Ajd web jan march 2016 by ijcp group

Volume 17, Number 9

January-March 2016

The Asian Journal of

Diabetology

Online Submission

IJCP Group of Publications Dr Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor Dr Deepak Chopra Chief Editorial Advisor

Volume 17, Number 9, January-March 2016

from the desk of THE group editor-in-chief 6 Kidney Disease Due to Hyperglycemia Starts Early in Prediabetic State Itself

KK Aggarwal

Dr KK Aggarwal Group Editor-in-Chief IJCP Group, eMedinewS and eMediNexus Dr Veena Aggarwal MD, Group Executive Editor

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, Dr Vijay Viswanathan, Dr V Mohan, Dr V Seshiah, Dr Vijayakumar ENT Dr Jasveer Singh, Dr Chanchal Pal Dentistry Dr KMK Masthan, Dr Rajesh Chandna Gastroenterology Dr Ajay Kumar, Dr Rajiv Khosla, Dr JS Rajkumar Dermatology Dr Hasmukh J Shroff, Dr Pasricha, Dr Koushik Lahiri, Dr Jayakar Thomas Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan, Dr Vineet Suri, Dr AV Srinivasan Oncology Dr V Shanta Orthopedics Dr J Maheshwari

from the desk of THE ConSUltant editor 7 Hypercalcemia in Indian Setting: Time for a Change in Approach

Ambrish Mithal

clinical Study 8 Prevalence of Gestational Diabetes Mellitus in a Medical College in South India: A Pilot Study K Sreekanthan, A Belicita, K Rajendran, Anil Vijayakumar

Anand Gopal Bhatnagar Editorial Anchor Advisory Bodies Heart Care Foundation of India Non-Resident Indians Chamber of Commerce & Industry World Fellowship of Religions

14 Macrovascular and Microvascular Complications in Newly Diagnosed Type 2 Diabetes Mellitus Deepa DV, Kiran BR, Gadwalkar Srikant R

Clinical study

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

19 Pattern of HbA1C in Newly Detected Type 2 Diabetes Mellitus

Prem Kumar D, Krishnamurthy VR, Pratap VGM

Printed at New Edge Communications Pvt. Ltd., New Delhi E-mail:edgecommunication@gmail.com Copyright 2016 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.

21 Association Between Indexes of Insulin Sensitivity/Resistance and Serum Magnesium Levels in Overweight Diabetic Subjects

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Neetesh Kumar Gupta, Sonali Sharma, GG Kaushik, Bhavana Gupta

Conference Update 27 TRENDO 2015

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from the desk of THE group editor-in-chief

Dr KK Aggarwal Group Editor-in-Chief, IJCP Group, eMedinewS and eMediNexus

Kidney Disease Due to Hyperglycemia Starts Early in Prediabetic State Itself

rediabetes might be a target for early treatment to prevent chronic kidney disease in chronic hyperglycemia. A study of 1,261 nondiabetic people aged 50 to 62 years has suggested that apparently healthy persons who have blood sugar levels higher than normal, but not yet in the diabetic range, are still at risk of developing kidney damage. Such individuals are more likely to have glomerular hyperfiltration and albuminuria. In the study, 595 people were found to have slightly abnormal blood glucose levels. And these individuals had higher probability of having glomerular hyperfiltration and albuminuria at 5-year follow-up compared to those who had normal blood sugar levels, indicating early kidney damage. Glomerular hyperfiltration (defined as GFR >90th percentile, adjusted for sex, age, weight, height and use of renin-angiotensin system inhibitors) and albuminuria is thought to contribute to kidney damage in diabetes. The findings of the study by Dr Toralf Melsom of the University of North Norway and colleagues are published online December 29 in the American Journal of Kidney Diseases. People with slightly elevated blood sugar should focus on lifestyle changes such as eating healthy, increasing physical activity and maintaining a healthy body weight. ■■■■

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

from the desk of THE ConSUltant editor

Dr Ambrish Mithal

Chairman and Head of Endocrinology and Diabetes Division Medanta - The Medicity, Gurgaon

Hypercalcemia in Indian Setting: Time for a Change in Approach

ypercalcemia is a common problem in clinical practice in India, especially in the hospital setting. The pathophysiology of hypercalcemia is largely unknown. Hypercalcemia is resorptive in nature based on calcium absorption tests. Since the patients have acute decompensation of CLD, some inflammatory substances elaborated could be the cause for increased bone resorption and subsequent hypercalcemia. The resorptive factors may include tumor necrosis factor, osteoclast-activating factor, interleukin-1, prostaglandins or transforming growth factor. Vitamin D toxicity is an important cause of serious hypercalcemia. Asymptomatic primary hyperparathyroidism is common in India - if serum calcium is checked in routine practice then patients may benefit from early diagnosis. As endemic goiters virtually disappeared following iodination of common salt, so have the large parathyroid tumors and osteitis fibrosa declined in the US after fortification of milk with vitamin D. ■■■■

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

clinical Study

Prevalence of Gestational Diabetes Mellitus in a Medical College in South India: A Pilot Study K Sreekanthan*, A Belicita†, K Rajendran‡, Anil Vijayakumar†

Abstract Background: The prevalence of diabetes is increasing in India with projected rates of 79.4 million in 2030 — a 15.1% increase from 31.7 million in 2000. The increased prevalence is attributed to the aging population structure, urbanization, the obesity epidemic and physical inactivity. Though prevalence of diabetes is alarmingly high among Indians, there have been very few studies assessing the effect of diabetes on pregnancy outcomes. Diabetes in pregnancy causes maternal and neonatal complications like stillbirth, hydramnios, etc. Among ethnic groups in South Asian countries, Indian women especially south Indians have the highest frequency of gestational diabetes mellitus (GDM) necessitating universal screening. The recognition of glucose intolerance during pregnancy is more relevant as Indian women have 11-fold increased risk of developing GDM compared to other places. Aims and objectives: To find the prevalence of GDM in Kollam and to find the relation of GDM with various risk factors like age, obesity, previous large baby, abortion, previous abnormal glucose tolerance test (GTT), complications in previous pregnancy like hydramnios, bleeding, etc. Study design: A retrospective study of prevalence and possible risk factors associated with gestational diabetes was undertaken on 71 mothers between the age group of 20 and 35 years who were screened. Setting: Details on the medical history, family history of diabetes and obstetric history were collected using a performa. All the study subjects underwent a complete physical examination and biochemical assessment was done. Results and conclusion: This study on prevalence of GDM in Kollam district showed that the prevalence of GDM was 17%. It was found out that the factors such as increased age of pregnant women, overweight and obesity, lack of exercise and diet control, GDM in first-degree relatives, previous abnormal GTT predispose to GDM. Also women with previous large weight babies (macrosomia), previous loss of pregnancy, GDM in previous pregnancy, complications in previous pregnancy like hydramnios, bleeding, etc. have increased chances of getting GDM. Keywords: Gestational diabetes mellitus, pregnancy, glucose intolerance

estational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. The definition applies whether insulin or only diet modification is used for treatment and whether or not the condition persists after pregnancy. It does not exclude the possibility that unrecognized glucose intolerance may have antedated or began concomitantly with the pregnancy. The prevalence of diabetes is increasing globally and the total number of people with this condition is projected to rise from 171 million in 2000 to 366 million in 2030. India is no exception, with projected rates of 79.4

*Professor † Associate Professor, Dept. of Medicine ‡ Professor and Head, Dept. of Pediatrics Azeezia Institute of Medical Sciences and Research Center Meeyannoor, Kollam, Kerala Address for correspondence Azeezia Institute of Medical Sciences and Research Center Meeyannoor, Kollam - 37, Kerala E-mail: medicalcollge@azeezia.com

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

million in 2030 — a 15.1% increase from 31.7 million in 2000. The increased prevalence is attributed to the aging population structure, urbanization, the obesity epidemic and physical inactivity. Diabetes can complicate pregnancy, but it is not the major complication of pregnancy. Although prevalence of diabetes is alarmingly high among Indians there have been very few studies assessing the effect of diabetes on pregnancy outcomes. Diabetes in pregnancy causes maternal and neonatal complications like stillbirth, hydramnios, etc. Maternal complications occurring in GDM are pregnancy-induced hypertension, maternal infection, fasting hyperglycemia, etc. Pregnancy complications include abortion, preterm labor, hydramnios and unexplained fetal deaths. Fetal complications are fetal macrosomia, fetal malnutrition, neural tube defects and cardiac anomalies like ventricular septal defect, atrial septal defect, etc. Among ethnic groups in South Asian countries, Indian women especially south Indians have

clinical Study the highest frequency of GDM necessitating universal screening. The recognition of glucose intolerance during pregnancy is more relevant as Indian women have 11-fold increased risk of developing GDM compared to other places.

Yes (17%)

Aims and Objectives The objectives of this study was to find the prevalence of GDM in the Kollam district and to find the relation of GDM with various risk factors like age, obesity, previous large baby, abortion, previous abnormal GTT, complications in previous pregnancy like hydramnios, bleeding, etc. Material and MethodS A study on the prevalence and possible risk factors associated with gestational diabetes was undertaken on 71 mothers between the age group of 20 and 35 years; among pregnant women recruited from Gynecology and Obstetrics outpatient of Azeezia Medical College, Kollam, Kerala, India from December 2013 to January 22, 2014. Details on the medical history, family history of diabetes and obstetric history were collected using a performa. All the study subjects underwent a complete physical examination and laboratory investigations were done. A self-administrative interview schedule was prepared and 71 pregnant ladies were selected for study. Data collected was entered in Microsoft Excel and analyzed further using SPSS Software version 20.0. Results According to this study, it was found that prevalence of GDM in Kollam district was 17% and there was a significant relationship between GDM and its risk factors. With data collected the statistical and chisquare value to find out the correlation between the risk factors and development of GDM were calculated. Exercise (p = 0.019) and age (p = 0.013) are significant in relation with diabetes. There was no relation between diabetes and hypertension. Out of 71 pregnant women 12 (17%) were having diabetes (Fig. 1) 10 (14.1%) were having hypertension 1 (1.4%) person had body mass index (BMI) <18, 34 (47.9%) had BMI between 18-24.9, 30 (42.3%) had BMI between 25-29.9 and 6 (8.5%) had BMI above 30 (Fig. 2). In those who are having diabetes, a relationship between BMI and diabetes mellitus (DM) was noted. Eight (66.66%) women had normal BMI and 4 (33.33%) were overweight. The chi-square value obtained was 13.928 with third-degree of freedom and the p value was

No (83%)

Figure 1. Frequency of diabetes mellitus.

15-20 21-25

26-30 31-35

1% 9% 42%

48%

Figure 2. Frequency of BMI of pregnant women.

