 1966. 13. Ramachandran A, Snehalatha C, Latha E, Manoharan M, Vijay V. Impacts of urbanisation on the lifestyle and on the prevalence of diabetes in native Asian Indian population. Diabetes Res Clin Pract 1999;44(3):207-13. 14. Iyer R, Upasani S, Baitule MN. Diabetes mellitus in Dombivli – an urban population study. 17th International Diabetes Federation Congress. Mexico city. Diabetes Res Clin Pract 2000;50(Suppl 1):519. 15. Mohan V, Shanthirani S, Deepa R, Premalatha G, Sastry NG, Saroja R; Chennai Urban Population Study (CUPS No. 4). Intra-urban differences in the prevalence of the metabolic syndrome in southern India - the Chennai Urban Population Study (CUPS No. 4). Diabet Med 2001;18(4):280-7. 16. V erma NPS, Madhu SV. Prevalence of known diabetes in urban east Delhi. Diabetes Res Clin Pract 2000;50 (Suppl 1):121. 17. Davey G, Ramachandran A, Snehalatha C, Hitman GA, McKeigue PM. Familial aggregation of central obesity in Southern Indians. Int J Obes Relat Metab Disord 2000;24(11):1523-7. 18. Ramachandran A, Snehalatha C, Satyavani K, Sivasankari SS, Vijay V. Metabolic syndrome in urban Asian Indian adults - a population study using modified ATP III criteria. Diabetes Res Clin Pract 2003;60(3):199-204. 19. Ramachandran A, Snehalatha C, Vijay V. Temporal changes in prevalence of type 2 diabetes and impaired glucose tolerance in urban southern India. Diabetes Res Clin Pract 2002;58(1):55-60. 20. Ramachandran A, Snehalatha C, Kapur A, Vijay V, Mohan V, Das AK, et al; Diabetes Epidemiology Study Group in India (DESI). High prevalence of diabetes and impaired

glucose tolerance in India: National Urban Diabetes Survey. Diabetologia 2001;44(9):1094-101. 21. Pope SK, Sowers MF, Welch GW, Albrecht G. Functional limitations in women at midlife: the role of health conditions, behavioral and environmental factors. Womens Health Issues 2001;11(6):494-502. 22. Luke A, Durazo-Arvizu R, Rotimi C, Prewitt TE, Forrester T, Wilks R, et al. Relation between body mass index and body fat in black population samples from Nigeria, Jamaica, and the United States. Am J Epidemiol 1997;145(7):620-8. 23. Willett WC. Anthropometric measures and body composition. In: Nutritional Epidemiology. Oxford University Press: New York 199:p.244-72. 24. Seidell JC, Pérusse L, Després JP, Bouchard C. Waist and hip circumferences have independent and opposite effects on cardiovascular disease risk factors: the Quebec Family Study. Am J Clin Nutr 2001;74(3):315-21. 25. Okura T, Nakata Y, Yamabuki K, Tanaka K. Regional body composition changes exhibit opposing effects on coronary heart disease risk factors. Arterioscler Thromb Vasc Biol 2004;24(5):923-9. 26. Lissner L, Björkelund C, Heitmann BL, Seidell JC, Bengtsson C. Larger hip circumference independently predicts health and longevity in a Swedish female cohort. Obes Res 2001;9(10):644-6. 27. Heitmann BL, Frederiksen P, Lissner L. Hip circumference and cardiovascular morbidity and mortality in men and women. Obes Res 2004;12(3):482-7. 28. S nijder MB, Dekker JM, Visser M, Yudkin JS, Stehouwer CD, Bouter LM, et al. Larger thigh and hip circumferences are associated with better glucose tolerance: the Hoorn study. Obes Res 2003;11(1):104-11. 29. Snijder MB, Dekker JM, Visser M, Bouter LM, Stehouwer CD, Kostense PJ, et al. Associations of hip and thigh circumferences independent of waist circumference with the incidence of type 2 diabetes: the Hoorn Study. Am J Clin Nutr 2003;77(5):1192-7.

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Artificial Sweeteners can Cause Diabetes Consumption of noncaloric, artificially sweetened beverages (ASBs) is associated with an increased risk for obesity, type 2 diabetes, metabolic syndrome and cardiovascular disease. This counterintuitive result reflects negative consequences of interfering with learned relationships between sweet tastes and typical postingestive outcomes, which may result in impaired ability to compensate for energy provided when caloric sweeteners are consumed. The study by Dr Susan E Swithers at Purdue University, West Lafayette, IN published in July issue of Trends in Endocrinology & Metabolism found an elevated risk for weight gain and obesity, metabolic syndrome, type 2 diabetes, coronary heart disease and hypertension in those who consumed ASBs. No decreased risk for weight gain or increased body fat percentage was associated with ASB intake.

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

CLINICAL STUDY

Comparison of Insulin Glargine with Human Premix Insulin in Patients with Type 2 Diabetes Inadequately Controlled on Oral Hypoglycemic Drugs in a 24-week Randomized Study Among Central Indian Population ABHISHEK SINGHAI*, SUBODH BANZAL**, DOLLY JOSEPH**, RAJESH KUMAR JHA†

ABSTRACT Objective: To compare the safety and efficacy of the long-acting analog insulin glargine and human premix insulin in patients with type 2 diabetes who were previously treated with oral hypoglycemic drugs alone but inadequately controlled. Research design and methods: A total of 750 subjects with type 2 diabetes who were receiving oral hypoglycemic drugs for diabetes control were randomized to receive insulin glargine once-daily (n = 370) or human premix insulin twice-daily (n = 380) for 24 weeks in an open-label, tertiary center study. Doses were adjusted systematically to obtain target fasting glucose <100 mg/dl. Outcomes included fasting blood sugar, glycosylated hemoglobin (HbA1C) levels, change in weight and insulin dose from study start to end. Results: At the start of study, age range was 30-70 years, BMI was 26.48 ± 6.3 kg/m2 and HbA1C was 11.9 ± 3.1% (mean ± SD) for both groups. The mean change (means ± SD) in HbA1C from baseline to endpoint was similar in the insulin glargine group (−3.0 ± 1.68%) and the human premix insulin group (−2.89 ± 1.79%) (p = 0.3861). The symptomatic hypoglycemic episodes were greater with human premix insulin than with glargine (significance level 0.00002). Subjects in the insulin glargine group experienced less weight gain than those in the premix human insulin group (0.4 vs 1.4 kg, p < 0.0001). Conclusions: In patients with type 2 diabetes, once-daily bedtime insulin glargine is as effective as twicedaily human premix insulin in improving and maintaining glycemia control. In addition, insulin glargine demonstrates a lower risk of symptomatic hypoglycemia and less weight gain compared with human premix insulin. The treatments were associated with similar reductions in fasting glucose levels and HbA1C levels. Keywords: Type 2 diabetes, insulin glargine, human premix insulin, oral hypoglycemic drugs

ype 2 diabetes is a progressive disorder of β-cell dysfunction. Patients using oral therapy for it seldom achieve and maintain the recommended 7% glycosylated hemoglobin (HbA1C) goal for glycemic control1,2 and are exposed to increasing risks of diabetic complications as control worsens over time.3,4 However, the majority of patients with a longer duration of diabetes remain poorly controlled with oral agents, and use of insulin, which could improve glycemic control, is often long delayed and not

*Assistant Professor **Associate Professor †Professor and Head Dept. of Medicine, Sri Aurobindo Medical College, Indore, MP Address for correspondence Dr Abhishek Singhai Assistant Professor Dept. of Medicine, Sri Aurobindo Medical College, Sanwer Road, Indore - 453 555, MP E-mail: drabhisheksinghai@gmail.com

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

aggressive enough. The reluctance to initiate insulin therapy seems partly due to its perceived complexity, and fear of hypoglycemia, which may be the greatest barrier.5 A regimen that may make initiation of insulin simpler and more effective has been tested in several small studies.6-8 A single bedtime injection of long-acting (basal) insulin is added while prior oral agents are continued, and insulin is systematically titrated, seeking a defined fasting glucose target. Glargine, a longacting insulin analog with a more favorable 24-hour time-action profile (no pronounced peak) than long- or intermediate-acting human insulin preparations,9,10 may be especially suited to this regimen. We compared the abilities of glargine and human premix insulin to reduce HbA1C to 7% when added to ongoing oral therapy and the hypoglycemia accompanying this effort using a simple algorithm for insulin dosage titration seeking fasting blood glucose (FBG) target of 100 mg/dl.

