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Background: Genetic markers conferring susceptibility to diabetes specific renal disease remains to be identified for early prediction and development of effective drugs and therapies. Inconsistent results obtained from analysis of genes from classical pathways generate need for examination of unconventional genetic markers having role in regulation of renal function. Experimental and clinical evidences suggest that dopamine is an important natriuretic hormone. Therefore, various genes involved in regulation of dopamine bioavailability could play a role in diabetic chronic renal insufficiency (CRI). We investigated the contribution of 12 polymorphisms from five Dopaminergic pathway genes to CRI among type-2 diabetic Asian Indian subjects. Methods: Genetic association of 12 polymorphisms (SNPs) from five genes namely-dopamine receptor-1 (DRD1), DRD2, DRD3, DRD4, andcatechol-O-methyltransferase (COMT) with diabetic CRI was investigated using a case-control approach. Logistic regression analysis was carried out to correlate various clinical parameters with genotypes, and to study pair wise interactions between SNPs of different genes. Results: SNPs -141 ins/del C and G>A (1 kb upstream from exon 2) in DRD2 gene showed significant allelic and genotypic association. Allele -141 insC and genotype -141 insC/insC of -141 ins/ del C polymorphism, and allele A of G>A SNP were found to be predisposing to CRI. Our result of allelic and genotypic association of -141 insC/delC SNP was also reflected in the haplotypic association. Heterozygous genotype of polymorphism 900 ins/del C in COMT gene was predisposing towards CRI. Conclusion: Some polymorphisms in DRD2 and COMT genes are significantly associated with susceptibility to CRI in the Asian Indian population which, if confirmed would be consistent with a suggested role of dopamine metabolism in disease occurrence. [ABSTRACT FROM AUTHOR]

Aims:Lipoprotein lipase (LPL), a pivotal enzyme in lipoprotein metabolism, catalyzes the hydrolysis of triglycerides of very low-density lipoproteins and chylomicrons. Assuming that the variants in the promoter of the LPL gene may be associated with changes in lipid metabolism leading to obesity and type 2 diabetes, we examined the role of promoter variants (–T93G and –G53C) in the LPL gene in an urban South Indian population.Methods:The study subjects (619 type 2 diabetic and 731 normal glucose-tolerant (NGT) subjects) were chosen from the Chennai Urban Rural Epidemiology Study, an ongoing population-based study in southern India. The polymorphisms were genotyped using polymerase chain reaction-restriction-fragment length polymorphism (PCR-RFLP). Linkage disequilibrium (LD) was estimated from the estimates of haplotypic frequencies.Results:The two polymorphisms studied were not in LD. The –T93G was not associated with type 2 diabetes but was associated with obesity. 11.5% of the obese subjects (62/541) had the XG(TG+GG) genotype compared with 6.4% of the nonobese subjects (52/809; P=0.001). The odds ratio for obesity for the XG genotype was 1.766 (95% CI: 1.19–2.63, P=0.005). Subjects with XG genotype also had higher body mass index and waist circumference compared with those with TT genotype. With respect to G53C, subjects with the XC(GC+CC) genotype had 0.527 and 0.531 times lower risk for developing type 2 diabetes and obesity, respectively.Conclusions:Among Asian Indians, the –T93G SNP of the LPL gene is associated with obesity but not type 2 diabetes, whereas the –G53C SNP appears to be protective against both obesity and type 2 diabetes.International Journal of Obesity (2007) 31, 913–918; doi:10.1038/sj.ijo.0803547; published online 13 February 2007 [ABSTRACT FROM AUTHOR]