0.003, which is <0.01, which shows that the relationship between BMI and DM was highly significant. Out of 12 diabetic women, eight of the pregnant women had history of abortion. The chi-square value obtained was 9.537 with first-degree of freedom and the p value was 0.002 which is <0.01, which shows that the relationship between history of abortion and diabetes was highly significant (Fig. 4). Out of 12, 9 (75%) had no control on diet. The chisquare value obtained was 10.187 with first-degree of freedom and the p value was 0.001 which is <0.01, which shows that the relationship between diet control and diabetes was highly significant (Fig. 6). While comparing with complications in present pregnancy 5 (41.66%) diabetics were having. The chi-square value obtained was 13.347 with first-degree of freedom and the p value was 0.000, which is <0.01, which shows that the relationship between complication in pregnancy and diabetes was highly significant (Fig. 7). Four diabetic women reported with diabetes in previous pregnancy. The chi-square

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

clinical Study

No GDM GDM

No. of persons

25 20 15 10 5 0

3 18-24

25-32 Age

50 45

25 20 15

13 8

1 No

Yes

Diet control

No GDM GDM 56

Yes

30 20

History of abortion

No GDM GDM

70 58

50 40 30 20 10 2

1 No

Figure 4. Relationship between history of abortion and diabetes.

No. of persons

Exercise

Yes

Figure 5. Relationship between exercise and diabetes mellitus.

value obtained was 15.248 with first-degree of difference and the p value was 0.000, which was <0.01, showing that the relationship between

No GDM GDM

Figure 6. Relationship between diet control and diabetes mellitus.

>32

Figure 3. Relationship between age and diabetes.

No GDM GDM

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

3 No

Complication in pregnancy

Yes

Figure 7. Relationship between complication in pregnancy and diabetes mellitus.

history of diabetes in previous pregnancy and diabetes in present pregnancy was highly significant (Fig. 8). Out of 12, 5 (41.66%) pregnant women had complication in previous pregnancy and 5 (41.66%) had history of diabetes in first-degree relatives. The chi-square value obtained was 9.017 with first-degree of difference, the p value was 0.003, which was <0.01, the relationship between complication during previous pregnancy and diabetes was highly significant (Fig. 10). Three women (25%) which shows that had baby of weight >3.5 kg in their previous delivery and 6 (50%) of them have baby within a range of 2.5足-3 kg and 3 (25%) had baby of weight <2.5. The chi-square value is 20.468 with third-degree of difference, the p value is 0.000, which is <0.01, the relationship between birth weight of baby and diabetes was highly significant (Fig. 9) Among the 12 diabetic pregnant women 10 (83.33%) were not doing any

clinical Study

70 58

60 No. of persons

<0.01, and hence the relationship between exercise and diabetes was significant (Fig. 5). In short the factors that found to be significant were BMI, history of abortion, diet control, complications in pregnancy, diabetes in previous pregnancy, complications during previous pregnancy, birth weight of baby and exercise.

No GDM GDM

50 40 30 20 8

No Yes History of diabetes in previous pregnancy

Figure 8. Relationship between history of diabetes in previous pregnancy and diabetes in present pregnancy. No GDM GDM

No. of persons

15 10

4 2

7 3

<2.5

2.5-3.5 >3.5 Birth weight

Figure 9. Relationship between birth weight of baby and diabetes.

No GDM GDM 53

No. of persons

40 30 20

It was found out that there exists a highly significant relationship (p = 0.002) between abortion and GDM. Eighty percent of cases of abortions had history of GDM during previous pregnancy. It occurs mainly due to fetal hyperinsulinemia (when maternal insulin level falls fetal insulin level rises). Abortions occur mainly due to lack of knowledge and awareness that GDM leads to abortions and lack of proper precautions like regular glucose level monitoring. Discussion

There exists a significant relationship between BMI and GDM (p = 0.003). The chance of getting GDM increases with obesity. Now-a-days, obesity is becoming a major health problems due to the lack of physical activity and diet control. Maternal health programs can be conducted by healthcare workers, focusing on prevention and control of modifiable risk factors during pregnancy period and introducing necessary corrective therapeutic interventions such as exercise and dietary modifications.

The study conducted on the basis of GDM and its risk factors showed that prevalence of GDM is 17%. According to the study, major significant risk factors were obesity, previous large birth weight baby (macrosomia), complications during previous pregnancy, history of abortion, diet control, DM in previous pregnancy and exercise.

No Yes History of diabetes in first-degree relatives

Figure 10. Relationship between history of diabetes in firstdegree relatives and diabetes.

exercise; only 2 (16.66%) were doing regular exercise. The chi-square value obtained was 5.523 with firstdegree of freedom and the p value was 0.019, which was

This study showed the prevalence of GDM as 17%. GDM prevalence has been reported variably from 0.7% to 31.6% in the previous studies conducted in India. A similar study in Keralite women gave a prevalence figure of 31.6%. GDM is an epidemically explosive problem, which is increasing at an unstoppable pace. The Diabetes in Pregnancy Study Group India (DIPSI) guidelines having suggested one time plasma sugar level as a measure to detect GDM is an attempt to preempt future possibility and predisposition for GDM. Finding of this study is largely at tandem with those literatures at the national as well as international level. We therefore, infer from the above study that Kerala, despite its varying ethnicity, food habits physical activities, living standards, etc. are very much a part

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

clinical Study of gestational diabetes spectrum the world over. In a study, it has seen that there was significant relationship between age of pregnant women and GDM (Fig. 3); 60.7% of women with GDM were above 25 years of age. In our study, 75% of women with GDM were also above 25 years of age. So, it is clear that there exists a significant relationship between age and GDM. The probable reason may be that in both studies considered population was well-educated and were working and most of them were multiparous. Even though, they are aware of chance of getting GDM with increasing age they never give it an importance in their busy schedule. A group of studies reveals that a significant proportion of subjects with GDM were overweight and obese. In a study, it was seen that 31.06% were overweight (BMI 25-30) and 27.2% were obese (BMI >30); according to our study, 45.2% of women with GDM were overweight (BMI 26-30) and 9% of them were obese (BMI 31-35). Hence, there exists highly significant relationship between overweight/obesity and GDM in both studies. In our state, there is a misbelief that during gestational period over nourishment is essential and even though they are educated, they follow this custom. They take lots of ayurvedic products for their nourishment and most of them hesitate to do even simple household works during gestational period due to fear of losing baby. In our study, along with these reasons lack of exercise and diet control plays an important role. In group of studies, family history of GDM had significant role in a large proportion of cases. The prevalence of family history of GDM in first-degree relative was found to be 36.2%, 86%, 11%, 85.7% and 16.6%, respectively. According to our study prevalence was 41.6%. All these studies express the role of family history of gestational diabetes in first-degree relatives was highly significant and this could be because of some genetic factors transmitting from generation-togeneration among the families. Some studies showed that 14%, 27.6% and 9% of cases had a previous macrosomic babies, respectively that is babies of birth weight >4 kg. Based on our study, 58.33% of diabetic pregnant women had a history of previous large birth weight babies (>3.5 kg). The reason may be that we took rural population and other studies considered urban population. Also, they considered babies of birth weight >4 kg as macrosomic and we considered babies of birth weight >3.5 kg as macrosomic so there is much variation in prevalence rates. As regards abortions, study showed the prevalence as 80%, whereas other studies showed prevalence as

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

68.96%, 34%, 2.7%, 89.96%, 85.71%, respectively. The high prevalence rate obtained may be due to choosing a population who never considered GDM as an important complication. In a study, the prevalence rate is low when they give proper care and maintain blood sugar levels by proper medication and diet control. While considering about exercise and diet control in the study population a prevalence rate of 18% and 17% was seen. But, in our study it was shown to be 16.66% and 25%, respectively. The population we considered is aware of importance of exercise and diet control but ignorance and lack of proper instructions is the problem here. In study conducted in Trivandrum, the populations were ignoring exercise and diet control even though they too knew the value of both exercise and diet control. Diabetes in previous pregnancy gave prevalence rate of 29.1% in a study and 33.33% in our study. The recurrence was due to ignoring the condition, which occurred in previous pregnancy and lack of proper follow-up medication and repeated screening for increase in blood sugar level. The study was also conducted in same community set up followed hence they got almost similar prevalence. In two studies, the prevalence of previous pregnancy complications was 7% and 1.4%, respectively. And in our study, the prevalence of 41.66% is much higher because most of the subjects we considered were multiparous and in above studies most of women were primigravida. A case-control study (300 cases and 300 controls) in SAT Hospital, Trivandrum in 2010 showed that 60.7% cases above 25 years of age and 39.3% were <25 years of age. BMI â&#x2030;Ľ25 was significantly higher in cases (37.9%). Around 24% cases had a history of irregular menstrual cycle and 36% of them had a family history of diabetes among first-degree relatives, especially in mother. About 68.96% of the women had previous losses as compared controls. A study on prevalence of GDM in South Kerala during 2002 showed that the prevalence of GDM was found to be 11.2%, 7% reported with hydramnios, 34% had history of loss of pregnancy, 14% with macrosomia, 18% were found not exercising and 17% had not taken proper diet control. A study was conducted to determine the incidence of GDM in South India in 2005. Among the 980 mothers studied only 7 (0.7%) were diagnosed with GDM and the rate of GDM detected in worldwide women population is 4% every year. Among them, six of them gave history of miscarriages and five of them

clinical Study were above 25 years of age and had family history of DM. A prospective study on pregnancy outcomes in pre-gestational and gestational diabetic women in comparison to non-diabetic women in Asian Indian women (2006) showed the following results, 82.3% of women who reported with GDM had a family history of diabetes in their first-degree relatives, 2.7% of them had history of abortion, 1.4% of their children showed congenital anomalies, 8.2% of them gave birth to low birth weight babies and 27.6% of them gave birth to large babies in their previous pregnancy. A prospective case-control study in diabetic women in a district tertiary hospital in South India (2008) showed that 89.96% cases reported with loss of pregnancy, 11.33% had incidence of diabetes in their first-degree relatives, 24% had irregular menstrual cycles and 21.33% had incidence of GDM in their first-degree relatives. In Apollo Hospital, Chennai; a study on 1,251 pregnant women who underwent the 50 g oral glucose challenge test (OGCT) during 2004, 168 (18.9%) were diagnosed to have GDM. Taking only 2-hour plasma glucose for analysis, 144 (16.2%) had value ≥140 mg/dL, that they were diabetic. A perspective study in GDM all over India (2002) showed the results as follows - the study conducted in North Chennai showed the prevalence of 16.2%, in South Chennai 15%, 15% in Trivandrum, 17.5% in Ludhiana, 12% in Bangalore, 31.6% in Alwaye, Kerala and 18.8% was in Erode, Tamil Nadu. Conclusion The prevalence of GDM in this study was 17%. It was found out that the factors such as increased age of pregnant women, overweight and obesity, lack of exercise and diet control, GDM in first-degree relatives and previous abnormal GTT predispose to GDM. Other factors were women with previous large weight babies (macrosomia) and previous loss of pregnancy. GDM in previous pregnancy, complications in previous