CLINICAL STUDY RESEARCH DESIGN AND METHODS Enrolled subjects were men or women aged 30-70 years, with type 2 diabetes and treated with stable doses of one or more oral hypoglycemic drugs (sulfonylurea, metformin or pioglitazone) for ≥6 months. There were no significant differences in the mean age, racial distribution, body mass index (BMI), admission blood glucose or HbA1C between treatment groups (Table 1). Inclusion criteria included BMI between 26 and 40 kg/m2, HbA1C >7.5 and FBG ≥140 mg/dl at screening. Exclusion criteria included prior use of insulin, current use of an α-glucosidase inhibitor or a rapid-acting insulin secretagogue, use of other agents affecting glycemic control (including systemic glucocorticoids, nonselective β-sympathetic blockers and antiobesity drugs), history of ketoacidosis or selfreported inability to recognize hypoglycemia, or serum creatinine (≥1.5 mg/dl for men and ≥1.4 mg/dl for women), and a history of drug or alcohol abuse. This single center, randomized, parallel, 24-week comparative study was performed at Sri Aurobindo Medical College, Indore, Madhya Pradesh between January 2009 and September 2012. Patients were randomized to either glargine (Lantus; Aventis) or human premix insulin (mixture of 30% neutral soluble insulin and 70% isophane insulin) to be administered subcutaneously at bedtime (glargine) or twice a day (human premix insulin), using a pen injector or insulin syringe as preferred by patient for 24 weeks. Oral hypoglycemic drugs were continued at similar dosages. The starting dose of glargine insulin was 10 IU/day, and dosage was titrated weekly according to laboratory blood glucose levels or self-monitored capillary FBG measurements using meters (Accu-Chek Advantage; Roche Diagnostics) that provide values corresponding closely to laboratory measurements of plasma glucose. Dosages were titrated till target FBG of ≤100 mg/dl was achieved (Table 2). Subjects visited center at baseline and 1, 3, 5, 7, 10, 12, 18 and 24 weeks and contacted telephonically on 2, 4, 6, 8, 9, 11, 13, 14, 20 and 22 weeks. Glucose values and insulin changes were recorded each time. Subjects were asked to test glucose whenever they experienced symptoms that might be related to hypoglycemia and to record the results. Subjects documenting hypoglycemia by glucose levels ≤70 mg/dl were asked to reduce insulin dose by 2 units. Insulin titration started after one week if symptoms of hypoglycemia did not recur.

Weight was measured, and venous blood for FPG was collected between 08:00 and 09:00 hours at each visit. Blood for HbA1C was collected at baseline and 12 and 24 weeks. RESULTS Of 750 patients screened, 370 were treated with glargine and 380 with human premix insulin. A total of five insulin glargine recipients and 15 human premix insulin recipients withdrew from the study after beginning of treatment. In three insulin glargine subjects and nine human premix insulin subjects, the reason was the subject’s desire to discontinue or loss to follow-up. Two insulin glargine subjects (0.54%) and six human premix insulin subjects (1.57%) discontinued treatment because of adverse events. Figure 1 illustrates that the mean improvements in HbA1C were similar: −3.00 ± 1.68% for glargine and −2.89 ± 1.79% for human premix insulin (p = 0.3861). The proportions of patients achieving HbA1C <7% were also similar (76.3 and 75.5%, respectively), but fewer human premix insulin than glargine-treated patients reached HbA1C <6.5% (14.6 and 26.7%, respectively). Table 1. Baseline Characteristics of Subjects in the Study

N Sex (F/M) (%) Age (years) Duration of diabetes (years) BMI (kg/m2)

Glargine

Human premix insulin

370

380

58/42

54/46

45 ± 9.5

46 ± 8.9

10 ± 5

9.0 ± 6

31.8 ± 3.63

32.2 ± 3.85

FPG (mg/dl)

188 ± 39

184 ± 47

HbA1C (%)

8.58 ± 0.7

8.46 ± 0.8

SU + metformin

SU + metformin + TZD

Prior therapy (%)

Table 2. Weekly Insulin Titration Start with 10 IU/day bedtime basal insulin and adjust weekly FBG values

Increase of insulin dosage (IU) day

>180 mg/dl

141-180 mg/dl

121-140 mg/dl

101-120 mg/dl

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

CLINICAL STUDY 10 9

Glargine

Human premix

7 HbA1C

6 5

Weight gain was significantly higher with human premix insulin versus glargine: 1.4 Âą 0.02 and 0.4 Âą 0.012 kg (p < 0.0001). Average glargine insulin dose was 0.26 IU/kg and average human premix insulin dose was 0.64 IU/kg (Fig. 3).

4 3 2 1 0

Weeks of treatment

DISCUSSION

Figure 1. Mean HbA1C variation during study. 200

Glargine

Fasting blood sugar (mg/dl)

180

Human premix

160 140 120 100 80 60 40 20 0

Weeks of treatment

Figure 2. Mean HbA1C variation during study.

Insulin dose (IU/kg)

1 0.9

Glargine

0.8

Human premix

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

20 24

Weeks of treatment

Figure 3. Mean daily insulin dose during study.

Change in FBG from baseline was significant at endpoint in both groups (p < 0.0001). Similar proportions of subjects receiving insulin glargine (29.6%) and neutral protamine Hagedorn (NPH) (27.1%) achieved FBG <90 mg/dl by study endpoint (Fig. 2). Risk of hypoglycemia was significantly higher with human

premix insulin. We found that subjects in the insulin glargine group had 12 episodes of hypoglycemia documented by a blood glucose value <70 mg/dl, compared with subjects in the human premix insulin group who reported 42 episodes (significance level 0.00002).

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

Insulin glargine was developed as improved longacting, basal insulin. It is an analog of human insulin that is produced in a nonpathogenic strain of Escherichia coli. Insulin glargine differs from human insulin by the addition of two arginine amino acids to the C-terminus of the B-chain and the replacement of asparagine at position A21 by glycine. These changes shift the isoelectric point so that the molecule is soluble at an acid pH, but less soluble at neutral physiological pH levels. This results in a clear solution (pH 4.0) that when injected forms a precipitate in the subcutaneous tissue, which delays absorption and prolongs duration of action.11 The absorption characteristics of insulin glargine are not affected by the site of injection (arm, leg or abdominal regions). Furthermore, compared with NPH insulin, the absorption rate is significantly slower with approximately 50% of the injected dose of insulin glargine still detectable after 24 hours compared with approximately 20% of the NPH insulin dose.12 A potential major advantage of insulin glargine over NPH insulin and ultralente preparations is a lack of pronounced peaks in plasma insulin concentrations and a more constant delivery of insulin over a 24-hour period. This smooth profile was clearly shown in studies of insulin glargine versus NPH insulin in healthy volunteers and of insulin glargine versus NPH and ultralente insulin in patients with type 1 diabetes.13,14 In fact, in this later study, the delayed absorption of insulin glargine provided a consistent delivery of insulin that closely mimicked insulin delivery by continuous subcutaneous insulin infusion (CSII). Furthermore, in this study, interindividual variability in plasma insulin concentrations was lower with insulin glargine than with NPH or ultralente. These pharmacokinetic studies highlight the potential of insulin glargine to be a better insulin for patients with diabetes. Riddle et al compared the addition of either insulin glargine or NPH insulin with existing regimens of

CLINICAL STUDY one or two oral antidiabetic agents. This 24-week, randomized trial enrolled 756 patients. Although both basal insulins reduced FPG and HbA1C levels by similar amounts (FPG: 6.4 mmol/l vs 6.6 mmol/l; HbA1C: 6.96% vs 6.97% for insulin glargine and NPH insulin, respectively), 25% more patients attained a target HbA1C level of = 7% without experiencing nocturnal hypoglycemia with insulin glargine than with NPH insulin (p < 0.05). The overall rate of hypoglycemia, rate of symptomatic events, and rate of confirmed events in the insulin glargine group were reduced by 21%, 29%, and 41%, respectively.15 Yki-Jarvinenâ&#x20AC;&#x2122;s group designed a similar trial, but the treatment period was one year. Again, insulin glargine and NPH insulin reduced HbA1C levels by a similar amount, but there was less nocturnal hypoglycemia (9.9% vs 24.0% of patients, p < 0.001) and insulin glargine was associated with better post-meal glucose control than NPH insulin (9.9 mmol/l vs 10.7 mmol/l, p < 0.002).16 While some studies have shown similar rates of hypoglycemia when compared with NPH insulin, there is also evidence that insulin glargine can maintain effective glucose control and reduce risk of hypoglycemia. Rosenstock et al randomized 518 patients with type 2 diabetes, who were already being treated with basal NPH insulin and regular insulin, to receive either insulin glargine or NPH insulin once- or twice-daily. While improvements in HbA1C were comparable, the group who switched to insulin glargine showed a 25% decrease in the rate of nocturnal hypoglycemia (26.5% vs 35.5%, p = 0.0136). A recent meta-analysis of four open-label, randomized trials of insulin glargine versus NPH insulin adds further weight to this assertion. In total, 2,304 patients were randomized and while glycemic control was similar between groups, there was a significant and consistent reduction in the risk of hypoglycemia.17 While in our study insulin glargine and human premix insulin were both associated with significant reductions in fasting blood sugar and HbA1C but hypoglycemia risk was lesser with insulin glargine. Weight gain has long been an issue with insulin therapy. Insulin glargine has been associated with a mean weight gain of upto 2.02 kg in a 39-month study of 239 patients being treated in combination with oral antidiabetic agents, but many studies have reported no significant weight gain despite significant improvements in HbA1C.18 Some evidence suggests that insulin glargine may be associated with less weight gain than NPH insulin. In two studies, NPH insulin

