Impact of individual and environmental factors on dietary or lifestyle interventions to prevent type 2 diabetes development: a systematic review.

BACKGROUND: The variability in the effectiveness of type 2 diabetes (T2D) preventive interventions highlights the potential to identify the factors that determine treatment responses and those that would benefit the most from a given intervention. We conducted a systematic review to synthesize the evidence to support whether sociodemographic, clinical, behavioral, and molecular factors modify the efficacy of dietary or lifestyle interventions to prevent T2D. METHODS: We searched MEDLINE, Embase, and Cochrane databases for studies reporting on the effect of a lifestyle, dietary pattern, or dietary supplement interventions on the incidence of T2D and reporting the results stratified by any effect modifier. We extracted relevant statistical findings and qualitatively synthesized the evidence for each modifier based on the direction of findings reported in available studies. We used the Diabetes Canada Clinical Practice Scale to assess the certainty of the evidence for a given effect modifier. RESULTS: The 81 publications that met our criteria for inclusion are from 33 unique trials. The evidence is low to very low to attribute variability in intervention effectiveness to individual characteristics such as age, sex, BMI, race/ethnicity, socioeconomic status, baseline behavioral factors, or genetic predisposition. CONCLUSIONS: We report evidence, albeit low certainty, that those with poorer health status, particularly those with prediabetes at baseline, tend to benefit more from T2D prevention strategies compared to healthier counterparts. Our synthesis highlights the need for purposefully designed clinical trials to inform whether individual factors influence the success of T2D prevention strategies.

Clinical trials to prevent development of type 2 diabetes (T2D) that test dietary and lifestyle interventions have resulted in different results for different study participants. We hypothesized that the differing responses could be because of different personal, social and inherited factors. We searched different databases containing details of published research studies investigating this to look at the effect of these factors on prevention of the development of T2D. We found a small amount of evidence suggesting that those with poorer health, particularly those with a higher amount of sugar in their blood, tend to benefit more from T2D prevention strategies compared to healthier counterparts. Our results suggest that further clinical trials that are designed to examine the effect of personal and social factors on interventions for T2D prevention are needed to better determine the impact of these factors on the success of diet and lifestyle interventions for T2D.

Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.

Role of sociodemographic, clinical, behavioral, and molecular factors in precision prevention of type 2 diabetes: a systematic review.

The variability in the effectiveness of type 2 diabetes (T2D) preventive interventions highlights the potential to identify the factors that determine treatment responses and those that would benefit the most from a given intervention. We conducted a systematic review to synthesize the evidence to support whether sociodemographic, clinical, behavioral, and molecular characteristics modify the efficacy of dietary or lifestyle interventions to prevent T2D. Among the 80 publications that met our criteria for inclusion, the evidence was low to very low to attribute variability in intervention effectiveness to individual characteristics such as age, sex, BMI, race/ethnicity, socioeconomic status, baseline behavioral factors, or genetic predisposition. We found evidence, albeit low certainty, to support conclusions that those with poorer health status, particularly those with prediabetes at baseline, tend to benefit more from T2D prevention strategies compared to healthier counterparts. Our synthesis highlights the need for purposefully designed clinical trials to inform whether individual factors influence the success of T2D prevention strategies.

Lower Dietary Intake of Plant Protein Is Associated with Genetic Risk of Diabetes-Related Traits in Urban Asian Indian Adults.