pregnancy like hydramnios, bleeding, etc. have increased chances of getting GDM. Further studies including larger samples will substantiate our study results. SUGGESTED READING 1. Bhat M, K N R, Sarma SP, Menon S, C V S, S GK. Determinants of gestational diabetes mellitus: A case control study in a district tertiary care hospital in south India. Int J Diabetes Dev Ctries. 2010;30(2):91-6. 2. Paulose KP. Prevalence of gestational diabetes in south Kerala. Kerala Med J. 2008;(3):14-6. 3. Shefali AK, Kavitha M, Deepa R, Mohan V. Pregnancy outcomes in pre-gestational and gestational diabetic women in comparison to non-diabetic women--A prospective study in Asian Indian mothers (CURES-35). J Assoc Physicians India. 2006;54:613-8. 4. Bose T. Incidence of gestational diabetes mellitus in general population. J Hum Ecol. 2005;17(4):251-4. 5. Wahi P, Dogra V, Jandial K, Bhagat R, Gupta R, Gupta S, et al. Prevalence of gestational diabetes mellitus (GDM) and its outcomes in Jammu region. J Assoc Physicians India. 2011;59:227-30. 6. Seshiah V, Balaji V, Balaji MS, Sanjeevi CB, Green A. Gestational diabetes mellitus in India. J Assoc Physicians India. 2004;52:707-11. 7. Seshiah V, Balaji V, Balaji MS, Paneerselvam A, Arthi T, Thamizharasi M, et al. Prevalence of gestational diabetes mellitus in South India (Tamil Nadu) - a community based study. J Assoc Physicians India. 2008;56:329-33. 8. Seshiah VS, Balaji V, Balaji M. Gestational diabetes mellitus - A prospective. Gestational Diabetes Mellitus 2011; p. 21-40. 9. Ferrara A. Increasing prevalence of gestational diabetes mellitus: a public health perspective. Diabetes Care. 2007;30 Suppl 2:S141-6. 10. Soheilykhah S, Mogibian M, Rahimi-Saghand S, Rashidi M, Soheilykhah S, Piroz M. Incidence of gestational diabetes mellitus in pregnant Women. Iranian J Reprod Med. 2010;8(1): 24-8.

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Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

clinical Study

Macrovascular and Microvascular Complications in Newly Diagnosed Type 2 Diabetes Mellitus Deepa DV*, Kiran BR†, Gadwalkar Srikant R‡

Abstract Objectives: To study the prevalence and clinical profile of microvascular and macrovascular complications in newly diagnosed type 2 diabetes mellitus patients in and around Bellary, Karnataka. Study design: The study was an observational cross-sectional study of 100 newly detected type 2 diabetics attending Dept. of Medicine (outpatient/ inpatient), VIMS combined hospitals, Bellary, from October 2012 to June 2013 (9 months) who matched the inclusion criteria. Material and methods: Cases were screened for vascular complications as per ADA criteria, data tabulated and analyzed. Statistical analysis: SPSS software package was used for analysis. Statistical significance was defined as a p value <0.05. Results: The mean age of presentation was 54.05 ± 13.24 with male:female ratio of 1.6:1. The prevalence of diabetic retinopathy, nephropathy, neuropathy, cardiovascular, cerebrovascular and peripheral vascular disease was 20%, 37%, 16%, 26%, 8% and 11%, respectively; retinopathy, nephropathy and coronary artery disease screening being significant (p < 0.05). Conclusion: There was a significant correlation between prevalence of diabetes and increased waist circumference and body mass index. There was high prevalence of coronary artery disease, nephropathy and retinopathy in South Indian population at diagnosis. Screening for all cases of diabetes at diagnosis for complications is recommended. Keywords: Type 2 diabetes mellitus, microvascular complications, macrovascular complications

iabetes mellitus is a common metabolic disorder and is associated with development of chronic complications leading to significant morbidity and mortality. The onset of type 2 diabetes (T2DM) is often silent and insidious. Pathogenic processes causing T2DM range from autoimmune destruction of cells of pancreas with consequent insulin deficiency to abnormalities that result in resistance to insulin action. The asymptomatic phase of hyperglycemia accounts for the relatively high prevalence of complications at initial presentation.1 Majority of India’s population is in the villages and the rural population is ignorant about the disease and its complications. It is therefore, essential to device cost-effective and simple screening tests to detect complications. The term ‘diabetes’ was first coined by Araetaeus of Cappodocia (81-133AD). Mellitus

(honey sweet) was added by Thomas Willis (Britain) in 1675, when he detected sweetness in urine. It is said that it was first noticed by the ancient Indians; Shushrutha had named it as ‘Madhumeha’.2

*Senior Resident Bangalore Medical College and Research Institute, Bangalore, Karnataka † Senior Resident Rajarajeshwari Medical College, Bangalore, Karnataka ‡ Professor and Head Dept. of General Medicine Vijayanagara Institute of Medical Sciences, Bellary, Karnataka Address for correspondence Dr Deepa DV No. 82, 5th Main, Maruthi HBCS, BTM I Stage, Bangalore - 560 029, Karnataka E-mail: drdeepa.dv@gmail.com, brkiranin@gmail.com

Material and Methods

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

According to Diabetes Atlas (5th edition) in 2011, the global prevalence of diabetes was estimated at 366 million; this figure is predicted to reach 552 million by 2030. Eighty percent people live in low and middle income countries. Diabetes caused 4.6 million deaths in 2011. China leads the world with largest number of diabetic subjects followed by India. According to the Diabetes Atlas 2011 published by the International Diabetes Federation, the number of people with diabetes in India currently around 61.3 million is expected to rise to 101.2 million by 2030.

Source of Data Newly detected patients with T2DM attending Dept. of Medicine (outpatient/inpatient), Vijayanagara Institute of Medical Sciences (VIMS) combined hospital, Bellary, form the subjects.

clinical Study Design of the Study

Method of Data Collection

Cross-sectional observational study.

Patients newly detected of T2DM attending Dept. of Medicine (outpatient/inpatient), VIMS combined hospital, Bellary were included for the study.

Duration of Study October 2012 to June 2013 (9 months).

Inclusion Criteria Newly diagnosed T2DM adult patients >20 years of age were included in the study. (Laboratory diagnosis of diabetes mellitus was confirmed by latest criteria laid by the American Diabetes Association (ADA). Blood glucose levels were checked on two separate occasions before the diagnosis of diabetes mellitus was made.) According to ADA,1 criteria for diagnosis are: ÂÂ Glycosylated hemoglobin (HbA1C) ≥6.5%. The test should be performed in a laboratory using a method that is NGSP (National Glycohemoglobin Standardization Program) certified and standardized to the DCCT (Diabetes Control and Complications Trial) assay.* OR ÂÂ Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 hours* OR ÂÂ 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during an OGTT (oral glucose tolerance test)† OR ÂÂ In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dL (11.1 mmol/L). *In the absence of unequivocal hyperglycemia, criteria 1-3 should be confirmed by repeat testing. †

The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.

Exclusion Criteria ÂÂ

Type 1 diabetes mellitus

ÂÂ

Any other severe illness

ÂÂ

Patients already diagnosed of diabetes mellitus and on treatment

ÂÂ

Refusal to be a part of the study

ÂÂ

Pregnancy

Sample Size Hundred cases of newly diagnosed T2DM were included in this study.

Detailed history such as age and sex, family history of diabetes was recorded. Symptoms suggestive of diabetes or of related complications were noted. Past history of hypertension and complications of diabetes was documented. Any previous treatment for these complications taken was recorded. Smoking or alcohol history was noted. General physical examination, vital parameters such as pulse, blood pressure (in sitting and standing position) temperature and respiratory rate were recorded. Anthropometric measurements: ÂÂ

Weight (in kilograms) and height (in centimeters) was recorded.

ÂÂ

The body mass index (BMI) was determined by dividing the weight (in kilograms) by height (in meters2).

ÂÂ

Measurement of waist circumference (cm): It was measured just above the uppermost lateral border of the right iliac crest, a horizontal mark was drawn, and then crossed with a vertical mark on the midaxillary line. The measuring tape was placed in a horizontal plane around the abdomen at the level of this marked point on the right side of the trunk.

Presence of skin infections, gangrene and ulcers was noted. Systemic examination was carried out in all patients. Presence of sensory neuropathy was defined4 by symptoms of tingling and numbness over the extremities (bilaterally symmetrical) with or without impaired touch, vibration sense or joint position sense. Presence of motor neuropathy was noted. Autonomic dysfunction in the form of resting tachycardia, orthostatic hypotension, gastroparesis/diarrhea or abnormal sweating was noted. Ten gram monofilament was used to note any reduced sensation due to neuropathy. Dilated pupil fundoscopy was carried out in all patients by an ophthalmologist and retinopathy was defined and graded as nonproliferative diabetic retinopathy and proliferative retinopathy.5 Proliferative retinopathy was described by the presence of any retinal or optic disc neovascularization, or the presence of preretinal or vitreous hemorrhage, whereas the presence of microaneurysms, exudates (lipid exudates or ‘cotton-wool spots’) and/or retinal hemorrhages only

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

clinical Study was defined as nonproliferative retinopathy. Fasting and postprandial blood sugars (venous blood samples drawn) on two separate occasions were determined using glucose oxidase-peroxidase method. Renal function tests included blood urea, serum creatinine and urine analysis. Urine was analyzed for glucose, ketone bodies and protein. Microalbuminuria was estimated by nephelometry. Microalbuminuria is defined as the mean urine albumin concentration of 30-300 mg/mL detected by nephelometry on three consecutive days.

confidence interval (CI) was calculated. Student’s t-test and Chi-square test was used to calculate the significance between the variables. RESULTS In this study, 62 were males and 38 were females. The mean age was 54.05 ± 13.24 years. The maximum incidence of diabetics was seen between 52-62 years. Table 1 shows various metabolic parameters in the study population. The patients presenting with complaints correlated with diabetic complications of CAD, cerebrovascular disease, peripheral artery disease, retinopathy, nephropathy and neuropathy was 15%, 7%, 7%, 2%, 9% 7%, respectively. Fundus examination revealed that 19 cases had nonproliferative diabetic retinopathy and one case had proliferative retinopathy. It was statistically significant. Microalbuminuria was seen in 30 cases, macroalbuminuria seen in four cases was statistically significant. ECG findings were normal in 74 cases, myocardial infarction (MI), left bundle branch block, left ventricular hypertrophy (LVH) in three cases each, old MI in seven cases, ischemic heart disease in six cases and arrhythmias in two cases. 2D-echocardiography showed regional wall motion abnormality in 23 cases, hypertensive heart disease in eight cases, concentric LVH and ischemic dilated cardiomyopathy in one case each. Carotid Doppler showed atherosclerosis in five cases and was statistically insignificant. ABI showed limb ischemia in 19 cases among which seven cases showed critical limb ischemia which was statistically insignificant. Twentyeight cases were detected on routine investigations,