Objective:To investigate the association of insulin receptor substrate-2 (IRS-2) G1057D polymorphism with type 2 diabetes and obesity in Asian Indians.Methods:The study comprised of 1193 normal glucose tolerant (NGT) subjects and 1018 subjects with type 2 diabetes, aged 20 years with an average body mass index of 23.7±4.6 and 25.3±4.2 kg/m2, respectively. The subjects were unrelated and randomly selected from the Chennai Urban Rural Epidemiology Study (CURES), a population-based study in Chennai in southern India. The G1057D polymorphism of the IRS-2 gene was genotyped using PCR-RFLP assay.Results:The genotype frequency of the IRS-2 G1057D polymorphism was significantly different between the NGT and type 2 diabetic groups (P=0.0007) in the total study subjects and among the obese subjects (P=0.00007). Logistic regression analysis showed that the DD genotype showed an increased susceptibility to diabetes with an odds ratio (adjusted for age and sex) of 2.19 (95% CI: 1.34–3.57, P=0.002) when compared to the GG+GD genotype, among the obese subjects, but not in non obese subjects. In order to explore possible interaction with obesity, logistic regression analysis was performed and the coefficient corresponding to the interaction parameter (genotype × obesity) was significant (P=0.0001).Conclusion:In Asian Indians, the DD genotype increases susceptibility to type 2 diabetes by interacting with obesity.International Journal of Obesity (2007) 31, 97–102. doi:10.1038/sj.ijo.0803356; published online 25 April 2006 [ABSTRACT FROM AUTHOR]

Background: Renal failure in diabetes is mediated by multiple pathways. Experimental and clinical evidences suggest that renin-angiotensin-aldosterone system (RAAS) has a crucial role in diabetic kidney disease. A relationship between the RAAS genotypes and chronic renal insufficiency (CRI) among type 2 diabetes subjects has therefore been speculated. We investigated the contribution of selected RAAS gene polymorphisms to CRI among type 2 diabetic Asian Indian subjects. Methods: Twelve single nucleotide polymorphisms (SNPs) from six genes namely-renin (REN), angiotensinogen (ATG), angiotensin converting enzyme I (ACE), angiotensin II type 1 receptor (AT1) and aldosterone synthase (CYP11B2) gene from the RAAS pathway and one from chymase pathway were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and tested for their association with diabetic CRI using a casecontrol approach. Successive cases presenting to study centres with type 2 diabetes of ≥2 years duration and moderate CRI diagnosed by serum creatinine ≥3 mg/dl after exclusion of non-diabetic causes of CRI (n = 196) were compared with diabetes subjects with no evidence of renal disease (n = 225). Logistic regression analysis was carried out to correlate various clinical parameters with genotypes, and to study pair wise interactions between SNPs of different genes. Results: Of the 12 SNPs genotyped, Glu53Stop in AGT and A>T (-777) in AT1 genes, were monomorphic and not included for further analysis. We observed a highly significant association of Met235Thr SNP in angiotensinogen gene with CRI (O.R. 2.68, 95%CI: 2.01-3.57 for Thr allele, O.R. 2.94, 95%CI: 1.88-4.59 for Thr∕Thr genotype and O.R. 2.68, 95%CI: 1.97-3.64 for ACC haplotype). A significant allelic and genotypic association of T>C (-344) SNP in aldosterone synthase gene (O.R. 1.57, 95%CI: 1.16-2.14 and O.R. 1.81, 95%CI: 1.21-2.71 respectively), and genotypic association of GA genotype of G>A (-1903) in chymase gene (O.R. 2.06, 95%CI: 1.34-3.17) were also observed. Conclusion: SNPs Met235Thr in angiotensinogen, T>C (-344) in aldosterone synthase, and G>A (-1903) in chymase genes are significantly associated with diabetic chronic renal insufficiency in Indian patients and warrant replication in larger sample sets. Use of such markers for prediction of susceptibility to diabetes specific renal disease in the ethnically Indian population appears promising. [ABSTRACT FROM AUTHOR]

