Sri Venkata Madhu

Antioxidant status, lipid peroxidation and nitric oxide end products in patients of type 2 diabetes mellitus with nephropathy.

OBJECTIVES Oxidative stress is considered to be a unifying link between diabetes mellitus (DM) and its complications including nephropathy. The aim of the present study was to evaluate oxidative stress status in Asian Indian patients of type 2 DM with nephropathy. DESIGN AND METHODS Serum levels of malondialdehyde (MDA) and nitric oxide end products (nitrite and nitrate), activities of erythrocyte superoxide dismutase (SOD), catalase (CAT) and reduced glutathione (GSH) content were estimated in controls, patients of type 2 DM without nephropathy (group 1) and with nephropathy (group 2). RESULTS Serum MDA concentration was significantly high in both the groups of diabetic patients as compared to controls, (p < 0.05), with group 2 having a significantly higher value than group 1 (p < 0.05). Significantly elevated serum nitrite levels were found in diabetic patients as compared to controls (p < 0.001), however, no significant difference was found between group 1 and group 2. Moreover, serum nitrate as well as nitrite + nitrate levels were significantly higher in group 2 as compared to controls (p < 0.05). Activity of erythrocyte SOD and CAT was significantly reduced in both groups as compared to controls (p < 0.001) with catalase activity in group 2 being significantly lower than group 1 (p < 0.05). Erythrocyte GSH content was significantly lower in group 2 as compared to controls (p < 0.05) and group 1 (p < 0.05). CONCLUSIONS Results of the present study indicate that oxidative stress is increased and antioxidant defenses are compromised in type 2 DM. These derangements are of a higher magnitude in patients of type 2 DM with nephropathy.

Genome-wide association study for type 2 diabetes in Indians identifies a new susceptibility locus at 2q21.

Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes–associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 × 10−9). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 × 10−12) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely the same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D.

Prevalence of dyslipidemia in urban and rural India: the ICMR-INDIAB study.

Aim To study the pattern and prevalence of dyslipidemia in a large representative sample of four selected regions in India. Methods Phase I of the Indian Council of Medical Research–India Diabetes (ICMR-INDIAB) study was conducted in a representative population of three states of India [Tamil Nadu, Maharashtra and Jharkhand] and one Union Territory [Chandigarh], and covered a population of 213 million people using stratified multistage sampling design to recruit individuals ≥20 years of age. All the study subjects (n = 16,607) underwent anthropometric measurements and oral glucose tolerance tests were done using capillary blood (except in self-reported diabetes). In addition, in every 5th subject (n = 2042), a fasting venous sample was collected and assayed for lipids. Dyslipidemia was diagnosed using National Cholesterol Education Programme (NCEP) guidelines. Results Of the subjects studied, 13.9% had hypercholesterolemia, 29.5% had hypertriglyceridemia, 72.3% had low HDL-C, 11.8% had high LDL-C levels and 79% had abnormalities in one of the lipid parameters. Regional disparity exists with the highest rates of hypercholesterolemia observed in Tamilnadu (18.3%), highest rates of hypertriglyceridemia in Chandigarh (38.6%), highest rates of low HDL-C in Jharkhand (76.8%) and highest rates of high LDL-C in Tamilnadu (15.8%). Except for low HDL-C and in the state of Maharashtra, in all other states, urban residents had the highest prevalence of lipid abnormalities compared to rural residents. Low HDL-C was the most common lipid abnormality (72.3%) in all the four regions studied; in 44.9% of subjects, it was present as an isolated abnormality. Common significant risk factors for dyslipidemia included obesity, diabetes, and dysglycemia. Conclusion The prevalence of dyslipidemia is very high in India, which calls for urgent lifestyle intervention strategies to prevent and manage this important cardiovascular risk factor.