Macroalbuminuria is defined as urine albumin >300 mg/dL.6 Fasting lipid profile included serum cholesterol, serum triglycerides, serum high-density lipoprotein (HDL) and serum low-density lipoprotein (LDL). Patient was termed to have dyslipidemia if LDL was >100 mg/dL, serum cholesterol >200 mg/dL, serum HDL <40 or serum triglycerides >150 mg/dL. A 12-lead electrocardiogram (ECG) and 2D- echocardiography was done to note the presence of ischemia or infarction to indicate coronary artery disease (CAD).6 Carotid Doppler was done to note for presence of stenosis. Ankle-brachial index (ABI) was determined using arterial Doppler. A value <0.9 was considered significant to have peripheral arterial disease.7

Statistical Analysis SPSS software package was used for the analysis. Statistical significance was defined as a p value <0.05 (two-sided). Mean standard deviation (SD) and

Table 1. Mean and Standard Deviation of the Metabolic Parameters Parameters Age

Diabetics (n = 100)

CAD (n = 25)

CVD (n = 8)

PVD (n = 11)

DR (n = 20)

DN (n = 34)

DNe (n = 16)

54.05 ± 13.24

Weight (kg)

74 ± 13

84.36

75.8

76.94

77.33

Height (cm)

165 ± 6.3

166

167.25

166

167

166

164

BMI

27.02 ± 12.8

28.04

30.10

30.6

27.28

27.85

28.81

Waist circumference

90.14 ± 9.43

96.25

95.54

88.75

90.6

93.73

208 ± 73.7

220

229

277

226

232

246

FBS PPBS

304 ± 95

326

344

426

334

344

338

Blood urea

29.6 ± 15.5

36.5

37.4

34.5

31.4

33.8

31.1

Serum creatinine

1.04 ± 0.39

1.24

1.275

1.9

1.24

1.203

1.129

HbA1C

8.65 ± 1.8

9.016

9.15

10.5

9.24

9.23

9.4

Total cholesterol

156 ± 49.9

170

183

196

168

160

176

BMI = Body mass index; CAD = Coronary artery disease; CVD = Cerebrovascular disease; DN = Diabetic nephropathy; DNe = Diabetic neuropathy; DR = Diabetic retinopathy; FBS = Fasting blood sugar; PPBS = Postprandial blood sugar; PVD = Peripheral vascular disease.

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

clinical Study 28 were incidentally detected when they attended the hospital for other illnesses and rest of the 44 cases presented with multiple complications due to diabetes. The metabolic parameters are described in Table 1. Common complications which they presented were CAD (15%), infection (12%), stroke (6%), ulcers (4%), neuropathy (4%) and diabetic ketoacidosis (1%). The prevalence of macrovascular complications CAD,

Table 3 shows correlation of HbA1C with diabetic complications. In our study, correlation coefficient of fasting blood sugar (FBS) and postprandial blood sugar (PPBS) in relation to HbA1C was 0.56 and 0.57, respectively.

Table 2. Prevalence of Complications at Diagnosis Complications

Percentage (%)

P value

CAD

0.011*

CVD

0.334

PVD

0.477

0.018*

0.003*

0.368

cerebrovascular disease and peripheral arterial disease was 26.0%, 8.0% and 11.0%, respectively and microvascular complications retinopathy, nephropathy and neuropathy was 20.0%, 34.0% and 16.0%, respectively. Table 2 shows p values of the vascular complications. Smoking and hypertension are confounding factors which influence CAD. High incidence of complications especially microvascular and CAD occur with HbA1C of range >6.5.

Discussion This is a study done over a period of 24 months in cases of newly detected T2DM attending the inpatient and outpatient department of VIMS combined hospital. In our study, 28 cases were detected on

*Significant p <0.05.

Table 3. HbA1C in Correlation with Diabetic Complications HbA1C (%)

Mean ± SD

CAD

CVD

PVD

DNe

P value

<6.5

5.95 ± 0.77

P-01 A-01

P-00 A-02

P-01 A-01

P-00 A-02

0.8602*

6.51-7.5

7.16 ± 0.22

P-08 A-29

P-02 A-35

P-01 A-36

P-05 A-32

P-06 A-31

P-03 A-34

0.0301**

7.51-8.5

7.94 ± 0.31

P-03 A-17

P-01 A-19

P-02 A-18

P-04 A-16

P-07 A-13

P-04 A-16

0.0021**

8.51-9.5

9.16 ± 1.9

P-04 A-09

P-00 A-13

P-03 A-10

P-08 A-05

P-02 A-11

0.0040**

>9.51

11.16 ± 1.23

P-10 A-28

P-04 A-34

P-08 A-30

P-12 A-26

P-06 A-32

0.0026**

P-26 A-74

P-08 A-92

P-11 A-89

P-20 A-80

P-34 A-66

P-15 A-85

Pool *Nonsignificant; **Significant p <0.05. A = Absent; N = Number; P = Present.

Table 4. Comparison of Prevalence of Complications with Other Studies Complications (%)

CAD

Mohan et al11 (n = 4,471)

Hoorn study10 (n = 255)

7.9

Weerasuriya et al9 (n = 597) 26.9

CVD

Drivsholm et al8 (n = 1,137)

Our study (n = 100)

28.4

27.9

5.1

3.4

2.4

4.6

16.1

17.5

1.9

15.2

5.4

26.7

48.1

37.4

48.3

25.2

19.1

PVD

2.3

34.2

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

clinical Study routine investigations out which 18 had symptoms of polydipsia, polyuria. Twenty-eight were incidentally detected when they attended the hospital for other illnesses and rest of the 44 cases presented with multiple complications due to diabetes. Total of about 43 cases had symptoms of polydipsia, polyuria. Present study correlates with findings seen in Drivsholm et al8 study. In T2DM, at diagnosis there is a high prevalence of complications. Our study showed similar results as Weerasuriya et al,9 which is a Sri Lankan study. In Western studies, there is low incidence of retinopathy. Drivsholm study8 showed higher prevalence of nephropathy in males. Table 4 shows prevalence of complications at diagnosis of various studies.8-11 In our study, correlation coefficient of FBS and PPBS in relation to HbA1C was 0.56 and 0.57, respectively. In DCCT12 it was 0.82 and in a study conducted by Nathan et al13 it was 0.89. The relative contribution of postprandial PG decreased progressively from the lowest to the highest quintile of HbA1C. By contrast, the relative contribution of fasting PG showed a gradual increase with increasing levels of HbA1C. Conclusion Large proportion of population presented because of complications occurring due to diabetes- a silent killer. Screening for CAD, retinopathy and nephropathy at diagnosis was statistically significant. There is high prevalence of CAD (26%), retinopathy (20%) and nephropathy (34%) at diagnosis, which is statistically significant. Prevalence of cerebrovascular disease, peripheral vascular disease and neuropathy is 8%, 11% and 16%, which is statistically insignificant. Nephropathy in our study defined by microalbuminuria has a high prevalence whereas overt kidney disease was negligible. This shows importance of screening at diagnosis and to treat and delay progression. HbA1C levels predict the prevalence of complications and there is moderate correlation between HbA1C and blood glucose levels. Screening with simple tests such as ECG, Echo, fundoscopy and urine microalbuminuria at diagnosis for all cases of diabetes is essential to identify the complications at an early reversible stage.

References 1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2006;29 Suppl 1:S43-8. 2. Ahmed AM. History of diabetes mellitus. Saudi Med J. 2002;23(4):373-8. 3. Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J. Harrison’s Principles of Internal Medicine. 18th Edition, Vol. 2. USA: McGraw-Hill; 2012;344: p. 2968-3002. 4. American Diabetes Association American Academy of Neurology. Consensus statement: Report and recommendations of the San Antonio conference on diabetic neuropathy. Diabetes Care. 1988;11(7):592-7. 5. Wilkinson CP, Ferris FL 3rd, Klein RE, Lee PP, Agardh CD, Davis M, et al; Global Diabetic Retinopathy Project Group. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology. 2003;110(9):1677-82. 6. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2005;28 Suppl 1:S4-S36. 7. American Diabetes Association. Peripheral arterial disease in people with diabetes. Diabetes Care. 2003;26(12): 3333-41. 8. Drivsholm T, de Fine Olivarius N, Nielsen AB, Siersma V. Symptoms, signs and complications in newly diagnosed type 2 diabetic patients, and their relationship to glycaemia, blood pressure and weight. Diabetologia. 2005;48(2):210-4. 9. Weerasuriya N, Siribaddana S, Dissanayake A, Subasinghe Z, Wariyapola D, Fernando DJ. Long-term complications in newly diagnosed Sri Lankan patients with type 2 diabetes mellitus. QJM. 1998;91(6):439-43. 10. Spijkerman AM, Dekker JM, Nijpels G, Adriaanse MC, Kostense PJ, Ruwaard D, et al. Microvascular complications at time of diagnosis of type 2 diabetes are similar among diabetic patients detected by targeted screening and patients newly diagnosed in general practice: the Hoorn screening study. Diabetes Care. 2003;26(9):2604-8. 11. Premlatha G, Rema M, Mohan V. Complications of diabetes mellitus at diagnosis in South Indian type 2 diabetic patients. Int J Diab Dev Ctries. 1998;18:1-4. 12. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). Diabetes Care. 2003;26(3):881-5. 13. Nathan DM, Turgeon H, Regan S. Relationship between glycated haemoglobin levels and mean glucose levels over time. Diabetologia. 2007;50(11):2239-44.

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Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

clinical Study

Pattern of HbA1C in Newly Detected Type 2 Diabetes Mellitus Prem Kumar D*, Krishnamurthy VR†, Pratap VGM‡

Abstract The incidence of type 2 diabetes mellitus is increasing day by day. The disease is now becoming a global burden. According to the latest American Diabetes Association (ADA) guidelines, glycosylated hemoglobin (HbA1C) should be maintained below 7 to avoid microvascular as well as macrovascular complications; however, higher values may be acceptable depending on comorbidities and age. But during the initial stages, it is recommended to control below 7. HbA1C above 6.5 can be taken as diagnostic criteria for diagnosis of diabetes. First visit HbA1C was measured to know the common HbA1C visit pattern in type 2 diabetes patients. Keywords: Glycosylated hemoglobin, type 2 diabetes mellitus, ADA guidelines

ype 2 diabetes mellitus is one of the most common forms of noncommunicable disease globally and few societies are ethnic groups are spared. It accounts for about 85% of cases of diabetes in the Caucasians and virtually all in certain nonCaucasian ethnic groups, 80% of the type 2 diabetes is developed in the developed countries and areas. Type 2 diabetes mellitus is a major component of metabolic syndrome characterized by dyslipidemia, hypertension and hyperglycemia with central obesity.