The increasing prevalence of type 2 diabetes among South Asians is caused by a complex interplay between environmental and genetic factors. We aimed to examine the impact of dietary and genetic factors on metabolic traits in 1062 Asian Indians. Dietary assessment was performed using a validated semi-quantitative food frequency questionnaire. Seven single nucleotide polymorphisms (SNPs) from the Transcription factor 7-like 2 and fat mass and obesity-associated genes were used to construct two metabolic genetic risk scores (GRS): 7-SNP and 3-SNP GRSs. Both 7-SNP GRS and 3-SNP GRS were associated with a higher risk of T2D (p = 0.0000134 and 0.008, respectively). The 3-SNP GRS was associated with higher waist circumference (p = 0.010), fasting plasma glucose (FPG) (p = 0.002) and glycated haemoglobin (HbA1c) (p = 0.000066). There were significant interactions between 3-SNP GRS and protein intake (% of total energy intake) on FPG (Pinteraction = 0.011) and HbA1c (Pinteraction = 0.007), where among individuals with lower plant protein intake (<39 g/day) and those with >1 risk allele had higher FPG (p = 0.001) and HbA1c (p = 0.00006) than individuals with ≤1 risk allele. Our findings suggest that lower plant protein intake may be a contributor to the increased ethnic susceptibility to diabetes described in Asian Indians. Randomised clinical trials with increased plant protein in the diets of this population are needed to see whether the reduction of diabetes risk occurs in individuals with prediabetes.

Circulating adiponectin mediates the association between omentin gene polymorphism and cardiometabolic health in Asian Indians.

BACKGROUND: Plasma omentin levels have been shown to be associated with circulating adiponectin concentrations and cardiometabolic disease-related outcomes. In this study, we aim to examine the association of omentin gene polymorphism with serum adiponectin levels and cardiometabolic health status using a genetic approach, and investigate whether these associations are modified by lifestyle factors. METHODS: The study included 945 normal glucose tolerant and 941 unrelated individuals with type 2 diabetes randomly selected from the Chennai Urban Rural Epidemiology Study (CURES), in southern India. Study participants were classified into cardiometabolically healthy and unhealthy, where cardiometabolically healthy were those without hypertension, diabetes, and dyslipidemia. Fasting serum adiponectin levels were measured by radioimmunoassay. The omentin A326T (rs2274907) single nucleotide polymorphism (SNP) was screened by polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. RESULTS: The 'A' allele of the omentin SNP was significantly associated with lower adiponectin concentrations after adjusting for age, sex, body mass index (BMI), waist circumference (WC) and cardiometabolic health status (p = 1.90 x 10-47). There was also a significant association between circulating adiponectin concentrations and cardiometabolic health status after adjusting for age, sex, BMI, WC and Omentin SNP (p = 7.47x10-10). However, after adjusting for age, sex, BMI, WC and adiponectin levels, the association of 'A' allele with cardiometabolic health status disappeared (p = 0.79) suggesting that adiponectin serves as a mediator of the association between omentin SNP and cardiometabolic health status. There were no significant interactions between the SNP and dietary factors on adiponectin levels and cardiometabolic health status (p>0.25, for all comparisons). CONCLUSIONS: Our findings show that adiponectin might function as a mechanistic link between omentin SNP and increased risk of cardiometabolic diseases independent of common and central obesity in Asian Indians. Before strategies to promote adiponectin modulation could be implemented, further studies are required to confirm the molecular mechanisms involved in this triangular relationship between omentin gene, adiponectin and cardiometabolic diseases.

A Nutrigenetic Approach to Investigate the Relationship between Metabolic Traits and Vitamin D Status in an Asian Indian Population.

Studies in Asian Indians have examined the association of metabolic traits with vitamin D status. However, findings have been quite inconsistent. Hence, we aimed to explore the relationship between metabolic traits and 25-hydroxyvitamin D [25(OH)D] concentrations. We investigate whether this relationship was modified by lifestyle factors using a nutrigenetic approach in 545 Asian Indians randomly selected from the Chennai Urban Rural Epidemiology Study (219 normal glucose tolerant individuals, 151 with pre-diabetes and 175 individuals with type 2 diabetes). A metabolic genetic risk score (GRS) was developed using five common metabolic disease-related genetic variants. There was a significant interaction between metabolic GRS and carbohydrate intake (energy%) on 25(OH)D (Pinteraction = 0.047). Individuals consuming a low carbohydrate diet (≤62%) and those having lesser number of metabolic risk alleles (GRS ≤ 1) had significantly higher levels of 25(OH)D (p = 0.033). Conversely, individuals consuming a high carbohydrate diet despite having lesser number of risk alleles did not show a significant increase in 25(OH)D (p = 0.662). In summary, our findings show that individuals carrying a smaller number of metabolic risk alleles are likely to have higher 25(OH)D levels if they consume a low carbohydrate diet. These data support the current dietary carbohydrate recommendations of 50%-60% energy suggesting that reduced metabolic genetic risk increases 25(OH)D.