Prevalence of diabetes and prediabetes in 15 states of India: results from the ICMR–INDIAB population-based cross-sectional study

BACKGROUND Previous studies have not adequately captured the heterogeneous nature of the diabetes epidemic in India. The aim of the ongoing national Indian Council of Medical Research-INdia DIABetes study is to estimate the national prevalence of diabetes and prediabetes in India by estimating the prevalence by state. METHODS We used a stratified multistage design to obtain a community-based sample of 57 117 individuals aged 20 years or older. The sample population represented 14 of Indias 28 states (eight from the mainland and six from the northeast of the country) and one union territory. States were sampled in a phased manner: phase I included Tamil Nadu, Chandigarh, Jharkhand, and Maharashtra, sampled between Nov 17, 2008, and April 16, 2010; phase II included Andhra Pradesh, Bihar, Gujarat, Karnataka, and Punjab, sampled between Sept 24, 2012, and July 26, 2013; and the northeastern phase included Assam, Mizoram, Arunachal Pradesh, Tripura, Manipur, and Meghalaya, with sampling done between Jan 5, 2012, and July 3, 2015. Capillary oral glucose tolerance tests were used to diagnose diabetes and prediabetes in accordance with WHO criteria. Our methods did not allow us to differentiate between type 1 and type 2 diabetes. The prevalence of diabetes in different states was assessed in relation to socioeconomic status (SES) of individuals and the per-capita gross domestic product (GDP) of each state. We used multiple logistic regression analysis to examine the association of various factors with the prevalence of diabetes and prediabetes. FINDINGS The overall prevalence of diabetes in all 15 states of India was 7·3% (95% CI 7·0-7·5). The prevalence of diabetes varied from 4·3% in Bihar (95% CI 3·7-5·0) to 10·0% (8·7-11·2) in Punjab and was higher in urban areas (11·2%, 10·6-11·8) than in rural areas (5·2%, 4·9-5·4; p<0·0001) and higher in mainland states (8·3%, 7·9-8·7) than in the northeast (5·9%, 5·5-6·2; p<0·0001). Overall, 1862 (47·3%) of 3938 individuals identified as having diabetes had not been diagnosed previously. States with higher per-capita GDP seemed to have a higher prevalence of diabetes (eg, Chandigarh, which had the highest GDP of US

Advanced glycation end products enhance reactive oxygen and nitrogen species generation in neutrophils in vitro

3433, had the highest prevalence of 13·6%, 12.8-15·2). In rural areas of all states, diabetes was more prevalent in individuals of higher SES. However, in urban areas of some of the more affluent states (Chandigarh, Maharashtra, and Tamil Nadu), diabetes prevalence was higher in people with lower SES. The overall prevalence of prediabetes in all 15 states was 10·3% (10·0-10·6). The prevalence of prediabetes varied from 6·0% (5·1-6·8) in Mizoram to 14·7% (13·6-15·9) in Tripura, and the prevalence of impaired fasting glucose was generally higher than the prevalence of impaired glucose tolerance. Age, male sex, obesity, hypertension, and family history of diabetes were independent risk factors for diabetes in both urban and rural areas. INTERPRETATION There are large differences in diabetes prevalence between states in India. Our results show evidence of an epidemiological transition, with a higher prevalence of diabetes in low SES groups in the urban areas of the more economically developed states. The spread of diabetes to economically disadvantaged sections of society is a matter of great concern, warranting urgent preventive measures. FUNDING Indian Council of Medical Research and Department of Health Research, Ministry of Health and Family Welfare, Government of India.