Background: The role of glucokinase (GCK) in the pathogenesis of maturity-onset diabetes of the young is well established. However, its role in the common form of type 2 diabetes is far from convincing. We investigated the role of the G-to-A polymorphism in the hepatic GCK promoter on insulin sensitivity and beta cell function in 63 normotensive Asian Indians with normal glucose tolerance. As proposed by Matsuda and DeFronzo, hepatic insulin sensitivity (ISIH) and total body insulin sensitivity (ISIM) were estimated from the oral glucose tolerance test. Beta cell function was estimated using %B from the Homeostasis Model Assessment and insulingenic index (dI/dG). Result: We identified 38 GG, 24 GA, and one AA subjects. The AA subject was pooled with the GA subjects during the analysis. No difference was noted in the demographic features between the two genotypic groups (GG vs. GA/AA). Compared to the GG group, the GA/AA group had a lower ISIH (p=0.002), a lower ISIM (p=0.009), a higher %B (p=0.014), and a higher dI/dG (p=0.030). Multivariate analysis revealed that this polymorphism is an independent determinant for ISIH (p=0.019) and along with age, waist-hip ratio, gender, and diastolic blood pressure accounted for 51.5% of t he variation of ISIH. However, this polymorphism was a weak, but independent determinant for ISIM (p=0.089) and %B (p=0.083). Furthermore, it had no independent effect on dI/dG (p=0.135). Conclusions: These data suggest that the G-to-A polymorphism in the hepatic GCK promoter is associated with hepatic insulin resistance in Asian Indians. [ABSTRACT FROM AUTHOR]

Presents information on several regarding primary prevention of type 2 diabetes to be discussed at the 65th Scientific Sessions of the American Diabetes Association at the San Diego Convention Center in California from June 10 to 14, 2005. Contribution of psychological risk factors to glucose metabolism in children; Effectiveness of lifestyle modification in preventing diabetes in non-obese Asian Indian prediabetic subjects; Prediction rule for incident type 2 diabetes in Framingham Offspring.

A letter to the editor is presented in response to a study by R. M. Anjana and colleagues regarding predictors of diabetes and prediabetes progression among Asian Indians, which appeared within the issue.

Asian Indians are highly susceptible to Type 2 Diabetes (T2D) and constitute the largest diabetic population in the world. The underlying etiology for this increased susceptibility for T2D among Asian Indians remains to be defined. To determine whether Asian Indians are more insulin resistant and whether their insulin resistance is associated with any differences in muscle gene transcript levels, we studied 13 non-diabetic (fasting glucose < 100 mg/dl) Asian Indians (Age=47.2±2.4 y, BMI=23.8±0.5 kg/m²) and 13 gender-matched Americans of North European origin (European Americans; Age=46.6±2.2 y, BMI=24.5±0.8 kg/m2). Insulin sensitivity was measured by hyperinsulinemic (1.5 mU/kg FFM/min) euglycemic clamp. To maintain identical plasma glucose levels, Asian Indians required a substantially lower glucose infusion rate than European American controls (42.3 ± 4.0 vs. 68.3 ± 4.2 µmol/Kg FFM/min,p<0.001). Percutaneous needle biopsy samples were collected for gene array analysis. Total RNA was extracted from snap frozen muscle biopsy samples, amplified, labeled with fluorescent probe, fragmented and hybridized to the U133 Pins 2.0 Affymetrix genechip and GCRMA software was used to analyze microarray data. Out of about 47,000 transcripts surveyed, 58 genes transcript levels were altered (52 increased and 6 decreased) in Asian Indians compared to European Americans. Examples are as follows: Lipid metabolism: Fatty acid binding protein 7 (↑3.7); Glucose metabolism: GAPDH (↑1.03), Lactate dehydrogenase A (↑1.3); Chaperone: heat shock proteins 70 (↓0.65); and Energy metabolism: NADH1 (↑1.07), ATP synthase (↑1.1), Cytochrome C oxidase Va (↑1.20), Cytochrome C oxidase VLLc (↑1.1). In conclusion, nondiabetic Asian Indians are significantly more insulin resistant and have altered skeletal muscle gene transcript levels involving multiple metabolic pathways including mitochondrial bioenergetics. The results indicate potential mechanisms for higher susceptibility of Asian Indians to become diabetic. [ABSTRACT FROM AUTHOR]