Evidence for the association between FTO gene variants and vitamin B12 concentrations in an Asian Indian population.

BACKGROUND: Low vitamin B12 concentrations have been associated with major clinical outcomes, including adiposity, in Indian populations. The Fat mass and obesity-associated gene (FTO) is an established obesity-susceptibility locus; however, it remains unknown whether it influences vitamin B12 status. Hence, we investigated the association of two previously studied FTO polymorphisms with vitamin B12 concentrations and metabolic disease-related outcomes and examined whether these associations were modified by dietary factors and physical activity. METHODS: A total of 176 individuals with type 2 diabetes, 152 with pre-diabetes, and 220 normal glucose-tolerant individuals were randomly selected from the Chennai Urban Rural Epidemiology Study. Anthropometric, clinical, and biochemical investigations, which included body mass index (BMI), waist circumference, vitamin B12, homocysteine, and folic acid were measured. A validated food frequency questionnaire was used for dietary assessment and self-reported physical activity measures were collected. An unweighted genetic risk score (GRS) was calculated for two FTO single-nucleotide polymorphisms (rs8050136 and rs2388405) by summation of the number of risk alleles for obesity. Interaction analyses were performed by including the interaction terms in the regression model. RESULTS: The GRS was significantly associated with increased BMI (P = 0.009) and risk of obesity (P = 0.023). Individuals carrying more than one risk allele for the GRS had 13.13% lower vitamin B12 concentrations, compared to individuals carrying zero risk alleles (P = 0.018). No associations between the GRS and folic acid and homocysteine concentrations were observed. Furthermore, no statistically significant GRS-diet or GRS-physical activity interactions with vitamin B12, folic acid, homocysteine or metabolic-disease outcomes were observed. CONCLUSION: The study shows for the first time that a genetic risk score using two FTO SNPs is associated with lower vitamin B12 concentrations; however, we did not identify any evidence for the influence of lifestyle factors on this association. Further replication studies in larger cohorts are warranted to investigate the association between the GRS and vitamin B12 concentrations.

Interaction between TCF7L2 polymorphism and dietary fat intake on high density lipoprotein cholesterol.

Recent evidence suggests that lifestyle factors influence the association between the Melanocortin 4 receptor (MC4R) and Transcription Factor 7-Like 2 (TCF7L2) gene variants and cardio-metabolic traits in several populations; however, the available research is limited among the Asian Indian population. Hence, the present study examined whether the association between the MC4R single nucleotide polymorphism (SNP) (rs17782313) and two SNPs of the TCF7L2 gene (rs12255372 and rs7903146) and cardio-metabolic traits is modified by dietary factors and physical activity. This cross sectional study included a random sample of normal glucose tolerant (NGT) (n = 821) and participants with type 2 diabetes (T2D) (n = 861) recruited from the urban part of the Chennai Urban Rural Epidemiology Study (CURES). A validated food frequency questionnaire (FFQ) was used for dietary assessment and self-reported physical activity measures were collected. The threshold for significance was set at P = 0.00023 based on Bonferroni correction for multiple testing [(0.05/210 (3 SNPs x 14 outcomes x 5 lifestyle factors)]. After Bonferroni correction, there was a significant interaction between the TCF7L2 rs12255372 SNP and fat intake (g/day) (Pinteraction = 0.0001) on high-density lipoprotein cholesterol (HDL-C), where the 'T' allele carriers in the lowest tertile of total fat intake had higher HDL-C (P = 0.008) and those in the highest tertile (P = 0.017) had lower HDL-C compared to the GG homozygotes. In a secondary analysis of SNPs with the subtypes of fat, there was also a significant interaction between the SNP rs12255372 and polyunsaturated fatty acids (PUFA, g/day) (Pinteraction<0.0001) on HDL-C, where the minor allele carriers had higher HDL-C in the lowest PUFA tertile (P = 0.024) and those in the highest PUFA tertile had lower HDL-C (P = 0.028) than GG homozygotes. In addition, a significant interaction was also seen between TCF7L2 SNP rs12255372 and fibre intake (g/day) on HDL-C (Pinteraction<0.0001). None of the other interactions between the SNPs and lifestyle factors were statistically significant after correction for multiple testing. Our findings indicate that the association between TCF7L2 SNP rs12255372 and HDL-C may be modified by dietary fat intake in this Asian Indian population.