There are several criteria recommended for diagnosis of diabetes such as oral glucose tolerance test, measurement of fasting and postprandial blood glucose and according to latest American Diabetes Association (ADA) guidelines, glycosylated hemoglobin (HbA1C) above 6.5 is diagnosed as diabetes. It is recommended to control HbA1C below 7 to minimize the progression of microvascular and *Professor and Registrar Dept. of Medicine Hassan Institute of Medical Sciences, Hassan and Rajiv Gandhi University of Health Sciences, Bangalore, Karnataka † Assistant Professor Dept. of Surgery Hassan Institute of Medical Sciences, Hassan, Karnataka ‡ Consultant Primary Care Physician in Diabetes Hassan Obesity and Diabetes Wellness Centre, Hassan, Karnataka Address for correspondence Dr Prem Kumar D Professor and Registrar Dept. of Medicine Hassan Institute of Medical Sciences, Hassan and Rajiv Gandhi University of Health Sciences, Bangalore, Karnataka E-mail: premdkumar@yahoo.com

macrovascular complications. The present study involved the measurement of glycemic control in the form of HbA1C during their first visit to their outpatient department. MATERIAL AND METHODS One hundred cases of freshly detected type 2 diabetes patients were screened and HbA1C was measured irrespective of patient age, sex and occupation. HbA1C was measured using chromatography-based highperformance liquid chromatography (HPLL) assay. All the records were tabulated and analyzed. RESULTS HbA1C of all the 100 patients over a period of 3 months was measured and analyzed as shown in Table 1 and Figure 1. Table 1. HbA1C of the Patients HbA1C

No. of patients

5.0-5.9

6.0-6.9

7.0-7.9

8.0-8.9

9.0-9.9

>10

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

clinical Study

>10

during their outpatient visits. These patient could be taken as potentially untreated, since they were freshly detected or they had not been screened previously. Most of the patients are frankly diabetic at the time of screening.

9 10

9.0-9.9

8.0-8.9 7.0-7.9

6.0-6.9

As HbA1C is a reliable test for diagnosis as well as assessing the control of diabetes, there is an increased need for the implementation of proper screening techniques and to detect the disease at an earlier stage.

5.0-5.9

3 0

Suggested Reading

HbA1C

Figure 1. Analysis of HbA1C of the patients.

1. American Diabetes Association. Diabetes care: clinical practice recommendations (revised), 2014.

DISCUSSION

2. DeFronzo RA, Ferrannini E, Zimmet P, Alberti G (Eds.). Epidemiology of type 2 diabetes. International Textbook of Diabetes, 4th Edition. USA: Wiley-Blackwell; 2015.

After analyzing the tabulated results, it was seen that more than 50 patients had HbA1C between 7.0 and 9.0

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Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

clinical Study

Association Between Indexes of Insulin Sensitivity/ Resistance and Serum Magnesium Levels in Overweight Diabetic Subjects Neetesh Kumar Gupta*, Sonali Sharma†, GG Kaushik‡, Bhavana Gupta#

Abstract Objective: To study the association of serum magnesium level and indexes of insulin sensitivity/resistance in overweight diabetic subjects and evaluate the relationship of serum magnesium level with body mass index (BMI) in overweight diabetic subjects. Study design: This case-control study was conducted on 50 overweight type 2 diabetic patients. The overweight diabetic subjects were defined as (BMI ≥ 25.0-30.0 kg/m2) according to the criteria of World Health Organization (WHO), 2004. Diagnosis of type 2 diabetes mellitus was made according to the criteria recommended by the American Diabetes Association standards - 2012. Material and methods: The study was conducted on 50 overweight type 2 diabetic patients of either gender attending/admitted in OPD/wards of the Dept. of General Medicine, Jawaharlal Nehru Medical College and Associated Group of Hospitals, Ajmer, Rajasthan over a period of 12 months. Results: In overweight diabetic subjects, serum magnesium level were found to be low, HOMA-IR was high and QUICKI values was found to be low in comparison to normal weight nondiabetics. Serum magnesium significantly inversely correlated with BMI, plasma glucose, HbA1C, serum insulin, HOMA-IR and a positive correlation of serum magnesium with QUICKI (overweight subjects) was found in our study. Conclusion: Poor glycemic control in hypomagnesemia patients has been observed in the present study when compared with normomagnesemia patients. Hypomagnesemia may aggravate insulin resistance state in overweight subjects. This can predispose them to metabolic complication of diabetes mellitus. Keywords: Diabetes mellitus, hypomagnesemia, insulin

ver the last decades, there has been a rapid increase in the prevalence of type 2 diabetes in parallel with the obesity epidemic. Diabetes mellitus is a leading cause of morbidity and mortality worldwide, with an estimated 346 million adults being affected in the year 2011-2012.1 Type 2 diabetes is characterized by peripheral insulin resistance, impaired regulation of hepatic glucose production, hyperinsulinemia, β-cell dysfunction and subsequent β-cell failure.2 Direct associations of trace microelements with diabetes mellitus have been observed in many research studies.3 Magnesium plays an important role in carbohydrate metabolism. It

*Postgraduate † Associate Professor ‡ Professor Dept. of Biochemistry # Postgraduate Dept. of Microbiology Jawaharlal Nehru Medical College, Ajmer, Rajasthan Address for correspondence Dr Sonali Sharma SONANK, 2-K-12, Shastri Nagar, Ajmer, Rajasthan E-mail: sonalisharma14@gmail.com

may influence the release and activity of insulin, the hormone that helps control blood glucose levels. Low blood levels of magnesium (hypomagnesemia) are frequently seen in individuals with type 2 diabetes.4 Study of role of magnesium in obese diabetic subjects has been a matter of interest of researchers in the past years. However, studies on association of trace microelement magnesium with indexes of insulin sensitivity/resistance in overweight type 2 diabetics are scarce. The present study was undertaken to study indexes of insulin sensitivity/resistance and their association with serum magnesium levels in overweight diabetic subjects. Material and methods This case-control study has been conducted on 50 type 2 diabetic overweight patients of either gender attending/admitted in OPD/wards of the Dept. of General Medicine, Jawaharlal Nehru Medical College and Associated Group of Hospitals, Ajmer, Rajasthan. The results were compared with age- and gendermatched 100 normal weight nondiabetic healthy

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

clinical Study subjects acting as controls. Consent from all the subjects was obtained for the study.

Inclusion Criteria Overweight adults in the age group of 35-55 years were screened for eligibility and majority of patients of either gender selected for the study were in the age group of 35-45 years. All participants were asked to maintain their usual diet and not make any significant changes in diet or physical activity. Dietary intake of magnesium in all subjects was adequate. The overweight diabetic subjects were defined as (BMI ≥ 25.0-30.0 kg/m2) according to the criteria of World Health Organization (WHO), 2004.5 Diagnosis of type 2 diabetes mellitus was made according to the criteria recommended by the American Diabetes Association standards 2012.6

Exclusion Criteria Patients with positive clinical history of malignancy, chronic alcoholism, pregnancy, insulin therapy, medical conditions predisposing to hypomagnesemia (gastroenteritis, chronic kidney disease, chronic liver disease), subjects receiving magnesium supplementation or treated with drugs known to modify magnesium metabolism e.g., diuretics, thyroxine, lithium or calcium antagonists were excluded from the study. The subjects selected for the study were grouped as follows: ÂÂ

Group I: Type 2 overweight diabetic subjects (n = 50).

ÂÂ

Group II: Nondiabetic normal weight control subjects (n = 100).

Anthropometric Measurements Weight was measured in light clothes and without shoes using a calibrated digital weighing scale with an accuracy of 0.1 kg and height was measured without shoes using a calibrated wall mounted stadiometer to the nearest 0.5 cm. Body mass index (BMI) was calculated by using the formula: mass (in kg)/height2 (in meters).7

analyzer (Randox Daytona). Fasting serum insulin was estimated using enzyme-linked immunosorbent assay (ELISA) technique. Following indexes derived from fasting blood samples for assessment of insulin sensitivity/resistance were calculated: ÂÂ

Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) was calculated using the formula of Matthews et al, 1985.8

ÂÂ

Quantitative Insulin Sensitivity Check Index (QUICKI) was calculated using the formula of Katz et al, 2000.9

Statistical Analysis Data were recorded in a predesigned proforma and managed in an excel spread sheet. Data were reported as mean ± SD (standard deviation) median (range). Comparison of physical and biochemical parameters between overweight diabetics and nondiabetics normal weight healthy control subjects was performed using equal or unequal variance unpaired student t-test for continuous variables (as applicable). The relation between continuous variables was examined using Pearson’s correlation coefficient (r). A multiple linear regression analysis was performed in order to explore the variables independently related to serum magnesium. The variables included were plasma glucose, HbA1C, serum insulin and BMI. All p values were based on Table 1. Age and Sex Distribution of Overweight Diabetics

Age (years) 35-45

Male 23 (46%)

46-55 Total

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

Total

Female 11 (22%)

34 (68%)

9 (18%)

7 (14%)

16 (32%)

32 (64%)

18 (36%)

50 (100%)

Table 2. Anthropometric Parameters of Overweight Diabetics and Normal Weight Nondiabetic Subjects (Controls) Parameters

Group I

Group II

Age (years)

Overweight diabetics mean ± SD (n = 50) 40.18 ± 2.8

Normal weight nondiabetics mean ± SD (n = 100) 40.35 ± 2.9

Biochemical Parameters An overnight, 12 hours fasting blood sample was aseptically collected from anticubital vein of all subjects, serum/plasma was separated and fasting plasma glucose, glycosylated hemoglobin (HBA1C) and serum magnesium were estimated on fully automated

Sex

Weight (kg)

70.34 ± 4.5

51.58 ± 4.9

Height (cm)

159.42 ± 0.05

155.52 ± 4.4

BMI (kg/m2)

27.72 ± 1.9

21.34 ± 1.5

clinical Study Table 3. Comparison of Biochemical Parameters of Overweight Diabetics and Normal Weight Nondiabetics Subjects (Controls) Parameters Plasma glucose (mg/dL) HbA1C (%) Serum insulin (µIU/mL) Serum magnesium (mg/dL)

Group I Overweight diabetics mean ± SD (n = 50) 230.82 ± 21.73 8.2 ± 0.45 9.8 ± 1.4 1.2 ± 0.14

Group II Normal weight nondiabetics mean ± SD (n = 100) 87.12 ± 10.6 4.90 ± 0.5 3.5 ± 0.8 2.0 ± 0.2

‘t’ value

‘p’ value*

44.21 40.77 29.50 28.43

< 0.0001 (HS) < 0.0001 (HS) < 0.0001 (HS) < 0.0001 (HS)

*p value <0.0001, highly significant (HS); p value <0.01, significant (S); p value >0.05, nonsignificant (NS).

a two-sided test of statistical significance. Significance was accepted at the level of p < 0.05.

