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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]

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]