Association of recently identified type 2 diabetes gene variants with Gestational Diabetes in Asian Indian population.

Earlier studies have provided evidence that the gestational diabetes mellitus (GDM) and Type 2 diabetes mellitus (T2DM) share common genetic background. A recent genome wide association study (GWAS) showed a strong association of six novel gene variants with T2DM among south Asians but not with Europeans. The aim of this study was to investigate whether these variants that confer susceptibility to T2DM in Asian Indian population also correlate with GDM in Asian Indian population. In addition to these novel variants, three T2DM associated SNPs that were previously identified by GWAS in Caucasian populations, which also showed association with T2DM in south Indian population in our previous study were also evaluated for their susceptibility to GDM in our population. The study groups comprised unrelated pregnant women with GDM (n = 518) and pregnant women with normal glucose tolerance (NGT) (n = 1220). A total of nine SNPs in or near nine loci, namely AP3S2 (rs2028299), BAZ1B (rs12056034), CDKN2A/B (rs7020996), GRB14 (rs3923113), HHEX (rs7923837), HMG20A (rs7178572), HNF4A (rs4812829), ST6GAL1 (rs16861329) and VPS26A (rs1802295) were genotyped using the MassARRAY system. Among these nine SNPs that previously showed an association with T2DM in Asian Indians, HMG20A (rs7178572) and HNF4A (rs4812829) gene variants showed a significant association with GDM. The risk alleles of rs7178572 in HMG20A and rs4812829 in HNF4A gene conferred 1.24 and 1.28 times higher risk independently and about 1.44 and 1.97 times increased susceptibility to GDM for one and two risk genotypes, respectively. We report that the HMG20A (rs7178572) and HNF4A (rs4812829) variants that have previously shown a strong association with T2DM in Asian Indians also contributes significant risk to GDM in this population. This is the first report of the association of HMG20A (rs7178572) and HNF4A (rs4812829) variants with GDM.

Association of rs11643718 SLC12A3 and rs741301 ELMO1 Variants with Diabetic Nephropathy in South Indian Population.

This study reports on the association of genetic variants selected from previous genome-wide association studies for type 2 diabetic nephropathy in south Indians. Eight variants were genotyped in 601 type 2 diabetic subjects without nephropathy (DM) and 583 type 2 diabetic subjects with nephropathy (DN) by MassARRAY. The minor allele frequencies of rs11643718 SLC12A3 variant and rs741301 ELMO1 variant were significantly different between DM and DN groups (P = 0.029 and 0.016, respectively). A combined analysis showed that the subjects carrying the risk genotypes of both these variants (GG of rs11643718 + AG/AA of rs741301) had a significant association with DN with an odds ratio [adjusted for age, sex, Body Mass Index (BMI), HbA1c, and systolic Blood Pressure (BP)] of 1.73 (1.30-2.30, P = 1.72 × 10-4 ) as compared to subjects carrying all other genotype combinations. This is the first study to report a significant association of the SLC12A3 rs11643718 and ELMO1 rs741301 (Single nucleotide Polymorphism) SNPs with diabetic nephropathy in south Indians.

Erratum to: Interaction between FTO gene variants and lifestyle factors on metabolic traits in an Asian Indian population.