Overweight diabetics

Normal weight nondiabetics

Majority of the patients satisfying the inclusion criteria were in the age group of 35-45 years (68%). Out of 50 patients of this study group, 32 were males (64%) and 18 were females (36%) (Table 1). Table 2 depicts the anthropometric parameters of overweight diabetics and normal weight nondiabetic, subjects. The biochemical parameters viz., plasma glucose (mg/dL), HbA1c (%), serum insulin (µIU/mL) and serum magnesium (mg/dL) levels in overweight diabetics and normal weight nondiabetics are summarized in Table 3. The mean plasma glucose level and mean HbA1C level in mean ± SD were found to be significantly high in Group I as compared to Group II. A similar trend was observed in mean serum insulin and magnesium levels in Group I, when statistically compared with Group II (Table 3 and Fig. 1). Table 4 shows statistically insignificant age difference between Group I and II. A highly significant increase in BMI has been observed in Group I when compared with Group II. In overweight diabetic subjects, serum magnesium levels were found to be low in comparison to normal weight nondiabetics. The difference was highly significant in Group I and II, respectively (Table 4 and Fig. 2). HOMA-IR and QUICKI, indexes of insulin resistance/sensitivity showed highly significant

Values of parameters

250 230.82

Results

200 150 100

87.12

50 0

Glucose (mg/dL)

8.2 4.9

9.8

HbA1C (%)

Insulin (µIU/mL)

3.5

1.2 2.0 Magnesium (mg/dL)

Parameters

Figure 1. Comparison of biochemical parameters of overweight diabetics and normal weight nondiabetics subjects (controls).

difference between Group I and Group II. The overweight diabetics had increased value of HOMA-IR and decreased value of QUICKI (Table 5 and 6, Fig. 3). Pearson correlation coefficient (r) analysis was used to determine the correlation of serum magnesium levels with BMI in overweight subjects. Magnesium significantly inversely correlated with BMI (in overweight subjects) (r = -0.50; p < 0.0001) (Fig. 4). Magnesium significantly negatively correlated with plasma glucose (r = -0.62; p < 0.0001) (Fig. 5), HbA1C (r = -0.29; p < 0.0001) (Fig. 6), serum insulin (r = -0.62; p < 0.0001), HOMA-IR (r = -0.63; p < 0.0001) and a positive correlation of serum magnesium with QUICKI

Table 4. Comparison of BMI and Serum Magnesium in Overweight Diabetics and Normal Weight Nondiabetic Subjects (Controls) Parameters Age (years) BMI (kg/m2) Serum magnesium (mg/dL)

Group I Overweight diabetics mean ± SD (n = 50) 40.18 ± 2.8 27.72 ± 1.9 1.2 ± 0.14

Group II Normal weight nondiabetics mean ± SD (n = 100) 40.35 ± 2.9 21.34 ± 1.5 2.0 ± 0.2

‘t’ value

‘p’ value*

-0.34 18.78 28.43

0.7290 (NS) < 0.0001 (HS) < 0.0001 (HS)

*p value <0.0001, highly significant (HS); p value <0.01, significant (S); p value >0.05, nonsignificant (NS).

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

clinical Study Overweight diabetics

25 20

26.81 21.34

10 5

1.2 2.0 BMI

5 4 3 2 0.75

1 0

Magnesium

HOMA-IR

Parameters

Figure 2. Comparison of BMI and serum magnesium in overweight diabetics and normal weight nondiabetics subjects (controls).

QUICKI

Group II Normal weight nondiabetics mean ± SD (n = 100)

5.7 ± 1.2

0.75 ± 0.20

0.30 ± 0.009

0.40 ± 0.020

(r = 0.65; p < 0.0001) was found in our study. Multiple linear regression analysis showed that serum insulin and BMI were independently related to serum magnesium levels in overweight diabetic subjects and explained 49.75% of the magnesium variation. Discussion Among the endocrine and metabolic disorders associated with magnesium deficiency, diabetes mellitus is the most common. The present study was undertaken in two groups viz. Group I and Group II i.e., overweight diabetics and normal weight nondiabetics, respectively. We have reported significantly lower serum magnesium levels in overweight subjects in comparison to normal weight

Indexes

QUICKI

2 Serum magnesium

HOMA-IR

Group I Overweight diabetics mean ± SD (n = 50)

0.3 0.4

Figure 3. Comparison between HOMA-IR and QUICKI in overweight diabetics and normal weight nondiabetics (controls).

Table 5. Indexes Derived from Fasting Blood Samples for Assessment of Insulin Sensitivity/Resistance in Overweight Diabetics and Normal Weight Nondiabetic Subjects (Controls) Indexes

Normal weight nondiabetics

5.7

Overweight diabetics

Values of indexes

Values of parameters

Normal weight nondiabetics

1.6 1.2 0.8 0.4 0

BMI

Figure 4. Linear correlation between BMI and serum magnesium level in overweight diabetic subjects.

nondiabetics. The results, thus confirm that magnesium is negatively regulated in overweight subjects. Previous reports have shown that serum magnesium level was found lower in overweight subjects.10 Magnesium deficiency may play an important role in both insulin sensitivity and insulin secretion processes. The release of insulin caused by a glucose challenge is partly dependent on adequate magnesium. Magnesium is essential for insulin secretion, insulin receptor interaction, postreceptor events (involving tyrosine kinase-mediated phosphorylation) and normal carbohydrate utilization (by magnesium-

Table 6. Comparison of Indexes for Assessment of Insulin Sensitivity/Resistance in Overweight Diabetic and Normal Weight Nondiabetic Subjects (Controls) Indexes HOMA-IR QUICKI

Group I Overweight diabetics mean ± SD (n = 50) 5.7 ± 1.2

Group II Normal weight nondiabetics mean ± SD (n = 100) 0.75 ± 0.20

‘t’ value

‘p’ value*

28.96

< 0.0001 (HS)

0.30 ± 0.009

0.40 ± 0.020

46.40

< 0.0001 (HS)

*p value <0.0001, highly significant (HS); p value <0.01, significant (S); p value >0.05, nonsignificant (NS).

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

clinical Study

Serum magnesium (mg/dL)

Limitations 1.8 1.6 1.4 1.2 1

Large scale prospective studies are needed to establish that magnesium plays an important role in improving insulin sensitivity and preventing diabetes mellitus in overweight subjects.

0.8

Conclusion

0.6 0.4 0.2 0

100

150 200 250 Plasma glucose (mg/dL)

300

Serum magnesium (mg/dL)

Figure 5. Linear correlation between plasma glucose and serum magnesium level in overweight diabetic subjects.

1.7 1.5 1.3 1.1 0.9 0.7 0.5

6 7 8 HbA1C (%)

Figure 6. Linear correlation between (HbA1C) and serum magnesium level in overweight diabetic subjects.

dependent enzymes).11 The mechanism by which magnesium deficiency may lead to insulin resistance has not yet been fully elucidated. Magnesium is a cofactor for multiple enzymes involved in carbohydrate metabolism. It may influence the release and activity of the hormones that helps control blood glucose levels. Hypomagnesemia may worsen insulin resistance, a condition that often precedes diabetes, or may be a consequence of insulin resistance. Individuals with insulin resistance cannot use insulin efficiently and require greater amounts of insulin to maintain blood glucose within normal levels. Kidneys possibly lose their ability to retain magnesium during periods of severe hyperglycemia. The increased loss of magnesium in urine may then result in lower blood levels of magnesium in older adults, and correcting magnesium depletion may improve insulin response and action.12

In overweight diabetic subjects, serum magnesium level were found to be low, HOMA-IR was high and QUICKI values was found to be low in comparison to normal weight nondiabetics. Serum magnesium significantly inversely correlated with BMI, plasma glucose, HbA1C, serum insulin, HOMA-IR and a positive correlation of serum magnesium with QUICKI was found in our study (overweight subjects). Type 2 diabetes mellitus is the main factor accounting for low serum magnesium levels in overweight diabetics. Hypomagnesemia may aggravate insulin resistance state in overweight subjects. This can predispose them to metabolic complications of diabetes mellitus. It can be stated that lower levels of magnesium reported in moderately obese subjects are related to the presence of diabetes and glycemic control. Thus in conclusion, it can be stated that poor glycemic control and hypomagnesemia has been observed in overweight diabetic patients in the present study when compared with normomagnesemia patients. Glycemic control is one of the most important therapeutic challenges in present day. Magnesium level should be monitored in all overweight diabetic patients. References 1. World Health Organization. Diabetes. Fact sheet N째312. October 2013. Available at: http://www.who.int/ mediacentre/factsheets/fs312/en/index. html. 2. Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet. 2005;365(9467):1333-46. 3. Nourmohammadi I, Kocheki-Shalmani I, Shabbani M, Gohari L, Nazari H. Zinc, copper, chromium, manganese and magnesium levels in serum and hair of insulindependent diabetics. Arch Iranian Med. 2000;3(3):88-100. 4. Ma B, Lawson AB, Liese AD, Bell RA, Mayer-Davis EJ. Dairy, magnesium, and calcium intake in relation to insulin sensitivity: approaches to modeling a dose-dependent association. Am J Epidemiol. 2006;164(5):449-58. 5. World Health Organization. Classification for overweight and obesity in relation to BMI. WHO, 2004.

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

clinical Study 6. American Diabetes Association. Clinical practice recommendations. Diabetes Care. 2012;6:1-16. 7. Murray RK, Granner DK, Mayes PA, Rodwell VW, et al. Harpers Illustrated Biochemistry. 26th Edition, McGraw Hill; 2003;(Chapter 44):478. 8. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412-9. 9. Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing

insulin sensitivity in humans. J Clin Endocrinol Metab. 2000;85(7):2402-10. 10. Lecube AL, Baena-Fustegueras JA, Fort JM, Pelegri D, Hernandez C, Simo R. et al. Diabetes is the main factor accounting for hypomagnesemia in obese subjects. PLoS One. 2012;7(1):e30599. 11. Pham PC, Pham PM, Pham SV, Miller JM, Pham PT. Hypomagnesemia in patients with type 2 diabetes. Clin J Am Soc Nephrol. 2007;2(2):366-73. 12. Paolisso G, Sgambato S, Gambardella A, Pizza G, Tesauro P, Varricchio M, et al. Daily magnesium supplements improve glucose handling in elderly subjects. Am J Clin Nutr. 1992;55(6):1161-7.