Asian Indians have high prevalence of diabetes and premature coronary artery disease (CAD). The aim of this study was to determine the association of CAD in Asian Indian type 2 diabetic subjects with normo, micro and macroalbuminuria. Type 2 diabetic subjects [n= 1736], inclusive of self reported diabetic subjects [1382/1529, response rate 90.4%] and randomly selected newly diagnosed diabetic subjects [n=354] were recruited from the Chennai Urban Rural Epidemiology Study [CURES], a population based study in Chennai in Southern India. Microalbuminuria, estimated by immunoturbidimetric assay, was diagnosed if albumin excretion was between 30 - 299 µg/mg of creatinine and macroalbuminuria, if ≥300 µg/mg of creatinine. Coronary artery disease [CAD] was diagnosed based on a past history of documented myocardial infarction and/or electrocardiographic [ECG] evidence of Q wave and/or ST segment changes. Analysis was restricted to 1596 individuals on whom data on albumin excretion and CAD were available [1596/1736, response rate 91.9%]. The overall prevalence of micoalbuminuria was 26.8% [427 / 1596], macroalbuminuria, 5.5% [87/1596] and CAD, 13.0% [208/1596]. Subjects with macroalbuminuria had the highest prevalence of CAD [34.5%], followed by microalbuminuric subjects [14.8%] and normoalbuminuria [10.6%, p for trend: <0.0001]. Univariate regression showed both microalbuminuria [Odds ratio [OR]: 1.46, 95% confidence interval [CI]: 1.05 - 2.02, p<0.001] and macroalbuminuria [OR: 4.46, 95% CI: 2.7 - 7.1, p<0.001] to be significantly associated with CAD. After adjusting for age, glycated hemoglobin, smoking, triglycerides and LDL cholesterol, the association remained significant only for macroalbuminuria [OR:3.73, 95% CI: 2.2 - 6.4, p< 0.001]. In conclusion, there is an association between albumin excretion and CAD in Asian Indian type 2 diabetic subjects and this is stronger in those with macroalbuminuria. [ABSTRACT FROM AUTHOR]

Transcription factor 7-like2 (TCF7L2) gene has been associated with type 2 diabetes in different ethnic groups. As TCF7L2 gene is involved in regulation of insulin secretion, we hypothesized that TCF7L2 gene variants may be associated with MODY. We examined the role of rs12255372(G/T) and rs7903146(C/T) polymorphisms of TCF7L2 gene in MODY, early-onset type 2 diabetes (EO-T2DM), late-onset type 2 diabetes (LO-T2DM), type 1 diabetes (T1DM) and normal glucose tolerant (NGT) Asian Indians. Subjects were selected from the Chennai Urban Rural Epidemiology Study, a population based study in south India (EO-T2DM, LO-T2DM and NGT) and a tertiary diabetes centre (MODY and TIDM). 136 MODY subjects with autosomal dominant inheritance (age at onset(AAO) <25years), 397 EO-T2DM (AAO:25-40years), 738 LO-T2DM (AAO:>40years), 174 T1DM and 996 NGT subjects were studied. Genotyping of the two polymorphisms was carried out using PCR-RFLP and confirmed by direct sequencing. Frequency of the 'T' allele of rs12255372 and rs7903146 was significantly higher in MODY (30%,p=0.00001 and 45%,p<0.00001 respectively) and EO-T2DM (25%,p=0.0004; 37%,p<0.00001) compared to NGT (19%;28%). Odds ratios (OR) for GT and TT genotypes of the rs12255372 were higher in the MODY (OR:l.53,p=0.032 and 3.77,p=0.00002 respectively) and EO-T2DM (OR:1.48,p=0.002 and 1.75,p=0.034) compared to GG. The OR for CT and TT genotypes of rs7903146 were higher in MODY (OR:2.73,p<0.00001 and 4.10,p<0.00001 respectively) and EO-T2DM (OR: 1.71,p=0.00002 and 1.94,p=0.001) compared to CC. The CT genotype of rs7903146 showed association with LO-T2DM (OR: 1.26,p=0.022 compared to CC) but the TT genotype did not show any association. There was no association of rs12255372 with LO-T2DM and both polymorphisms were not associated with T1DM. Among Asian Indians, rs12255372(G/T) and rs7903146(C/T) polymorphisms of TCF7L2 gene are more strongly associated with MODY and EOT2DM and rs7903146 less strongly with LO-T2DM, while both polymorphisms are not associated with T1DM. [ABSTRACT FROM AUTHOR]