[This corrects the article DOI: 10.1186/s12986-016-0098-6.].

Catestatin Gly364Ser Variant Alters Systemic Blood Pressure and the Risk for Hypertension in Human Populations via Endothelial Nitric Oxide Pathway.

Catestatin (CST), an endogenous antihypertensive/antiadrenergic peptide, is a novel regulator of cardiovascular physiology. Here, we report case-control studies in 2 geographically/ethnically distinct Indian populations (n≈4000) that showed association of the naturally-occurring human CST-Gly364Ser variant with increased risk for hypertension (age-adjusted odds ratios: 1.483; P=0.009 and 2.951; P=0.005). Consistently, 364Ser allele carriers displayed elevated systolic (up to ≈8 mm Hg; P=0.004) and diastolic (up to ≈6 mm Hg; P=0.001) blood pressure. The variant allele was also found to be in linkage disequilibrium with other functional single-nucleotide polymorphisms in the CHGA promoter and nearby coding region. Functional characterization of the Gly364Ser variant was performed using cellular/molecular biological experiments (viz peptide-receptor binding assays, nitric oxide [NO], phosphorylated extracellular regulated kinase, and phosphorylated endothelial NO synthase estimations) and computational approaches (molecular dynamics simulations for structural analysis of wild-type [CST-WT] and variant [CST-364Ser] peptides and docking of peptide/ligand with ß-adrenergic receptors [ADRB1/2]). CST-WT and CST-364Ser peptides differed profoundly in their secondary structures and showed differential interactions with ADRB2; although CST-WT displaced the ligand bound to ADRB2, CST-364Ser failed to do the same. Furthermore, CST-WT significantly inhibited ADRB2-stimulated extracellular regulated kinase activation, suggesting an antagonistic role towards ADRB2 unlike CST-364Ser. Consequently, CST-WT was more potent in NO production in human umbilical vein endothelial cells as compared with CST-364Ser. This NO-producing ability of CST-WT was abrogated by ADRB2 antagonist ICI 118551. In conclusion, CST-364Ser allele enhanced the risk for hypertension in human populations, possibly via diminished endothelial NO production because of altered interactions of CST-364Ser peptide with ADRB2 as compared with CST-WT.

Interaction between FTO gene variants and lifestyle factors on metabolic traits in an Asian Indian population.

BACKGROUND: Lifestyle factors such as diet and physical activity have been shown to modify the association between fat mass and obesity-associated (FTO) gene variants and metabolic traits in several populations; however, there are no gene-lifestyle interaction studies, to date, among Asian Indians living in India. In this study, we examined whether dietary factors and physical activity modified the association between two FTO single nucleotide polymorphisms (rs8050136 and rs11076023) (SNPs) and obesity traits and type 2 diabetes (T2D). METHODS: The study included 734 unrelated T2D and 884 normal glucose-tolerant (NGT) participants randomly selected from the urban component of the Chennai Urban Rural Epidemiology Study (CURES). Dietary intakes were assessed using a validated interviewer administered semi-quantitative food frequency questionnaire (FFQ). Physical activity was based upon the self-report. Interaction analyses were performed by including the interaction terms in the linear/logistic regression model. RESULTS: There was a significant interaction between SNP rs8050136 and carbohydrate intake (% energy) (Pinteraction = 0.04), where the 'A' allele carriers had 2.46 times increased risk of obesity than those with 'CC' genotype (P = 3.0 × 10(-5)) among individuals in the highest tertile of carbohydrate intake (% energy, 71 %). A significant interaction was also observed between SNP rs11076023 and dietary fibre intake (Pinteraction = 0.0008), where individuals with AA genotype who are in the 3(rd) tertile of dietary fibre intake had 1.62 cm lower waist circumference than those with 'T' allele carriers (P = 0.02). Furthermore, among those who were physically inactive, the 'A' allele carriers of the SNP rs8050136 had 1.89 times increased risk of obesity than those with 'CC' genotype (P = 4.0 × 10(-5)). CONCLUSIONS: This is the first study to provide evidence for a gene-diet and gene-physical activity interaction on obesity and T2D in an Asian Indian population. Our findings suggest that the association between FTO SNPs and obesity might be influenced by carbohydrate and dietary fibre intake and physical inactivity. Further understanding of how FTO gene influences obesity and T2D through dietary and exercise interventions is warranted to advance the development of behavioral intervention and personalised lifestyle strategies, which could reduce the risk of metabolic diseases in this Asian Indian population.