was associated with significantly more weight gain than insulin glargine.19,20 In a 16-week trial in patients with type 2 diabetes, weight gain was 0.4 kg with insulin glargine versus 1.4 kg with NPH insulin (p < 0.0007).17 In contrast, one study reported similar gains in mean body weight following one year of treatment of patients with type 2 diabetes with insulin glargine (+2.6 kg, n = 214) and NPH insulin (+2.3 kg, n = 208).16 While in our study, weight gain was significantly higher with human premix insulin versus glargine: 1.4 Âą 0.02 and 0.4 Âą 0.012 kg (p < 0.0001). Case reports of nausea and vomiting in patients receiving insulin glargine have been published,21 although these adverse events were not seen in our study. CONCLUSION Managing diabetes with insulin is primarily based on the balance between the necessity of tight glycemic control and the risks associated with hypoglycemia. Insulin glargine appears to improve this balance such that at least equivalent glycemic control can be achieved with a lower risk of hypoglycemia than traditional basal insulins. In patients with type 2 diabetes, the reduced risk of hypoglycemia with insulin glargine, combined with the flexibility of once-daily dosing at any time of the day, is likely to make insulin a more acceptable option, which may mean that patients are more open to start insulin earlier and to intensify their insulin sooner. In the long-term this may lead to improvements in HbA1C and thereby a reduction in the long-term complications of diabetes. Insulin glargine treatment was associated with significantly less weight gain than NPH insulin treatment (0.40 vs 1.40 kg). Presumably, the difference in weight gain despite comparable improvement in glycemic control reflects the less frequent hypoglycemia seen with insulin glargine, the correction of which requires supplemental caloric intake. REFERENCES 1. Harris MI, Eastman RC, Cowie CC, Flegal KM, Eberhardt MS. Racial and ethnic differences in glycemic control of adults with type 2 diabetes. Diabetes Care 1999;22(3): 403-8. 2. Turner RC, Cull CA, Frighi V, Holman RR; UK Prospective Diabetes Study Group. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA 2005;281(21):2005-12.

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CLINICAL STUDY 3. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. Association of glycemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321(7258):405-12. 4. Klein R, Klein BE, Moss SE. Relation of glycemic control to diabetic microvascular complications of diabetes mellitus. Ann Intern Med 1996;124(1 Pt 2)90-6. 5. Hayward RA, Manning WG, Kaplan SH, Wagner EH, Greenfield S. Starting insulin therapy in patients with type 2 diabetes: effectiveness, complications, and resource utilization. JAMA 1997;278(20):1663-9. 6. Taskinen MR, Sane T, Helve E, Karonen SL, Nikkila EA, Yki-Jarvinen H. Bedtime insulin for suppression of overnight free fatty-acid, blood glucose, and glucose production in NIDDM. Diabetes 1989;38(5):580-8. 7. Riddle MC. Evening insulin strategy. Diabetes Care 1990; 13(6):676-86. 8. Shank ML, Del Prato S, DeFronzo RA. Bedtime insulin/ daytime glipizide: Effective therapy for sulfonylurea failures in NIDDM. Diabetes 1995;44(2):165-72. 9. Bolli GB, Owens DR. 2000;356(9228):443-5.

Insulin

glargine.

Lancet

10. Rosenstock J, Schwartz SL, Clark CM Jr, Park GD, Donley DW, Edwards MB. Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care 2001;24(4):631-6. 11. Bähr M, Kolter T, Seipke G, Eckel J. Growth promoting and metabolic activity of the human insulin analogue [GlyA21, ArgB31, ArgB32] insulin (HOE 901) in muscle cells. Eur J Pharmacol 1997;320(2-3):259-65. 12. Owens DR, Coates PA, Luzio SD, Tisbergen JP, Kurzhals R. Pharmacokinetics of 125-Ilabeled insulin glargine (HOE 901) in healthy men: comparison with NPH insulin and the influence of different subcutaneous injection sites. Diabetes Care 2000;23(6):813-9. 13. Heinemann L, Linkeschova R, Rave K, Hompesch B, Sedlak M, Heise T. Time-action profile of the long-acting

insulin analog insulin glargine (HOE901) in comparison with those of NPH insulin and placebo. Diabetes Care 2000;23(5):644-9. 14. Lepore M, Pampanelli S, Fanelli C, Porcellati F, Bartocci L, Vincenzo A, et al. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes 2000;49(12):2142-8. 15. 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):30806. 16. Yki-Jarvinen H, Dressler A, Ziemen M; HOE 901/300S Study Group. Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. HOE 901/3002 Study Group. Diabetes Care 2000;23(8):1130-6. 17. Rosenstock J, Schwartz SL, Clark CM Jr, Park GD, Donley DW, Edwards MB. Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care 2001;24(4):631-6. 18. Dunn CJ, Plosker GL, Keating GM, McKeage K, Scott LJ. Insulin glargine: an updated review of its use in the management of diabetes mellitus. Drugs 2003;63(16): 1743-78. 19. Raskin P, Klaff L, Bergenstal R, Halle JP, Donley D, Mecca T. A 16-week comparison of the novel insulin analog insulin glargine (HOE 901) and NPH human insulin used with insulin lispro in patients with type 1 diabetes. Diabetes Care 2000;23(11):1666-71. 20. Garg SK, Paul JM, Karsten JI, Menditto L, Gottlieli PA. Reduced severe hypoglycemia with insulin glargine in intensively treated adults with type 1 diabetes. Diabetes Technol Ther 2004;6(5):589-95. 21. Dixon AN, Bain SC. Nausea and vomiting due to insulin glargine in patient with type 1 diabetes mellitus. BMJ 2005;330(7489):455.

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Alogliptin Wins FDA Go-ahead for Type 2 Diabetes After a long delay, the FDA approved the oral drug alogliptin (Nesina) for treatment of adults with type 2 diabetes, as well as two products combining alogliptin with other antidiabetic drugs. Approved simultaneously with Nesina were alogliptin combinations with metformin (Kazano) and with pioglitazone (Oseni). Alogliptin is the fourth dipeptidyl-peptidase-4 inhibitor to win FDA approval, joining sitagliptin (Januvia), saxagliptin (Onglyza) and linagliptin (Tradjenta). (Source: Medpage Today)

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

CLINICAL STUDY

A Study of Metabolic Syndrome and its Components in Type 2 Diabetes Mellitus Subjects and their Asymptomatic First-degree Relatives JL PATEL*, AM SUTHAR*, VB DALSANIYA*, AP PARIKH**, NN SUTHAR†, KL PATEL‡

ABSTRACT Objectives: To study clinical profile of metabolic syndrome and its individual components in type 2 diabetes mellitus subjects and their asymptomatic first-degree relatives. To identify risk factors of glucose intolerance. Material and methods: Randomly selected type 2 diabetes mellitus (T2DM) subjects age >40 years (n = 20; 10 males, 10 females) and their asymptomatic first-degree relatives age >30 years (excluding pregnant women) (n = 80; 46 males, 34 females) subjected to regression analysis with reference to components of metabolic syndrome (waist circumference, serum triglyceride, serum high-density lipoprotein (HDL), fasting plasma glucose, hypertension) and other variables. Student t-test was used for comparison of results. Results: Among T2DM subjects: Ninety percent were hypertensive, 85% had low HDL, 30% males and 80% females had central obesity, 85% had metabolic syndrome. Among asymptomatic first-degree relatives of T2DM subjects: 48.7% had metabolic syndrome; hypertension, low HDL, central obesity, impaired glucose tolerance, T2DM were present in 52.5%, 68.7%, 48.7%, 26.2%, 35%, respectively. In subjects with abnormal glucose level (n = 49) 59.18% subjects and in subjects with normal glucose level (n = 31) 32.25% met the criteria for metabolic syndrome (p = 0.023). Impaired fasting glucose, increased hip circumference and low HDL independently determined two hours glycemia value in OGTT (R2 = 0.7; p = 0.001). Conclusion: In T2DM and their asymptomatic first-degree relatives, hypertension and low HDL were commonest components of metabolic syndrome, females were more obese. Glucose intolerance was significantly associated with other components of metabolic syndrome. Impaired fasting glucose, increased hip circumference and low HDL levels were risk factors for glucose intolerance. Keywords: Metabolic syndrome, diabetes mellitus, first-degree relatives of type 2 diabetes mellitus subjects, impaired glucose tolerance

etabolic syndrome is a constellation of metabolic abnormalities that includes central obesity, hypertension, elevated fasting glucose, low high-density lipoprotein (HDL) cholesterol, high triglyceride (National Cholesterol Education Program Adult Treatment Panel III [NCEP ATP III]). It is associated with increased risk of coronary artery disease and stroke.

a formal definition of metabolic syndrome. Three years later, the NCEP ATP III proposed metabolic syndrome based on clinical parameters. The European Group for the study of Insulin Resistance (EGIR) has also developed its own definition.