Common variants of FTO and the risk of obesity and type 2 diabetes in Indians

Increased oxidative stress (OS) in diabetes mellitus is one of the major factors leading to diabetic pathology. However, the mediators and mechanism that provoke OS in diabetes is not fully understood, and it is possible that accumulation of advanced glycation end products (AGEs) formed secondary to hyperglycemic conditions may incite circulating polymorphonuclear neutrophils (PMN) to generate reactive oxygen species (ROS). In this report, we aim to investigate the effect of AGE on reactive oxygen and nitrogen species generation and subsequent OS in PMN. AGE-HSA exert dose- and time-dependent enhancement of ROS and reactive nitrogen intermediates (RNI) generation by PMN. Increased ROS and RNI generation were found to be mediated through the upregulation of NADPH oxidase and inducible nitric oxide synthase (iNOS), respectively, as evident from the fact that AGE-treated neutrophils failed to generate ROS and RNI in presence of diphenyleneiodonium, a flavoprotein inhibitor for both enzymes. Further increased generation of ROS and RNI ceased when the cells were incubated with anti-RAGE antibody suggesting the involvement of AGE–RAGE interaction. Also increased malondialdehyde (MDA) and protein carbonyl formation in AGE-exposed PMN suggest induction of OS by AGE. This study provides evidence that AGEs may play a key role in the induction of oxidative stress through the augmentation of PMN-mediated ROS and RNI generation and this may be in part responsible for development of AGE-induced diabetic pathology.

Prevalence of generalized & abdominal obesity in urban & rural India- the ICMR - INDIAB Study (Phase-I) [ICMR - INDIAB-3]

Common variants of fat mass and obesity-associated gene (FTO, fat mass- and obesity-associated gene) have been shown to be associated with obesity and type 2 diabetes in population of European and non-European ethnicity. However, studies in Indian population have provided inconsistent results. Here, we examined association of eight FTO variants (rs1421085, rs8050136, rs9939609, rs9930506, rs1861867, rs9926180, rs2540769 and rs708277) with obesity and type 2 diabetes in 5364 North Indians (2474 type 2 diabetes patients and 2890 non-diabetic controls) in two stages. None of the variants including previously reported intron 1 variants (rs1421085, rs8050136, rs9939609 and rs9930506) showed body mass index (BMI)-dependent/independent association with type 2 diabetes. However, rs1421085, rs8050136 and rs9939609 were associated with obesity status and measures of obesity (BMI, waist circumference and waist-to-hip ratio) in stage 2 and combined study population. Meta-analysis of the two study population results also revealed that rs1421085, rs8050136 and rs9939609 were significantly associated with BMI both under the random- and fixed-effect models (P (random/fixed)=0.02/0.0001, 0.004/0.0006 and 0.01/0.01, respectively). In conclusion, common variants of FTO were associated with obesity, but not with type 2 diabetes in North Indian population.

A study on serum advanced glycation end products and its association with oxidative stress and paraoxonase activity in type 2 diabetic patients with vascular complications.

Background & objectives: Overweight and obesity are rapidly increasing in countries like India. This study was aimed at determining the prevalence of generalized, abdominal and combined obesity in urban and rural India. Methods: Phase I of the ICMR-INDIAB study was conducted in a representative population of three States [Tamil Nadu (TN), Maharashtra (MH) and Jharkhand (JH)] and one Union Territory (UT)[Chandigarh (CH)] of India. A stratified multi-stage sampling design was adopted and individuals ≥20 yr of age were included. WHO Asia Pacific guidelines were used to define overweight [body mass index (BMI) ≥23 kg/m2 but <25 kg/m2), generalized obesity (GO, BMI≥25kg/m2), abdominal obesity (AO, waist circumference ≥90 cm for men and ≥80cm for women) and combined obesity (CO, GO plus AO). Of the 14,277 participants, 13,800 subjects (response rate, 96.7%) were included for the analysis (urban: n=4,063; rural: n=9737). Results: The prevalence of GO was 24.6, 16.6, 11.8 and 31.3 per cent among residents of TN, MH, JH and CH, while the prevalence of AO was 26.6, 18.7, 16.9 and 36.1 per cent, respectively. CO was present in 19.3, 13.0, 9.8 and 26.6 per cent of the TN, MH, JH and CH population. The prevalence of GO, AO and CO were significantly higher among urban residents compared to rural residents in all the four regions studied. The prevalence of overweight was 15.2, 11.3, 7.8 and 15.9 per cent among residents of TN, MH, JH and CH, respectively. Multiple logistic regression analysis showed that female gender, hypertension, diabetes, higher socio-economic status, physical inactivity and urban residence were significantly associated with GO, AO and CO in all the four regions studied. Age was significantly associated with AO and CO, but not with GO. Interpretation & conclusions: Prevalence of AO as well as of GO were high in India. Extrapolated to the whole country, 135, 153 and 107 million individuals will have GO, AO and CO, respectively. However, these figures have been estimated from three States and one UT of India and the results may be viewed in this light.