Association of TCF7L2 Polymorphism with Diabetic Nephropathy in the South Indian Population.

The transcription factor 7-like 2 (TCF7L2) gene plays a significant role in the development of type 2 diabetes and diabetic nephropathy. The aim of this study was to investigate the association of TCF7L2 rs12255372 (G/T)polymorphism with type 2 diabetic nephropathy in the South Indian population. A total of 2102 subjects, 927 normal glucose tolerant (NGT) subjects, 598 type 2 diabetic subjects without nephropathy (DM), and 577 type 2 diabetic subjects with nephropathy (DN) were genotyped by MassARRAY. As compared to the NGT group, the odds ratio (adjusted for age, sex, BMI, HbA1c, and systolic BP) computed for the GT/TT genotype taking the GG genotype as reference was found to be 2.02 (95% CI: 1.16-3.51, p = 0.013) for DN and 1.94 (95% CI: 1.36-2.78, p = 0.0002) for DM. The genotype frequency was not significantly different between the DM and DN groups. In conclusion, the rs12255372 polymorphism in the TCF7L2 gene is associated with type 2 diabetes and DN but its association with DN is mediated through diabetes.

Identification of Genetic Variants of Gestational Diabetes in South Indians.

BACKGROUND: This study examined the association in a South Indian population with gestational diabetes mellitus (GDM) of type 2 diabetes risk variants that have previously conferred susceptibility to GDM in other populations. SUBJECTS AND METHODS: The study groups comprised 518 women with GDM and 910 pregnant women with normal glucose tolerance (NGT). Women with GDM were recruited from a tertiary diabetes center in Chennai, in south India, and NGT women were selected from antenatal clinics also in Chennai. Genomic DNA was isolated from whole blood using the phenol chloroform method. Twelve previously reported GDM-associated single nucleotide polymorphisms (SNPs) in or near nine loci were genotyped using the MassARRAY™ system (Sequenom, San Diego, CA). RESULTS: Among the 12 SNPs genotyped, 11 SNPs were in Hardy-Weinberg equilibrium and had a call rate of >95%. Of the 11 SNPs previously associated with GDM in other populations, significant association was observed only with the rs7754840 and rs7756992 SNPs of the CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1) gene in this population. The minor alleles of the SNPs rs7754840 and rs7756992 showed significant susceptibility to GDM with an odds ratio of 1.34 (95% confidence interval, 1.12-1.60; P = 0.0013) and 1.45 (95% confidence interval, 1.21-1.72; P = 0.00004), respectively. CONCLUSIONS: The rs7754840 and rs7756992 SNPs of the CDKAL1 gene were found to be associated with GDM in this south Indian population. This is the first study describing genetic susceptibility of GDM in Asian Indians.

Novel ABCC8 (SUR1) gene mutations in Asian Indian children with congenital hyperinsulinemic hypoglycemia.