■■■■

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

Conference Update

TRENDO 2015 Long-term Steroid Therapy: Clinical Issues ÂÂ

Indications for long-term steroid therapy: Neurological disorders, dermatology, rheumatologic, renal and organ transplant, hemato-oncology, pulmonary.

ÂÂ

Consequences of long-term steroid therapy: Exogenous glucocorticoid excess state (iatrogenic Cushing’s syndrome), hypothalamo-pituitaryadrenal (HPA) axis suppression.

ÂÂ

Glucocorticoid excess state – Clinical features: Obesity or weight gain, facial plethora, rounded face, decreased libido, thin skin, decreased linear growth, menstrual irregularity, hypertension, hirsutism, depression, glucose intolerance, weakness, osteopenia or fractures, nephrolithiasis, bruising easily. Metabolic effects: Hyperglycemia and diabetes mellitus, hypertension, osteoporosis and osteonecrosis, myopathy, growth suppression in children. Glucocorticoid-induced osteoporosis (GIO) is most pronounced in the first few months of use, typically affects cancellous bone, fractures occur at a higher bone mineral density versus menopausal osteoporosis and fractures heal with exuberant callus.

ÂÂ

Factors determining growth suppression with steroid therapy: Duration of therapy, age at onset of therapy, potency of steroids, route of therapy, time of administration.

ÂÂ

Medroxyprogesterone suppression.

ÂÂ

Factors determining HPA axis suppression: Dose of steroid, duration of therapy, potency of the steroid, mode of administration, daily versus alternate day therapy, time of administration.

ÂÂ

Adrenal insufficiency after discontinuation of glucocorticoid occurs frequently.

ÂÂ

Assessment of HPA axis suppression: Clinical - Cushing`s phenotype, Biochemical (8 am cortisol - <5 µg/dL-suppressed HPA axis; >18 µg/ dL-normal HPA axis; short Synacthen test - >18 µg/dL-normal HPA axis; <18 µg/dL-suppressed HPA axis; insulin-induced hypoglycemia).

ÂÂ

Steroid withdrawal syndrome: Anorexia, nausea, lethargy, fever, arthralgia, weight loss.

ÂÂ

Management of acute crisis: Fluid resuscitation, random cortisol (ideally SST), IV hydrocortisone (6 mg/hour IV, 50 mg q 6 hours, taper to replacement doses over 72 hours, treat precipitating cause).

can

cause

HPA axis

The table represents the protocols for withdrawal Dose

Duration <3 weeks

>3 weeks

<5 mg/day

Stop

Stop and assess HPA axis

>7.5 mg/day

Stop

Taper dose to 2.5 mg/day, stop and assess HPA axis ■■■■

Debate Statin for All Diabetics: Are We Justified? –Yes ÂÂ

Unless contraindicated, evidence points to treating all diabetics with statins.

ÂÂ

Periodically assess risk to consider high potency statins.

ÂÂ

Benefits of statins in reducing cardiovascular risk far outweigh the risk. ■■■■

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

Conference Update Statin for Every Diabetic: No Way ÂÂ

In the view of the evidence, it is difficult to refute that an association exists between statin use and new-onset diabetes.

ÂÂ

Statins should be considered individually for each patient only in case of lifestyle interventions failure.

ÂÂ

The small absolute increase in diabetes mellitus (DM) risk and the proven clinical utility of statins in primary and secondary prevention require clinicians to weigh the risk and benefit of statin therapy for any given patient.

ÂÂ

A major take-home message for the clinician involved in either primary or secondary prevention of cardiovascular disease is that all individuals on a statin who have major risk factors for DM particularly impaired glucose tolerance, need to be informed about the risk, monitored regularly for hyperglycemia and advised to lose weight and perform regular physical exercise to mitigate the emergence of DM.

ÂÂ

So is statin recommended for all diabetics? - No.

■■■■

Glycemic Control in Diabetes – Overcoming the Barrier of Hypoglycemia ÂÂ Good glycemic control is essential to reduce the risk of diabetic complications. ÂÂ Based on the Diabetes Control and Complications Trial (DCCT) data, the relative risk for microvascular complications such as diabetic retinopathy, nephropathy, neuropathy and microalbuminuria increases with increasing levels of A1c. ÂÂ The UKPDS results of intensive therapy: Metformin versus conventional therapy data suggested that intensive glycemic control with metformin versus conventional therapy was associated with a significant reduction in risk of diabetes-related endpoints as a whole. ÂÂ For every percentage point decrease in HbA1c (e.g., 9% to 8%), the risk of complications is reduced by 37%. ÂÂ The current definition of hypoglycemia, as suggested by the ADA hypoglycemia work group, 2005 is plasma glucose <70 mg/dL. Below this threshold counter-regulatory responses start, and it has significant implication in defining safe glycemic goals during intensive treatment. ÂÂ Symptoms of hypoglycemia: General: Headache, nausea, malaise, dry mouth. Autonomic: Sweating, palpitations, tremors, hunger, anxiety. Neuroglycopenic: Confusion, drowsiness, odd behavior, poor concentration, incoordination, visual blurring, perioral tingling. ÂÂ

In the ACCORD trial, in both arms, patients with severe hypoglycemia had higher mortality than those without but among patients with at least one episode of severe hypoglycemia, mortality was higher in the standard arm while in patients

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

without severe hypoglycemia, mortality was higher in intensive arm. ÂÂ

ÂÂ

Other likely explanations for mortality in ACCORD trial include: Weight gain overall 3.5 kg; 27% patients >10 kg weight gain. More use of insulin and glitazones and combinations of drugs. Though absolute level of glycemia comparable to ADVANCE, rate of fall of A1c faster. Risk factors for hypoglycemia in diabetes: Absolute or relative therapeutic insulin excess

Insulin or insulin secretagogue doses are excessive, ill-timed or of the wrong type:

↓ Exogenous glucose delivery (e.g., missed meals, overnight fast)

↑ Glucose utilization (e.g., exercise)

↓ Endogenous glucose production (e.g., alcohol ingestion)

↑ Sensitivity to insulin (e.g., night-time, following weight loss, improved fitness or improved glycemic control)

↓ Insulin clearance (e.g., renal failure). Approaches to reducing hypoglycemia:

ÂÂ

Preventing relative or absolute insulin excess - Training in insulin self-management; blood glucose awareness training; insulin analogs; continuous subcutaneous insulin infusion; pancreas transplantation; islet-cell transplantation.

Alerting patients to impending hypoglycemia - Hypoglycemia alarms utilizing continuous glucose monitoring technology.

Conference Update

Restoring

awareness

hypoglycemia;

Hypoglycemia unawareness reversal programs. ÂÂ

ÂÂ ÂÂ

To minimize hypoglycemia risk in type 2 diabetes:

Avoid older sulfonylureas (SUs).

Prefer new generation SUs/modified release formulations.

Attention to age, comorbidities, drug interactions.

Short-acting non-SU secretagogues (Glinides).

Use of antihyperglycemic agents (metformin, glitazones, alpha glucosidase inhibitors).

Incretin based treatments (GLP-1 analogs, DPP-IV inhibitors).

Hypoglycemia is common with SUs. Glycemic control in diabetes recommendations of ADA, AHA/ACC: In patients with short duration of diabetes, long life expectancy and no CVD, more stringent target than <7%, for incremental benefits in microvascular outcomes. Less stringent goals than <7% may be appropriate for patients with h/o severe hypoglycemia, limited life expectancy, advanced micro/macrovascular complications extensive comorbidities or long duration of disease in whom goal is difficult to attain despite standard care.

■■■■

Are Sulfonylureas Losing Ground to Newer Antidiabetic Agents? ÂÂ Time has not yet come to retire sulfonylureas unless newer molecules with good efficacy, lesser side effects and cost take over its place. ÂÂ Sulfonylureas, if properly selected, ideal dose identified and given to the right patient, give a good diabetic control with minimum expenditure. ÂÂ Moreover, it is within reach of all Indian diabetic patients. ÂÂ Hence, it is still recommended as one of the second-line therapies after metformin for type 2 diabetes mellitus. ■■■■

Cardiovascular Safety of Gliptins ÂÂ

ÂÂ

Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) was conducted to demonstrate that the risk of cardiovascular (CV) events in patients treated with sitagliptin in addition to usual care was noninferior to that in patients treated without sitagliptin in addition to usual care.

ÂÂ

According to an Italian database of 2,82,000 patients treated with antidiabetic drugs, dipeptidyl peptidase-4 (DPP-4) inhibitor was not associated with an increased risk of heart failure (HF).

ÂÂ

The SAVOR study has shown that patients with deteriorating renal function are at increased risk of HF:

For the primary composite CV outcome (CV death, nonfatal myocardial infarction [MI], nonfatal stroke or hospitalization for unstable angina) sitagliptin, compared with placebo, was noninferior and not superior. For the secondary composite cardiovascular outcome (CV death, nonfatal MI, or nonfatal stroke) sitagliptin, compared with placebo, was noninferior and not superior. The rate of hospitalization for heart failure did not differ between sitagliptin and placebo treatment groups.

Patients with diabetes and chronic kidney disease (CKD) have cardiovascular autonomic neuropathy (CAN), which is associated with increased CV mortality.

DPP-4i acts through incretin pathways, which may alter existing CAN and impact CV outcome.

This may possibly explain increased hHF in saxagliptin arm in SAVOR study.

ÂÂ

Future CV outcome studies should include baseline CAN in patients to evaluate this hypothesis.

ÂÂ

Irrespective of cardiophenotype, cardiac/vascular history, smoking status, drug intake, coronary status, ejection fraction, gliptins are safe.

The incidence of severe hypoglycemia did not differ between sitagliptin and placebo treatment groups. ■■■■

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

Conference Update Common Errors in Insulin Management

ÂÂ

Golden Rules

ÂÂ

Check the prescribed and the actual dose the patient is taking before changing the dose. Advice not to alter the regimen without your knowledge.

ÂÂ

Sick day rules should be emphasized.

ÂÂ

Timing of insulin is equally important.

ÂÂ

Check for any mismatch of insulin and syringe.

ÂÂ

Shaking of vial prior to injection should be stressed.

ÂÂ

Storage between 2-8°C is recommended.

ÂÂ ÂÂ ÂÂ

ÂÂ

One should be careful during mixing of two types of insulin. Advice not to change from one insulin to another without your knowledge. Check expiry date always. Specify injection sites also. Train the patients and supervise injection technique at frequent intervals. Newer devices are good but be vigilant.