Asian Indians particularly those with type 2 diabetes have accelerated atherosclerosis at younger age. The aim of the present study was to assess the association of hsCRP, TNF-α with carotid IMT in individuals with different grades of glucose intolerance among Asian Indians. Three groups were randomly recruited from the Chennai Urban Rural Epidemiology Study [CURES], a population based study in Chennai in South India, Group 1: normal glucose tolerance (NGT) (n=150); Group 2: impaired glucose tolerance (IGT) (n=150) and Group 3: type 2 diabetes (DM) (n = 150). hs-CRP [Nephelometry, DadeBehring], TNF-α [enzyme linked immunosorbent assay] and carotid IMT [high resolution B-mode ultrasonography] were assessed. Subjects with diabetes had higher IMT values [0.85 ± 0.30 mm] compared to IGT [0.79 ± 0.16 mm; p<0.05] and NGT subjects [0.71 ± 0.12 mm; p<0.001]. HsCRP levels were higher in those with DM and IGT [DM: 2.8 mg/L, IGT: 2.1 mg/L] compared to NGT [1.2 mg/L, p for trend 0.003]. TNF-α levels were also higher in IGT and DM groups compared to NGT subjects [NGT: 3.5 ± 2.2, IGT: 4.6 ± 2.1, DM: 6.1 ± 2.4 pg / ml, p for trend <0.001]. HsCRP [r = 0.104, p=0.02] and TNF-α [r = 0.265, p<0.001] showed a positive correlation with IMT in the total study population and in subjects with NGT [hsCRP: r = 0.253, p = 0.002, TNF-α: r = 0.265, p = 0.001]. In multiple linear regression analysis, hsCRP [β =0.006, p<0.034] and TNF-α [β =0.015, p<0.001] showed an association with IMT among NGT subjects even after adjusting for age and gender. We conclude that among Asian Indians (1) levels of hsCRP and TNF-α increase with increasing degrees of glucose intolerance (2) among NGT subjects, both hsCRP and TNF-α are associated with increase in carotid IMT and this is independent of age and gender. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the prevalence of, and risk factors for, diabetic neuropathy among Asian Indian type 2 diabetic subjects. Subjects were recruited from CURES, a population-based study conducted on a representative population of Chennai city in south India. Of the 1529 known diabetic [KD] subjects, 1382 participated in the study [response rate: 90.4%]; in addition, 354 newly detected diabetic [NDD] subjects were also randomly selected. Neuropathy was diagnosed if the vibratory perception threshold of the right great toe measured by biothesiometry (Biomedical Instrument Co., Newbury, Ohio, USA) was ≥25. Of the total of 1736 individuals, biothesiometry studies were performed in 1632 subjects (94.0% response rate). The overall prevalence of neuropathy was 11% [age-standardized-5.8%], while it was 12.2% [age-standardized-6.5%] and 10% [age-standardized-5.2%] in male and female subjects respectively. The prevalence of neuropathy was significantly higher among KD subjects compared to NDD subjects [12.1% vs 6.8%, p=0.006]. It was also higher among subjects with diabetic retinopathy [26.9% vs 16.9%, p=0.001] and proteinuria [9.6% vs 5.3%, p=0.019] compared to those without. There was a linear increase in the prevalence of neuropathy with increasing age among both genders [p<0.0001]. The odds ratio (OR) for neuropathy in subjects having duration of diabetes >15 years was 5.51 [95% confidence interval (CI): 3.04-10.01, p<0.0001]. Multivariate logistic regression analysis showed age [OR: 1.16, 95% CI: 1.13-1.19, p<0.001], height [OR: 1.04, 95% CI: 1.01 -1.07, p=0.016] and fasting plasma glucose [OR: 1.00, 95% CI: 1.00 -1.01, p=0.001] to be significantly associated with neuropathy. Duration of diabetes showed an association with neuropathy but significance was lost when age was introduced into the model. This is the first population-based data on prevalence of diabetic neuropathy from India, which has the largest number of diabetic patients in the world. [ABSTRACT FROM AUTHOR]