Knowledge and awareness of diabetes in urban and rural India: The Indian Council of Medical Research India Diabetes Study (Phase I): Indian Council of Medical Research India Diabetes 4

OBJECTIVES Enhanced formation of advanced glycation end products (AGEs) formed secondary to hyperglycemic conditions has been linked to diabetes mellitus (DM) associated complications. We investigated the clinical relevance of estimating AGEs and their relationship with oxidative stress (OS) and paraoxonase (PON1) activity in type 2 DM (T2DM) in relation to development of vascular complications. DESIGN AND METHODS Serum AGEs along with PON1 activity, protein carbonyl (PCO), advanced oxidation protein products (AOPP), lipid peroxidation (MDA), and total thiol (T-SH) were determined in 157 T2DM patients (DM without complications n=57, DM micro-vascular complications n=53, DM macro-vascular complications n=47) and 40 healthy controls. RESULTS Serum AGE level increased significantly in various study groups in following manner: healthy control<DM without complications<DM-macro<DM-micro. Logistic regression analysis using diabetic complications as dependent variable showed significant association with AGE level and PON1 activity even after adjustment for confounding factors. Receiver-operating-characteristics curve analysis showed that 2-fold increased in glycation and 50% decrease in PON1 activity may lead to development of vascular complications in diabetic subjects. PCO, AOPP and MDA were higher and PON1 activity was lower in T2DM with complications than those without complications. Among diabetic patients AGEs showed significant positive correlation with HbA(1C), MDA, AOPP, and negative correlation with PON1 activity and T-SH. CONCLUSION High serum AGE concentration and low PON1 activity may be considered as additional risk factor for development of vascular complications in T2DM. AGE formation plays significant role in induction of OS in diabetes.

Role of advanced glycation end product (AGE)-induced receptor (RAGE) expression in diabetic vascular complications.

Background: Representative data on knowledge and awareness about diabetes is scarce in India and is extremely important to plan public health policies aimed at preventing and controlling diabetes. Aim: The aim of the following study is to assess awareness and knowledge about diabetes in the general population, as well as in individuals with diabetes in four selected regions of India. Materials and Methods: The study subjects were drawn from a representative sample of four geographical regions of India, Chandigarh, Tamil Nadu, Jharkhand and Maharashtra representing North, South, East and West and covering a population of 213 million. A total of 16,607 individuals (5112 urban and 11,495 rural) aged ≥20 years were selected from 188 urban and 175 rural areas. Awareness of diabetes and knowledge of causative factors and complications of diabetes were assessed using an interviewer administered structured questionnaire in 14,274 individuals (response rate, 86.0%), which included 480 self-reported diabetic subjects. Results: Only 43.2% (6160/14,274) of the overall study population had heard about a condition called diabetes. Overall urban residents had higher awareness rates (58.4%) compared to rural residents (36.8%) (P < 0.001). About 46.7% of males and 39.6% of females reported that they knew about a condition called diabetes (P < 0.001). Of the general population, 41.5% (5726/13,794) knew about a condition called diabetes. Among them, 80.7% (4620/5726) knew that the prevalence of diabetes was increasing, whereas among diabetic subjects, it was 93.0% (448/480). Among the general and diabetic population, 56.3% and 63.4% respectively, were aware that diabetes could be prevented. Regarding complications, 51.5% of the general population and 72.7% diabetic population knew that diabetes could affect other organs. Based on a composite knowledge score to assess knowledge among the general population, Tamil Nadu had the highest (31.7) and Jharkhand the lowest score (16.3). However among self-reported diabetic subjects, Maharashtra had the highest (70.1) and Tamil Nadu, the lowest score (56.5). Conclusion: Knowledge and awareness about diabetes in India, particularly in rural areas, is poor. This underscores the need for conducting large scale diabetes awareness and education programs.