Congenital hyperinsulinemic hypoglycemia (HI) is a heterogeneous genetic disorder of insulin secretion characterized by persistent hypoglycemia, most commonly associated with inactivating mutations of the ß-cell ATP-sensitive K(+) channel (K(ATP) channel) genes ABCC8 (encoding SUR1) and KCNJ11(encoding Kir6.2). This study aimed to screen the mutations in the genes associated with congenital HI in Asian Indian children. Recessive mutations of these genes cause hyperinsulinism that is unresponsive to treatment with channel agonists like diazoxide. Dominant K(ATP) mutations have been associated with diazoxide-responsive disease. The KCNJ11, ABCC8, GCK, HNF4A, and GLUD1 genes were analyzed by sequence analysis in 22 children with congenital HI. We found 10 novel mutations (c.1delA, c.61delG, c.267delT, c.619-629delCCCGAGGACCT, Gln444*, Leu724Pro, Ala847Thr, Trp898*, IVS30-2A>C, and Leu1454Arg) and two known mutations (Gly111Arg and Arg598*) in the ABCC8 gene. This study describes novel and known ABCC8 gene mutations in children with congenital HI. This is the first large genetic screening study on HI in India and our results will help clinicians in providing optimal treatment for patients with hyperinsulinemia and in assisting affected families with genetic counseling.

Association study of the ABCC8 gene variants with type 2 diabetes in south Indians.

BACKGROUND: The ABCC8 gene which encodes the sulfonylurea receptor plays a major role in insulin secretion and is a potential candidate for type 2 diabetes. The -3c → t (rs1799854) and Thr759Thr (C → T, rs1801261) single nucleotide polymorphisms (SNPs) of the ABCC8 gene have been associated with type 2 diabetes in many populations. The present study was designed to investigate the association of these two SNPs in an Asian Indian population from south India. MATERIALS AND METHODS: A total of 1,300 subjects, 663 normal glucose tolerant (NGT) and 637 type 2 diabetic subjects were randomly selected from the Chennai Urban Rural Epidemiology Study (CURES). The -3c → t and Thr759Thr were genotyped in these subjects using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and a few variants were confirmed by direct sequencing. RESULTS: The frequency of the 't' allele of the -3c → t SNP was found to be 0.27 in NGT and 0.29 in type 2 diabetic subjects (P = 0.44). There was no significant difference in the genotypic frequency between the NGT and type 2 diabetic group (P = 0.18). Neither the genotypic frequency nor the allele frequency of the Thr759Thr polymorphism was found to differ significantly between the NGT and type 2 diabetic groups. CONCLUSION: The -3c → t and the Thr759Thr polymorphisms of the ABCC8 gene were not associated with type 2 diabetes in this study. However, an effect of these genetic variants on specific unidentified sub groups of type 2 diabetes cannot be excluded.

Association of His1085His INSR gene polymorphism with type 2 diabetes in South Indians.

BACKGROUND AND OBJECTIVE: The INSR gene, which encodes the insulin receptor, is a candidate gene for type 2 diabetes (T2D). The objective of the present study was to sequence some of the crucial exons in the INSR gene such as exon 2, which encodes the insulin-binding domain of the INSR protein, and exons 17-21, which encode the protein tyrosine kinase domain for mutations/polymorphisms, and to study their association with T2D in the South Indian population. SUBJECTS AND METHODS: The INSR gene was sequenced in 25 normal glucose-tolerant (NGT) and 25 T2D subjects, and the variant found was genotyped by polymerase chain reaction-restriction fragment length polymorphism in 1,016 NGT and 1,010 T2D subjects, randomly selected from the Chennai Urban Rural Epidemiology Study. RESULTS: Only one previously reported polymorphism, His1085His [rs1799817, (C→T)], in exon 17 was detected by sequencing. The frequency of the "T" allele of the His1085His polymorphism was significantly lower in the T2D subjects (31%) compared with the NGT subjects (35%) and showed significant protection against diabetes (odds ratio 0.85, 95% confidence interval 0.75-0.97, P=0.019). Regression analysis according to a recessive model taking the CC+CT genotype as the reference showed that the TT genotype was protective against diabetes (odds ratio 0.71, 95% confidence interval 0.50-0.99, P=0.048). Adjusting this P value by the number of competing models (three) using Bonferroni's correction, we found that the association finding did not remain significant. CONCLUSIONS: The "T" allele of the His1085His polymorphism in the INSR gene shows significant protection against diabetes. This study gains importance because there are no data available to date on the role of INSR variants in T2D in the Indian population.