ÂÂ

Beer-Belly syndrome

In 1988, Reaven proposed the concept of syndrome X. In 1988, World Health Organization (WHO) proposed

ÂÂ

Atherothrombogenic syndrome

ÂÂ

Deadly quarter

ÂÂ

Dysmetabolic syndrome

ÂÂ

Insulin resistance syndrome

ÂÂ

Syndrome X

*Final Year Resident **Professor †Associate Professor ‡Assistant Professor Dept. of Medicine, Vadilal Sarabhai General Hospital, Ellisebridge Ahmedabad, Gujarat Address for correspondence Dr JL Patel Final Year Resident E-7, Doctor Quarters, VS Hospital Campus, Ellisebridge, Ahmedabad, Gujarat E-mail: jigsp2008@gmail.com

Different terminologies used for metabolic syndrome:

NCEP ATP III 2001 CRITERIA FOR METABOLIC SYNDROME The purpose of ATP III was to identify people at higher long-term risk for cardiovascular diseases (CVDs)

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

CLINICAL STUDY who deserved clinical lifestyle intervention to reduce risk. Presence of three of the following five factors is required for diagnosis of metabolic syndrome. ÂÂ

Central obesity: Abdominal waist circumference: Men >102 cm, women >88 cm

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Fasting plasma glucose >110 mg/dl or diagnosed type 2 diabetes mellitus (T2DM)

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Fasting plasma medication

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Fasting plasma HDL cholesterol: Men <40 mg/dl, women <50 mg/dl or medication

ÂÂ

Blood pressure ≥130/85 mmHg or medication.

triglyceride

>150

mg/dl

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Metabolic syndrome is associated with increased risk of diabetes, coronary artery disease, stroke and cardiovascular mortality more than individual components.

ÂÂ

Family history of noninsulin-dependent diabetes mellitus (NIDDM) is associated with increased risk of diabetes. First-degree relatives of NIDDM patients have 40% lifetime risk of developing diabetes.

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Diabetes occurs a decade earlier in Asian population. India has a large and growing population of diabetic patients, its prevalence will reach 350 million by 2025. Diabetes is associated with increased risk for CVD, stroke and other risk factors of metabolic syndrome. So, early recognition of metabolic syndrome in such subjects and timely intervention along with lifestyle modification can delay emergence of diabetes mellitus (DM), CVD, stroke and subsequent mortality.

ATP III specifically noted that some individual having only two criteria of metabolic syndrome appear to be insulin resistance when the waist circumference is only marginally elevated. If so they should be benefited from clinical intervention similarly to others who have greater increases in waist circumference. RECENT DEFINITIONS In 2003, the American Association of Clinical Endocrinologists (AACE) modified ATP III criteria to refocus on insulin resistance as the primary cause of metabolic risk factors. No specified number of factors qualified for diagnosis, which was left to clinical judgment. Other factors used for clinical judgment were a family history of CVD or T2DM, polycystic ovary syndrome and hyperuricemia. In 2005, the International Diabetes Foundation (IDF) published new criteria that again modified the ATP III definition. They considered that abdominal obesity is so highly correlated with insulin resistance. The IDF clinical definition thus makes the presence of abdominal obesity necessary for diagnosis. Insulin resistance syndrome is associated with:

AIMS AND OBJECTIVES ÂÂ

To study clinical profile of metabolic syndrome and its individual components in T2DM subjects and their asymptomatic first-degree relatives.

ÂÂ

To study clinical profile of metabolic syndrome and its individual components in asymptomatic first-degree relatives of T2DM subjects.

ÂÂ

To identify risk factors of glucose intolerance.

MATERIAL AND METHODS For this study, 20 T2DM patients and their family members were subjected to analysis at a large teaching general hospital.

Inclusion Criteria ÂÂ

Patient with T2DM with age >40 years

ÂÂ

All asymptomatic first-degree relative >30 years (men and nonpregnant women).

ÂÂ

T2DM

ÂÂ

CVD

ÂÂ

Essential hypertension

ÂÂ

Polycystic ovary syndrome (PCOS)

ÂÂ

Nonalcoholic fatty liver disease

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Patient with T2DM age <40 years

ÂÂ

Certain forms of cancers

ÂÂ

All first-degree relative age <30 years

ÂÂ

Sleep apnea

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Pregnant women

One of the most important reasons for introducing concept of metabolic syndrome is to heighten the awareness of the increased risk associated with metabolic abnormalities.

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

Excluding Criteria

Family selection was random.

Study Design Retrospective and cross-sectional study.

age

CLINICAL STUDY Study Size

Definition and Diagnostic Criteria

Randomly selected T2DM subjects age >40 years (n = 20; 10 males, 10 females) and their asymptomatic first-degree relatives age >30 years (excluding pregnant women) (n = 80; 46 males, 34 females).

We counted participants who reported currently using antihypertensive or antidiabetic medication (insulin or oral agents) or antihyperlipidemics as participants with high blood pressure or diabetes or dyslipidemia, respectively. According to NCEP/ATP III report, participant who had ≥3 of the following criteria were defined as having the metabolic syndrome:

Tenure August 2010 to October 2012.

Protocol Participant were interviewed at home and were invited to attend the OPD at VS General Hospital, where they were asked to complete additional questionnaires, undergo various examinations and provide blood samples for: Glucose tolerance test (GTT) if they were undetected asymptomatic relatives of the patients with diabetes, or fasting blood sugar (FBS) and postprandial blood sugar (PPBS) levels in diabetic patients and serum lipid profile. Blood pressure was measured with a mercury sphygmomanometer and the mean of three seated resting values recorded. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meter.

Waist Circumference Measurement Technique Place measuring tape, holding it parallel to the floor, around abdomen at the level of the iliac crest. Hold tape snug but don’t compress the skin and measure circumference at the end of normal expiration.

ÂÂ

Central obesity: Abdominal waist circumference: Men >102 cm, women >88 cm

ÂÂ

Fasting plasma glucose >110 mg/dl or diagnosed T2DM

ÂÂ

Fasting plasma medication

ÂÂ

Fasting plasma HDL cholesterol: Men <40 mg/dl, women <50 mg/dl or medication

ÂÂ

Blood pressure ≥130/85 mmHg or medication.

>150

Classification of OGTT as per ADA ÂÂ

ÂÂ

FBS zz

Normal <110 mg/dl

IGT >110 mg/dl and <126 mg/dl

DM >126 mg/dl

First hour blood glucose zz

Normal <140 mg/dl

IGT >140 mg/dl and <200 mg/dl

DM >200 mg/dl

Second hour blood glucose zz

Normal <140 mg/dl

Oral Glucose Tolerance Test (OGTT)

IGT >140 mg/dl and <200 mg/dl

After a 12-hour overnight fast, the subject ingested a solution that contained 75 g dextrose and venous blood samples were obtained at 0, 60 and 120 minutes for determination of plasma glucose. Stages of plasma glucose were classified as per American Diabetic Association (ADA).

DM >200 mg/dl

Blood glucose was measured using glucose oxidase/ peroxidase method. Low-density lipoprotein (LDL) and HDL fractions were separated from fresh serum by ultracentrifugation, cholesterol oxidase/ p-aminophenazone (CHOD-PAP) method. Lipoprotein fraction cholesterol and triglycerides were measured by standard enzymatic spectrophotometric technique.

mg/dl

First-degree relatives were classified as normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and NIDDM after an OGTT.