Unless these common errors are thought of and adequate measures taken in the form of EDUCATION of our patients, paramedical staff and our own self, insulin therapy will not achieve the desired goal.

■■■■

Newly Diagnosed Diabetes in Young: How to Evaluate ÂÂ There is increasing prevalence of type 2 diabetes mellitus in the young. ÂÂ Better recognition of comorbid conditions required. ÂÂ Sophisticated genetic methods are now available to diagnose monogenic diabetes. ÂÂ More awareness required among physicians to suspect and diagnose diabetes in the young. ■■■■

Short Stature: Role of Growth Hormone Treatment ÂÂ

Short stature is not always a disease. Evaluation should always rule out nutritional causes and chronic illness.

ÂÂ

Growth hormone therapy has wider indications apart from growth hormone deficiency.

ÂÂ

Growth hormone therapy - successes depend on the diagnosis, age and dosage. ■■■■

thyroid autoantibodies can cross the placenta and lead to fetal/neonatal toxicosis. Careful clinical, ultrasound and biochemical (FT4 levels) monitoring is required. Pediatrician/Neonatologist must be available to manage neonatal toxicosis, should it occur.

Thyroid Diseases in Pregnancy ÂÂ

Hypothyroidism – clinical or subclinical can lead to anovulation and infertility. It is better identified and corrected especially in women worked up for infertility.

ÂÂ

Hypothyroid women who conceive must have TSH measured in the first trimester; thyroxine dose must be titrated to achieve TSH level below 2.5 µIU/mL in early pregnancy.

ÂÂ

Thyrotoxicosis must be treated and the woman rendered euthyroid preconception. Even then,

ÂÂ

Thyroxine replacement should not be stopped in hypothyroid women who become pregnant. In thyrotoxicosis, ideally PTU is given in the first trimester, followed by a switch to thioanimides.

ÂÂ

(Universal) neonatal screening for hypothyroidism is desirable.

■■■■

Primary Amenorrhea: When and How to Evaluate? ÂÂ

Primary amenorrhea is not infrequently encountered in endocrine, pediatric and gynecological practice.

ÂÂ

Thorough history, clinical examination and focussed investigations would help in confirming the diagnosis most often.

ÂÂ

Detailed counseling and appropriate individualized hormonal replacement therapy and regular follow-up would ensure long-term reproductive and general health of the girl.

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

Conference Update Glycemic Management in Diabetic Nephropathy ÂÂ

Diabetes mellitus contributes to nearly half of the prevalent cases of CKD.

ÂÂ

Diabetic nephropathy complicates nearly 25-30% of type 2 diabetes.

ÂÂ

Glucose monitoring by HbA1c is unreliable in CKD.

ÂÂ

Conventionally, insulin is the ideal drug of choice in DM with CKD. Its dose and formulation is to be individualized.

ÂÂ

Other safe drugs in DM with CKD include glipizide, gliclazide, repaglinide, pioglitazone and linagliptin. ■■■■

Thyroid Nodules: Diagnostic Dilemma and Management Issues ÂÂ

Thyroid nodules are not uncommon.

ÂÂ

Ultrasonography and FNAC guide in decisionmaking in majority of cases.

ÂÂ

Majority of nodules can be managed conservatively.

ÂÂ

Surgical option is the definitive treatment with minimal morbidity for malignant and indeterminate nodules.

ÂÂ

Each case has to have individualized approach with coordination by the endocrinologist, endocrine surgeon, pathologist and radiologist.

■■■■

Evaluation of New-onset Diabetes in the Young ÂÂ

This is a rapidly growing problem among the youth.

ÂÂ

T2DM is ever increasing in the young.

ÂÂ

Screening for T2DM in young is important.

ÂÂ

Methods of distinguishing T1DM and T2DM.

ÂÂ

Monogenic diabetes and LADA has to be ruled out. ■■■■

Severe Insulin Resistance – Clinical and Genetic Solutions ÂÂ

Insulin resistance may have common nonconventional causes.

ÂÂ

Genetic causes for insulin resistance are not uncommon.

ÂÂ

Autoimmune causes for insulin resistance need specific therapeutic maneuvers. ■■■■

Understanding Thyroid Function Tests? Common Pitfalls in Interpretation…. ÂÂ

Undiagnosed thyroid disease leaves patients at risk of cardiovascular diseases, osteoporosis and infertility.

ÂÂ

When thyroid dysfunction is suspected, a thyroid profile that includes free thyroid hormones (free T4 and free T3 - as appropriate) and TSH should be tested. TSH is the most important test and should be measured using a highly sensitive method with a detection limit of <0.1 mU/L.

ÂÂ

The most common cause of hyperthyroxinemia with nonsuppressed TSH is poor compliance to therapy.

ÂÂ

Drugs such as amiodarone, glucocorticoids, propranolol and iodine contrast media can also affect thyroid function. Nonthyroidal illness especially while the patient is admitted in hospital with illness can be very confusing.

ÂÂ

Rare causes such as TSHoma, thyroid hormone resistance, heterophille antibodies will need multiple analyses over a period of time with a good history and complete evaluation.

ÂÂ

In the above circumstances regular contact and advice from a senior endocrinologist or biochemist would be very valuable. ■■■■

Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

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Asian Journal of Diabetology, Vol. 17, No. 9, January-March 2016

Discussion –

This should consist of a review of the literature 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.

References 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 in Journals 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. Articles in Books – Stansfield AG. Lymph Node Biopsy Interpretation. New York: Churchill Livingstone; 1985. –

Strong MS. Recurrent respiratory papillomatosis. In: Evans JNG (Ed.). Scott Brown’s Otolaryngology. Paediatric Otolaryngology, London; Butterworths; 1987. pp. 466-70.

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. 17, No. 9, January-March 2016

Figures – Two complete sets of glossy prints of high quality should be submitted. The labelling must be clear and neat. – All photomicrographs should indicate the magnification of the print. – Special features should be indicated by arrows or letters which contrast with the background. – The back of each illustration should bear the first author’s last name, figure number and an arrow indicating the top. This should be written lightly in pencil only. Please do not use a hard pencil, ball point or felt pen. – Color illustrations will be accepted if they make a contribution to the understanding of the article. –

Do not use clips/staples on photographs and artwork.

–

Illustrations must be drawn neatly by an artist and photographs must be sent on glossy paper. No captions should be written directly on the photographs or illustration. Legends to all photographs and illustrations should be typed on a separate sheet of paper. All illustrations and figures must be referred to in the text and abbreviated as “Fig.”.

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

This report has been produced by Novo Nordisk for promotional purposes

Ryzodeg® (insulin degludec/insulin aspart): the first true insulin analogue combination product Landmark studies have shown that maintaining good glycaemic control is associated with reductions in long-term health complications for type 2 diabetes.1,2 Although treatment with antidiabetic drugs can provide effective control in the early stages of type 2 diabetes, for more advanced type 2 diabetes, insulin-replacement therapy becomes necessary to prevent a deterioration in control. The aim for any insulin therapy is to successfully provide or, where some endogenous insulin secretion persists, complement a patient’s physiological need for insulin throughout the day. A healthy human pancreas dynamically regulates insulin release to provide a low and near-constant basal level of circulating insulin, with rapidly produced ‘spikes’ in concentration in response to the ingestion of meals.3 Insufficient insulinisation will result in persistent hyperglycaemia, whilst excess insulin has the opposite effect, producing distressing and potentially dangerous episodes of hypoglycaemia. Unfortunately, exogenous insulin cannot be dynamically regulated by physiological signals. Consequently, most insulin products have been modified to mimic either the slow, continuous basal rate of insulin release, or the rapid, short-lived increases in secretion rate in response to meals, thus requiring the use of two complementary preparations to provide full coverage. The alternatives to this are the premixed insulin products, which aim to address both types of insulin requirement. For many patients with type 2 diabetes, basal insulin supplementation may be sufficient initially, with the need for additional mealtime support increasing over time. This can be achieved either by administering a short-acting insulin at mealtimes, to create a ‘basal–bolus’ regimen, or by using a premixed insulin. Premixed solutions contain either a mixture of regular human insulin and isophane insulin or a rapid-acting insulin analogue, a percentage of which is protaminated to retard release. However, basal–bolus regimens can be complex, requiring numerous injections each day and titration of both components, whilst premixed insulins require re-suspension before injection and have less refined pharmacokinetic (PK) and pharmacodynamic (PD) characteristics, which may confound the goal of providing both a flat continual basal insulin action and a discrete peaked mealtime insulin action.4 In theory, combining a long-acting basal insulin and a true rapid-acting insulin in a single injection would provide the closest similitude of a physiological profile while minimising injection frequency. However, to date this has not been possible due to the incompatibility of the individual insulin analogue preparations: the long-acting insulin glargine is only soluble at low pH and would form precipitates if combined with rapid-acting insulin analogues that are soluble at neutral pH,5 and the long-acting insulin detemir forms mixed hexamers in solution with rapid-acting insulin aspart.4 The arrival of insulin degludec has provided a unique opportunity for coformulation. Insulin degludec is a novel basal insulin with a distinctive mode of protraction giving a flat, stable, ultra-long profile and a lower intra-patient variability of action than insulin glargine,6,7 which has been shown to provide effective glycaemic control with a lower hypoglycaemia risk profile than comparator basal insulins in type 2 diabetes.8–12 The unique structure of insulin degludec facilitates the formation of stable dihexamers in solution, which can be combined with insulin aspart hexamers without mixed hexamers forming13 (Figure 1a). Once injected, the di-hexamers of insulin degludec join into long chains containing hundreds of hexamers to form a soluble depot. Over time, insulin degludec monomers are released from these multihexamers at a constant and slow rate and freely enter the circulation.13 Ryzodeg® is the first combination of two distinct insulin analogues in a single injection, comprising a soluble co-formulation of 70% insulin degludec and 30% insulin aspart. Size-exclusion chromatography indicates that insulin degludec and insulin aspart exist separately in the solution, as well as in a model of the subcutaneous environment (Figure 1b).14 Following administration of a single dose of Ryzodeg® to 22 patients with type 1 diabetes who had attained steady state with insulin degludec, the mean glucose infusion-rate profile showed a rapid onset of action and a distinct peak due to insulin aspart, followed by a separate, clearly defined basal glucose-lowering effect that was flat and stable over 24 hours.4 Modelling PK/PD data suggest that twice-daily administration of Ryzodeg® would reach a steady-state PK/PD profile that provides prandial coverage at two separate mealtimes, along with consistent, full 24-hour basal insulin coverage.4 This translated into lower fasting plasma glucose and reduced hypoglycaemia rates in a multinational phase 3 trial versus biphasic insulin aspart.15

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