Hip Circumference Measurement Technique Place measuring tape, holding it parallel to the floor, around the hip at the level of greater trochanter of femur. Hold tape snug but don’t compress the skin and measure circumference.

triglyceride

Statistical Analysis All the data were computed on Excel database and statistical analysis were done using SPSS PC Windows. Student’s t-test was used for comparison of means of frequencies. We calculated prevalence of metabolic syndrome by age and sex. Subjects with diabetes and IGT were grouped together as glucose intolerance for regression analysis. Variables like age, sex, waist, BMI, waist-hip ratio, systolic and diastolic blood pressure, family history of diabetes were used as independent variables for the regression analysis. The step-wise

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

CLINICAL STUDY Table 1. Physical, Clinical and Metabolic Characteristics of Diabetic Patients Mean ± Standard deviation Males (n = 10)

Females (n = 10)

Total (n = 20)

Age (years)

62.20 ± 6.80

64.30 ± 10.11

63.25 ± 8.45

Ht (cm)

1.63 ± 0.11

1.56 ± 0.12

1.60 ± 0.12

Wt (kg)

66.90 ± 9.86

80.15 ± 19.51

73.53 ± 16.51

Waist (cm)

97.50 ± 7.91

105.95 ± 17.39

101.73 ± 13.84

Hip (cm)

98.30 ± 4.57

117.40 ± 17.24

107.85 ± 15.71

BMI (kg/m2)

66.90 ± 9.86

80.15 ± 19.51

73.53 ± 16.51

BP systolic (mmHg)

143.00 ± 26.13

145.00 ± 19.89

143.50 ± 22.88

BP diastolic (mmHg)

87.80 ± 12.20

84.60 ± 12.40

86.20 ± 11.91

FBS (mg/dl)

133.00 ± 59.25

117.80 ± 41.88

125.40 ± 50.54

2 hour (mg/dl)

219.50 ± 68.79

193.50 ± 67.11

206.50 ± 67.48

S. TG (mg/dl)

138.50 ± 63.25

159.20 ± 88.65

148.85 ± 75.70

S. HDL (mg/dl)

35.70 ± 3.30

41.00 ± 9.24

38.35 ± 7.28

S. LDL (mg/dl)

111.27 ± 41.11

100.12 ± 25.28

105.70 ± 33.70

S. VLDL (mg/dl)

87.43 ± 120.04

33.53 ± 17.78

57.11 ± 81.82

Total (mg/dl)

627.61 ± 295.42

693.22 ± 141.35

662.35 ± 222.06

Ht: Height; Wt: Weight; s.: Serum.

Table 2. Physical, Clinical and Metabolic Characteristics of First-degree Relatives of T2DM Patients Mean ± Standard deviation Males (n = 46)

Females (n = 34)

Total (n = 80)

41.93 ± 10.53

42.94 ± 10.51

42.36 ± 10.47

Ht (cm)

1.68 ± 0.08

1.56 ± 0.08

1.63 ± 0.10

Wt (kg)

73.26 ± 12.56

71.24 ± 12.38

72.40 ± 12.45

Waist (cm)

94.89 ± 11.01

99.38 ± 14.55

96.80 ± 12.75

Hip (cm)

97.76 ± 8.92

107.47 ± 11.83

101.89 ± 11.27

BMI (kg/m2)

26.01 ± 3.92

29.21 ± 5.58

27.37 ± 4.93

BP systolic (mmHg)

127.22 ± 18.32

134.53 ± 17.22

130.33 ± 18.12

BP diastolic (mmHg)

80.96 ± 11.34

82.29 ± 8.97

81.53 ± 10.36

FBS (mg/dl)

111.98 ± 67.51

107.06 ± 38.48

109.89 ± 56.75

1-hour (mg/dl)

166.59 ± 64.91

144.81 ± 45.02

157.88 ± 58.39

2-hour (mg/dl)

169.52 ± 101.44

138.35 ± 57.72

156.28 ± 86.56

S. TG (mg/dl)

167.62 ± 110.05

163.79 ± 76.49

166.00 ± 96.68

Age (years)

S. HDL (mg/dl)

40.84 ± 13.42

42.32 ± 8.00

41.47 ± 11.39

S. LDL (mg/dl)

104.44 ± 33.85

122.89 ± 116.29

112.38 ± 80.33

S. VLDL (mg/dl)

34.59 ± 22.57

33.29 ± 15.27

34.03 ± 19.64

711.23 ± 179.31

718.35 ± 150.96

714.25 ± 166.78

Total (mg/dl)

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

CLINICAL STUDY multiple linear regression applied to first-degree relatives to assess the independent contribution of IGT (glycemia at 120 mins) to separate components of metabolic syndrome. RESULTS In diabetic population, there were 10 males and 10 females. Among first-degree relatives, 46 were males and 34 were females. Tables 3 shows anthropometric, clinical and metabolic characteristics of first-degree relatives of patients with NIDDM globally and age-wise. Blood pressure, FBS, 2nd hour glucose, and total lipid tend to rise with age. In the diabetic patients, 90% were hypertensive and 85% had low HDL, which forms the commonest criteria for metabolic syndrome. Central obesity was more common in females (55% average, 30% males and 80% females); 40% had high TG level. Eighty-five percent of diabetic patient had metabolic syndrome (90% males and 80% females); 40% of diabetic patient had four components of metabolic syndrome (60% males and 20% females) and 25% had five criteria satisfying metabolic syndrome (10% males and 40% females). Among first-degree relatives of diabetic patients, 48.75% had metabolic syndrome (39.13% males and 61% females); 13.75% had four criteria and 6.25% had five criteria satisfying metabolic syndrome. There was

no significant difference in prevalence of metabolic syndrome in males and females (p = 0.4). Among asymptomatic first-degree relatives of T2DM subjects, hypertension, low HDL, central obesity, IGT, T2DM were present in 52.5%, 68.7%, 48.7%, 26.2%, 35%, respectively. Among first-degree relatives of diabetic patients prevalence, the prevalence of metabolic syndrome was at age 31-39 years: 10%, at 40-49 years: 13.75%, at 50-59 years: 18.75% and at >60 years: 6.25%. Thus, the prevalence of metabolic syndrome was highest in age group 50-59 years (Table 3). According to ADA, first-degree relatives were classified as NGT, IGT or DM after OGTT (Table 4). Forty-nine out of 80 subjects displayed an abnormal glucose level either as IGT (26.2%) or as DM (35%) (Table 4). T2DM subjects were significantly older than IGT (IGT vs DM; p = 0.01) and NGT (NGT vs DM; p = 0.03) subjects. Thus age was a contributing factor for DM. BMI (p = 0.029) was significantly higher in both pathological groups. When blood pressure was considered, diastolic values were higher in abnormal OGTT compared to NGT. No difference in terms of sex distribution was found in any category.

Table 3. Physical, Clinical and Metabolic Characteristics of First-degree Relatives Age-wise Mean ± Standard deviation Age (years)

30-39 years

40-49 years

50-59 years

≥ 60 years

33.44 ± 2.88

43.88 ± 2.91

53.17 ± 2.90

63.67 ± 4.23

Ht (cm)

1.63 ± 0.10

1.65 ± 0.09

1.62 ± 0.11

1.58 ± 0.04

Wt (kg)

69.84 ± 12.96

78.18 ± 11.04

73.97 ± 11.69

68.00 ± 10.94

Waist (cm)

92.62 ± 11.74

102.82 ± 13.24

102.22 ± 11.54

90.67 ± 9.71

Hip (cm)

99.36 ± 10.51

106.29 ± 11.78

104.28 ± 9.74

98.67 ± 15.88

BMI (kg/m2)

26.22 ± 4.73

28.83 ± 4.79

28.51 ± 5.42

27.31 ± 4.28

BP systolic (mmHg)

124.31 ± 15.78

133.18 ± 17.39

133.67 ± 18.61

151.33 ± 16.33

BP diastolic (mmHg)

78.97 ± 10.07

82.24 ± 8.30

82.67 ± 10.98

92.67 ± 9.44

FBS (mg/dl)

97.62 ± 43.03

99.29 ± 22.69

140.06 ± 89.08

129.17 ± 53.69

1-hour (mg/dl)

148.19 ± 56.35

179.27 ± 65.97

159.58 ± 56.92

161.50 ± 13.44

2-hour (mg/dl)

142.39 ± 78.72

147.12 ± 52.53

182.22 ± 117.45

194.67 ± 97.92

S. TG (mg/dl)

157.25 ± 110.77

192.76 ± 87.55

151.06 ± 59.53

191.83 ± 114.94

S. HDL (mg/dl)

42.41 ± 14.61

38.62 ± 6.12

39.72 ± 8.39

42.17 ± 8.18

S. LDL (mg/dl)

115.60 ± 111.46

104.61 ± 37.96

115.17 ± 32.49

105.65 ± 12.75

32.86 ± 22.88

38.51 ± 17.55

30.83 ± 11.90

36.72 ± 23.24

695.01 ± 190.01

756.53 ± 123.79

701.33 ± 101.80

739.00 ± 295.05

S. VLDL (mg/dl) Total (mg/dl)

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

CLINICAL STUDY Table 4. Clinical and Metabolic Characteristics of NGT, IGT and DM Subjects among First-degree Relatives P (T < t) two-tail Mean ± Standard deviation

T-test: two sample assuming equal variance

NGT (n = 31)

IGT (n = 21)

DM (n = 28)

NGT vs IGT

NGT vs DM

IGT vs DM

Age (years)

40.84 ± 9.40

38.71 ± 9.40

46.79 ± 11.12

0.43

0.03

0.01

Ht (cm)

1.62 ± 0.10

1.62 ± 0.08

1.65 ± 0.10

0.95

0.32

0.37

Wt (kg)

68.97 ± 12.12

76.90 ± 13.74

72.82 ± 10.99

0.03

0.32

0.25

Waist (cm)

94.19 ± 11.77

98.52 ± 15.15

98.39 ± 11.78

0.25

0.18

0.97

Hip (cm)

98.97 ± 9.73

104.57 ± 12.12

103.11 ± 11.86

0.07

0.15

0.67

(kg/m2)

26.27 ± 4.12

29.54 ± 6.41

26.96 ± 4.07

0.03

0.09

BP systolic (mmHg)

128.39 ± 19.60

128.76 ± 17.07

133.64 ± 17.33

0.94

0.33

BP diastolic (mmHg)

80.45 ± 11.99

82.38 ± 9.02

82.07 ± 9.59

0.53

0.57

0.91

FBS (mmHg)

84.90 ± 11.71

86.14 ± 15.20

155.36 ± 76.16

0.74

0.00

2-hour (mmHg)

101.19 ± 26.23

129.10 ± 29.82

237.65 ± 97.86

0.00

S. TG (mmHg)

153.28 ± 79.55

149.71 ± 63.05

192.28 ± 127.53

0.86

0.17

S. HDL (mmHg)

40.38 ± 7.26

42.12 ± 6.84

42.18 ± 16.87

0.38

0.59

0.99

S. LDL (mmHg)

122.71 ± 9.46

113.75 ± 37.25

120.34 ± 35.77

0.74

0.34

0.18

BMI

Table 5. No. of first-degree relatives of T2DM patients

Metabolic syndrome

Total

Components

Present

Absent

With IGT/T2DM

With NGT

Total

Table 6. Regression Analysis of Impaired Glucose Tolerance with Reference to FBS, Hip Measure, S. HDL Dependent variable

Standardized coefficient

p value

0.752

0.0001

FBS

0.703

0.0001

Hip measure

-0.320

0.005

FBS

0.723

0.0001

Hip measure

–0.256

0.021

S. HDL

–0.214

0.048

Model 1

0.566

FBS Model 2

Model 3

0.666

0.707

a. predictors: (constant), FBS b. predictors: (constant), FBS, HIP c. predictors: (constant), FBS, HIP, s. HDL d. dependent variable: 2-hour glycemia

Table 7. Comparisons between Botnia Study with our Study

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

Botnia Study

Our Study

Male (%)

Female (%)

Male (%)

Female (%)

93.33

Dyslipidemia

57.3

Hypertension

55.6

100

Metabolic syndrome Obesity

In subjects with abnormal glucose level (n = 49), 59.18% subjects and in subjects with normal glucose level (n = 31), 32.25% met the criteria for metabolic syndrome (Table 5). So, prevalence of metabolic syndrome was significantly increased if the subject had glucose intolerance (p = 0.023). FBS, hip measure and serum HDL independently determined two hours glycemia value in OGTT (R2 = 0.707, p = 0.001). FBS, Hip measure and serum HDL together explains 70% of variation in data of two hours glycemia control (Table 6). DISCUSSION Until 1970, the prevalence of T2DM was considered to be low in India. The projection from the WHO in the year

CLINICAL STUDY Male Female Total

120 90

55 40 40 40

20 HTN

Low HDL

High TG

20 15

MS4

80 90

Total Female Male

11.76 2.17 13.75 20.58 8.69 48.75 61

39.13

0 10 20 30 40 50 60 70 Percentage

Figure 3. Percentage of first-degree relatives of diabetic patients with 4, 5 components of metabolic syndrome.

82.35

Male Female Total

79.41

68.75 58.69

59 47.82

52.5 45.65

50 48.75

48.75 40 45.65

HTN

MS4

Low HDL High TG Central obesity

30 22.4

26.2

IGT

T2DM

Figure 4. Percentage of individual components of metabolic syndrome and T2DM in first-degree relatives of diabetic patients.

10 6.25

2.5 1.25

MS5

Total MS

7.5 3.75 1.25

No MS

Metabolic syndrome absent Metabolic syndrome present p = 0.023

60 40

6.25

MS4

1.25

100

Figure 2. Percentage of diabetic patients with 4, 5 components of metabolic syndrome.

MS5

MS3

6.25

80 60

13.75

11.25 7.5 6.25 3.75

Figure 5. Age-wise prevalence of metabolic syndrome in first-degree relatives of T2DM patients.

18.75

100

Percentage

No. of components of MS

Total Female Male

Prevalence

Percentage

No. of components

MS5

30-39 40-49 50-59 60-69

38.75

Metabolic syndrome

Central obesity

Figure 1. Prevalence of metabolic syndrome and its individual components in diabetic patients.

90 80 70 60 50 40 30 20 10 0

Age group

Prevalence

100

IGT/T2DM

NGT

Figure 6. Prevalence of metabolic syndrome in first-degree relatives with IGT/T2DM and NGT.

1998 has highlighted that India would lead the world in the prevalence of diabetes. Studies done in Western countries have confirmed that the prevalence of diabetes among migrant Indians is significantly higher than the host populations. This might be explained by a higher genetic susceptibility to the development of diabetes among Asian Indians or stronger environmental factors (e.g., decreased physical activities, eating habits, etc.). Studies on native Indian population during the last 30 years have shown rising trends in the prevalence of diabetes. The prevalence of metabolic syndrome has also increased in the world. METABOLIC SYNDROME IN DIABETIC PATIENTS In our study, 85% of the diabetic patients (n = 20), aged >40 years (female: 80% and male: 90%) met the criteria for diagnosis of metabolic syndrome as per ATP III guidelines. In Botnia study 2001 (in Finland and Sweden), the prevalence of metabolic syndrome according to WHO criteria in T2DM among males and females was 84% and 78%, respectively. Cardiovascular mortality was markedly increased in subjects with metabolic syndrome (12%; p < 0.001).

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

CLINICAL STUDY The percentage of T2DM patients with age >40 years with metabolic syndrome in both the studies are comparable. Obesity in Botnia study was classified using BMI or Waist-hip ratios. This may explain a higher prevalence of obesity in Botnia study as compared to our study, where we used the ATP III criteria for central obesity (i.e., waist circumference >88 cm in females and >102 cm in males). The cut-off for hypertension in Botnia study was higher; 160 mmHg systolic or 90 mmHg diastolic blood pressure, whereas in our study, hypertension was considered as per ATP III guidelines (normal levels were taken as 130/85 mmHg). Difference in cut-off value may explain higher percentage of study population having hypertension in present study. However, other racial, environmental and personal factors cannot be ruled out in both instances. In our study, 40% diabetic patients had four components satisfying criteria for metabolic syndrome. Twenty percent had three criteria and 25% had five criteria. It has been suggested by Cruz et al that number of criteria for metabolic syndrome may be inversely proportional to insulin sensitivity. The NCEP ATP III has recently recognized the metabolic syndrome as an important risk factor for IHD among men and women. It has been estimated, on the bases of the results of Third National Health and Nutrition Examination Survey (NHANES) that >1 in five adults in USA have metabolic syndrome with almost a doubling prevalence (43%) among people >60 years of age. The prevalence of unstable angina and myocardial infarction were highest among patients with five insulin-resistant syndrome features as defined by NCEP-III. Hence, for individuals with established DM, risk factor management must be intensified to diminish their higher risk for CVD. Among first-degree relatives of patients with T2DM, 48.75% aged >30 years (males 39.1% and among females 61%) met the criteria for metabolic syndrome. One-third of the first-degree relatives with metabolic syndrome belonged to the age group 50-59 years. Hypertension and low HDL have contributed maximum among the components of metabolic syndrome. These data shows high prevalence of metabolic syndrome among the Indian population. The Deepa study in Chennai 2002 used the EGIR criteria to compute the prevalence of metabolic syndrome in random population with age group of 20-75 years and hence a lower occurrence of metabolic syndrome is seen in this study. Gupta et al held at Jaipur, 2003 was carried

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

out on random population with age >20 years while the present study was carried out on first-degree relatives of age >30 years. This may explain a high percentage of subjects having metabolic syndrome. Ramachandra et al observed a prevalence of 41% and the Strong Heart Study on American Indians observed a prevalence of 55.2%. The above studies had been done on random population, whereas our study was carried out on first-degree relatives. This explains higher percentage of study population having metabolic syndrome in the present study. Because of the documented high relatives risk of AV, CVD events and T2DM, the metabolic syndrome undoubtedly carries a relatively high lifetime risk for these disorders even when shorter term (10 years) risk is in low moderate range. The prime emphasis in management of metabolic syndrome per se is to mitigate the modifiable, underlying risk factor (obesity, physical inactivity and atherogenic diet) through lifestyle changes. Its absolute risk is high enough, therapeutic interventions like metformin, statins, etc. may be incorporated to the regimes. More than 61.25% (49 out of 80) of first-degree relatives of diabetic patient with NIDDM displayed abnormal glucose tolerance either as IGT (26.25%) or NIDDM (35%). The Catalonia study and Aragon study were done on general population and hence showed a lesser prevalence of abnormal glucose tolerance than our study. However, the Catalonia study done on firstdegree relatives with age >20 years shows a much higher prevalence of 30% for abnormal glucose tolerance than in general population (20%). Racial difference would explain the higher prevalence of abnormal glucose tolerance in our study. Further Indian studies are required to support our data. Individuals with a parent with T2DM have increased risk of DM and if both parents have T2DM it approaches 40%. Insulin resistance as demonstrated by decreased glucose utilization in skeletal muscle is present in many nondiabetic first-degree relative of T2DM. Annually, IGT carries 1-10% rate of progression to frank T2DM. Thus, all patients in whom diabetes develops probably go through stage IGT and this condition confirms a non-negligible risk in terms of CVDs as well as its progression to NIDDM. Thus by identifying this cluster of individuals at high-risk for metabolic syndrome, we can delay the emergence of DM, CVD, dyslipidemia, stroke and

CLINICAL STUDY obesity by pharmacological and nonpharmacology measure. The Diabetes Prevention Program (DPP) demonstrated that intense lifestyle changes (diet and exercise for 30 mins/d) in individuals with IGT prevented or delayed development of T2DM by 58%. By lifestyle intervention, IGT lost 5.7% of body weight in three years. The use of metformin in IGT prevented DM by 31%. When subjects with abnormal glucose tolerance were analyzed, they displayed a higher BMI, blood pressure, triglyceride level, central obesity and lower HDL levels, than NGT groups, all well-recognized features of metabolic syndrome. NIDDM subjects were significantly older than IGT (IGT vs DM; p < 0.01) and NGT (NGT vs DM; p < 0.03) subjects. BMI was significantly higher in both pathological groups (p < 0.0294). When blood pressure was considered, diastolic values were higher in abnormal OGTT compared to NGT. No difference in terms of sex distribution was found in any category. Our study dealt with the identification of factors, which determine plasma glucose concentration after two hours in OGTT. A step-wise multiple linear regression was applied using SPSS to all first-degree relatives to assess the independent contribution of IGT to separate components of metabolic syndrome; which demonstrated that FBG, hip circumference and low HDL levels were independent determined two hours glycemia value in OGTT (R2 = 0.70; p < 0.00%) of oral glucose tolerance. So IGT, increased hip circumference and low HDL levels can be considered as risk factors for glucose intolerance. This piece of information can be further used with support from a larger Indian study in setting up criteria for precocious screening for IGT and DM in first-degree relatives. This would minimize the number of OGTT and thereby reduce the cost of screening for the given family. Our study shows a high prevalence of metabolic syndrome and IGT in a selected native Indian population. The study also demonstrates that impaired fasting glucose, increased hip circumference and low HDL levels were associated with glucose intolerance. Furthermore, synergistic effect on increasing the risk for diabetes by lifestyle factors and family history of diabetes was observed in this study. These populations with family history of DM have increased risk for both cardiovascular disease and T2DM.

ÂÂ

Metabolic syndrome being a cardiovascular risk factor according to ATP III lifestyle modification, timely therapeutic intervention is crucial in the prevention of both T2DM and premature CVD in a risk population.

ÂÂ

With high-degree of heritability and increased urbanization, diabetes could become a major health hazard in India and this underscores the fact that prevention of diabetes must be one of the important health targets for the nation in this century.

CONCLUSION ÂÂ

In T2DM and their asymptomatic first-degree relatives, hypertension and low HDL were commonest components of metabolic syndrome, females were more obese.

ÂÂ

Glucose intolerance was significantly associated with other components of metabolic syndrome.

ÂÂ

Impaired fasting glucose, increased hip circumference and low HDL levels were independently associated with, so were the risk factors for glucose intolerance.

Acknowledgment We sincerely acknowledge our medical institute VS General Hospital, their staff, our teachers and also the all patients and their relatives without whom this study can’t be possible.

SUGGESTED READING 1. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Executive summary publication no. 01-3670. Bethesda, National Institutes of Health, 2001. 2. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002;287(3):356-9. 3. Granner DK, O’Brien RM. Molecular physiology and genetics of NIDDM. Importance of metabolic staging. Diabetes Care 1992;15(3):369-95. 4. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37(12):1595-607. 5. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15(7):539-53. 6. Balkau B, Charles MA, Drivsholm T, Borch-Johnsen K, Wareham N, Yudkin JS, et al; European Group For The Study Of Insulin Resistance (EGIR). Frequency of the WHO metabolic syndrome in European cohorts, and an

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

CLINICAL STUDY alternative definition of an insulin resistance syndrome. Diabetes Metab 2002;28(5):364-76. 7. Assmann G, Nofer JR, Schulte H. Cardiovascular risk assessment in metabolic syndrome: view from PROCAM. Endocrinol Metab Clin North Am 2004;33(2):377-92. 8. Harrison’s Principles of Medicine. 18th edition, 1995:p.95. 9. Einhorn D, Reaven GM, Cobin RH, Ford E, Ganda OP, Handelsman Y, et al. American College of Endocrinology position statement on the insulin resistance syndrome. Endocr Pract 2003;9(3):237-52. 10. Shah T, Jonnalagadda SS, Kicklighter JR, Diwan S, Hopkins BL. Prevalence of metabolic syndrome risk factors among young adult Asian Indians. J Immigr Health 2005;7(2):117-26. 11. International Diabetes Federation. Worldwide definition of the metabolic syndrome. Available at: http://www.idf. org/webdata/docs/IDF_Meta_def_final.pdf. 12. Grundy SM, Brewer HB, Cleeman JI, Smith SC, Lenfant C. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Arterioscler Thromb Vasc Biol 2004;24(2):e13-8. 13. Ramachandran A, Snehalatha C, Satyavani K, Sivasankari S, Vijay V. Metabolic syndrome in urban Asian Indian adults - a population study using modified ATP III criteria. diabetes Res Clin Pract 2003;60(3): 199-204.

14. Nyholm B, Nielsen MF, Kristensen K, Nielsen S, Ostergard T, Pedersen SB, et al. Evidence of increased visceral obesity and reduced physical fitness in healthy insulinresistant first-degree relatives of type 2 diabetic patients. Eur J Endocrinol 2004;150(2):207-14. 15. Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24(4):683-9. 16. Cruz ML, Weigensberg MJ, Huang TT, Ball G, Shaibi GQ, Goran MI. The metabolic syndrome in overweight Hispanic youth and the role of insulin sensitivity. J Clin Endocrinol Metab 2004;89(1):108-13. 17. Shen BJ, Todaro JF, Niaura R, McCaffery JM, Zhang J, Spiro A 3rd, et al. Are metabolic risk factors one unified syndrome? Modeling the structure of the metabolic syndrome X. Am J Epidemiol 2003;157(8):701-11. 18. Diabetes & Obesity: Time to Act. International Diabetes Federation 2004. 19. Klein S, Sheard NF, Pi-Sunyer X, Daly A, WylieRosett J, Kulkarni K; American Diabetes Association; North American Association for the Study of Obesity; American Society for Clinical Nutrition. Weight management through lifestyle modification for the prevention and management of type 2 diabetes: rationale and strategies: a statement of the American Diabetes Association, the North American Association for the Study of Obesity, and the American Society for Clinical Nutrition. Diabetes Care 2004;27(8):2067-73.

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Eating Refined Sugar can Cause Diabetes Eating too much refined white sugar can cause insulin resistance and future diabetes. Diabetes does not mean that one cannot have desserts forever. While eating too many sugary foods should be avoided, one can have an occasional dessert, especially if one exercises and otherwise eats healthy. It’s better to substitute brown sugar or Jaggery in that case. Artificial sweeteners including stevia are the other options. Fruits are healthy for diabetics but cannot be consumed in huge amounts, as they contain carbohydrates. As per Ayurveda, diabetes is a Kapha disorder and diabetics should limit the intake of sweet, salt and sour taste in the diet. Any fruit or vegetable which is bitter and dark green has antidiabetic properties. One should combine a bitter taste with a sweet taste when choosing a vegetable of a fruit. For example one should not combine peas with potatoes but one can combine potatoes with methi or palak. Diabetics are not more susceptible to colds and other illnesses but may have more complications of flu. Taking insulin does not cause hardening of the arteries or high blood pressure. Diabetes is not contagious and one cannot catch diabetes from someone else. —KK Aggarwal

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

PRACTICE GUIDELINES

ACP Releases Guideline on Intensive Insulin Therapy in Hospitalized Patients

yperglycemia is a common condition in medical and surgical patients during hospital admission, with a prevalence of approximately 40 percent. It is linked to poor immune response, increased cardiovascular events, and thrombosis, among other problems. Uncontrolled hyperglycemia is associated with increased morbidity, mortality, and costs. Achieving tight glycemic control in hospitalized patients often involves intensive insulin protocols. Intensive insulin therapy is defined as the use of intravenous insulin to meet target blood glucose levels with frequent glucose testing and adjustment of insulin doses. In the intensive care unit (ICU) setting, the usual target range for blood glucose (normoglycemia) is 80 to 110 mg per dL (4.4 to 6.1 mmol per L). In non-ICU settings, target glucose levels vary, ranging from 80 to 110 mg per dL to less than 200 mg per dL (11.1 mmol per L). The American College of Physicians (ACP) has issued a clinical guideline on the use of intensive insulin therapy in hospitalized patients with or without diabetes mellitus to achieve glycemic control and improve health outcomes. Most of the studies evaluated in the literature search focused on patients in the medical intensive care unit (MICU) and surgical intensive care unit (SICU). Recommendation 1: Intensive insulin therapy should not be used to strictly control blood glucose in non-SICU/MICU patients with or without diabetes (strong recommendation; moderate-quality evidence). Available evidence showed no reduction in mortality with a target blood glucose level of 80 to 180 mg per dL (4.4 to 10.0s mmol per L) compared with a higher or unspecified target. Studies found in the literature review used a variety of intensive insulin therapy regimens in patients with myocardial infarction, stroke, or acute brain injury, or in patients under perioperative care. Harms were more likely to occur at lower target levels; therefore, target levels less than 140 mg per dL (7.8 mmol per L) should be avoided. The effects of hypoglycemia in hospitalized patients are

Source: Adapted from Am Fam Physician. 2011;84(9):1058-1060.

unclear, although there is some evidence for increased mortality or extended length of stay in patients who have one or more episode of hypoglycemia. Some studies found that hypoglycemia is associated with an increased risk of dementia in patients with type 2 diabetes, and that hypoglycemia may induce transient ischemia and catecholamine surges. There is no optimal target blood glucose level in non-SICU/MICU patients because studies found that intensive insulin therapy was associated with an increased risk of hypoglycemia, with no differences in mortality at any specific target level. Recommendation 2: Intensive insulin therapy should not be used to normalize blood glucose in SICU/MICU patients with or without diabetes (strong recommendation; highquality evidence). No mortality benefit was found using intensive insulin therapy to achieve normoglycemia. Some studies showed an increase in mortality associated with intensive insulin therapy and hypoglycemia. Data were inconclusive on the association between intensive insulin therapy targeted to normoglycemia and the length of stay in the ICU. Recommendation 3: A target blood glucose level of 140 to 200 mg per dL (7.8 to 11.1 mmol per L) is recommended if insulin therapy is used in SICU/MICU patients (weak recommendation; moderate-quality evidence). Because poorly controlled hyperglycemia is associated with increased morbidity and mortality, and worse health outcomes in ICU patients, a target blood glucose level of 140 to 200 mg per dL is appropriate. Insulin therapy targeted to this range is associated with similar mortality outcomes and a lower risk of hypoglycemia compared with therapy targeted to 80 to 110 mg per dL. There is not enough evidence to determine whether blood glucose levels of 180 to 200 mg per dL (10.0 to 11.1 mmol per L) are associated with outcomes similar to those of lower target levels. Hypoglycemia was observed in studies using a range of target levels, although the risk was higher when lower target values were used. Achieving glucose targets with low rates of hypoglycemia may be associated with titration characteristics of the protocol, patient characteristics, staffing ratios, and physician acceptance. Quality improvement and training initiatives should be incorporated in hospitals to achieve target glucose levels while minimizing rates of hypoglycemia in ICU patients.

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

LIGHTER READING

A young man asked Socrates the secret to success. Socrates told the young man to meet him near the river the next morning. They met. Socrates asked the young man to walk with him towards the river. When the water got up to their neck, Socrates took the young man by surprise and ducked him into the water. The boy struggled to get out but Socrates was strong and kept him there until the boy started turning blue. Socrates pulled his head out of the water and the first thing the young man did was to gasp and take a deep breath of air. Socrates asked, ‘What did you want the most when you were there?” The boy replied, “Air.” Socrates said, “That is the secret to success. When you want success as badly as you wanted the air, then you will get it.” There is no other secret. Moral of the Story: A burning desire is the starting point of all accomplishment. Just like a small fire cannot give much heat, a weak desire cannot produce great results. The motivation to succeed comes from the burning desire to achieve a purpose.

LAUGH A WHILE

The Secret of Success!

Fact: Not everyone has a gun, but almost everyone has at least one doctor. Please alert your friends to this alarming threat immediately. We must ban doctors before this gets completely out of hand! Note: Out of concern for the public at large, the statistics on lawyers have been withheld for fear the shock would cause people to panic and seek medical attention.

“For success, attitude is equally as important as ability.” —Harry F. Banks

QUOTE

AN INSPIRATIONAL STORY

Lighter Side of Medicine

“Some of us think holding on makes us strong; but sometimes it is letting go.” —Herman Hesse

“It takes less time to do things right than to explain why you did it wrong.” —Henry Wadsworth Longfellow

Doctors vs Guns Doctors: The number of physicians in the US is 7,00,000 Accidental deaths caused by Physicians per year are 1,20,000

Dr. Good and Dr. Bad SITUATION: A diabetic during fasting was taking the two

allowed meals close to each other.

Statistics courtesy of US Dept. of Health Human Services.

Its OK

It CAN HARm

Guns: The number of gun owners in the US is 80,000,000 The number of accidental gun deaths per year, all age groups, is 1,500

©IJCP Academy

LAUGH A WHILE

Accidental deaths per physician is 0.171

The number of accidental deaths per gun owner is .000188. Statistics courtesy of FBI Statistically, doctors are approximately 9,000 times more dangerous than gun owners. Remember, “Guns don’t kill people, doctors do.”

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

LESSON: If the period of fasting is longer and the two

meals are eaten close together it can be tricky.

Dr KK Aggarwal

The Asian Journal of

DIABETOLOGY Information for Authors

Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767).

The title should be of no more than 80 characters and should represent the major theme of the manuscript. A subtitle can be added if necessary.

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The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review. The checklist should accompany each manuscript.

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1. Introduction - The introduction should state why the study was carried out and what were its specific aims/objectives. Methods - These should be described in sufficient detail to permit evaluation and duplication of the work by others. - Ethical guidelines followed by the investigations should be described. Statistics -

The following information should be given:

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Statistical methods used for presentation and analysis of data i.e., in terms of mean and standard deviation values or percentages and statistical tests such as Student’s ‘t’ test, Chi-square test and analysis of variance or non-parametric tests and multivariate techniques.

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Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g., practicality and cost.

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These should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses). At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution. Examples of common forms of references are: Articles Paintal AS. Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of those receptors to phenylguanide, potato S-hydroxytryptamine and their role in respiratory and cardiovascular reflexes. Q. J. Expt. Physiol. 1955;40:89-111. Books Stansfield AG. Lymph Node Biopsy Interpretation Churchill Livingstone, New York 1985. Articles in Books Strong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470. Tables - These should be typed double spaced on separate sheets with the table number (in Roman Arabic numerals) and title above the table and explanatory notes below the table. Legends - These should be typed double spaces on a separate sheet and figure numbers (in Arabic numerals) corresponding with the order in which the figures are presented in the text. - The legend must include enough information to permit interpretation of the figure without reference to the text.

Asian Journal of Diabetology, Vol. 16, No. 2, April-June 2013

Please complete the following checklist and attach to the manuscript: 1. Classification (e.g. original article, review, selected summary, etc..)_____________________________ 2. Total number of pages _______________________ 3. Number of tables ___________________________ 4. Number of figures __________________________ 5. Special requests ___________________________ 6. Suggestions for reviewers (name and postal address) Indian 1.___________ Foreign 1.______________ 2.___________ 2.______________ 3.___________ 3.______________ 4.___________ 4.______________ 7. All authors’ signatures_______________________ 8. Corresponding author’s name, current postal and e-mail address and telephone and fax numbers ___________________________________________ ___________________________________________ ___________________________________________

For Editorial Correspondence Dr K.K. Aggarwal Group Editor-in-Chief

Asian Journal of Diabetology

E-219, Greater Kailash, Part-1 New Delhi - 110 048 E-mail: editorial@ijcp.com, Website: www.ijcpgroup.com