Genes, dietary, and lifestyle factors have been shown to be important in the pathophysiology of diabetes and associated microvascular complications. Epigenetic modifications, such as DNA methylation, histone acetylation, and post-transcriptional RNA regulation, are being increasingly recognized as important mediators of the complex interplay between genes and the environment. Recent studies suggest that diabetes-induced dysregulation of epigenetic mechanisms resulting in altered gene expression in target cells can lead to diabetes-associated complications, such as diabetic cardiomyopathy, diabetic nephropathy, retinopathy, and so on, which are the major contributors to diabetes-associated morbidity and mortality. Thus, knowledge of dysregulated epigenetic pathways involved in diabetes can provide much needed new drug targets for these diseases. In this review, we constructed our search strategy to highlight the role of DNA methylation, modifications of histones and role of non-coding RNAs (microRNAs and long non-coding RNAs) in vascular complications of diabetes, including cardiomyopathy, nephropathy, and retinopathy.

Patients with type 2 diabetes (T2DM) are usually obese and concurrent obesity results into activation of the renin-angiotensin-system (RAS) which is a risk factor for diabetic nephropathy (DN). Gene-gene interaction between acetyl-coenzymeA carboxylase beta (ACACβ) gene, which is involved in fatty acid metabolism and angiotensin II receptors (AGTR1) gene, which mediates RAS proteins actions on renal tissue, polymorphism with DN have not been studied earlier. The present study was designed with the aim to examine the association of an ACACβ (rs2268388) and AGTR1 (rs5186) gene polymorphism with the risk of DN in Asian Indians. 1,158 patients with T2DM belonging to two independently ascertained North Indian and one South Indian cohorts were genotyped for ACACβ (rs2268388) and AGTR1 (rs5186) polymorphism using real time PCR-based Taq-man assay and PCR-RFLP assays. In all the three cohorts, a significantly higher frequency of T allele and TT genotypes of ACACβ and C allele and CC genotypes of AGTR1 were found in patients with DN as compared to patients without nephropathy. Further, T allele of ACACβ and C allele of AGTR1 were found to be significantly associated with proteinuria, a hallmark of DN. We also found significant epistatic interactions between these two genes. TT genotypes of ACACβ gene and CC genotype of AGTR1 gene confers the risk of DN and both genes had significant epistatic interaction in Asian Indian patients with T2DM.

Endothelial nitric oxide synthase (eNOS) has been shown to play an essential role in retinal vascular function, and disequilibrium in its production can lead to diabetic retinopathy (DR). Genetic polymorphisms of eNOS gene have been suggested to play a role in nitric oxide (NO) abnormalities which may contribute to the development and progression of DR. In view of the variable results that have been reported for the association between eNOS gene polymorphisms and DR, the present study was designed to study the association and interaction between eNOS gene polymorphisms and the development and progression of DR in Asian Indian type 2 diabetes mellitus patients (T2DM). We screened 1,720 T2DM patients, belonging to two independently ascertained cohorts out of which 1,446 were genotyped for three polymorphisms of eNOS (two SNPs: T-786C, G894T and one 27-bp repeat polymorphism in intron 4 (27VNTR)) using validated PCR-RFLP assays. In both the cohorts, consistently lower prevalence and decreased risk of DR was observed in patients with ba, aa and ba + aa genotype of 27VNTR (a/b), C-a-G and C-a-T haplotype (allele of T-786C, 27VNTR a/b and G894T) carrying "C" allele of T-786C and "a" allele of 27VNTR (a/b). Also, mean NO levels in T2DM subjects carrying ba + aa genotype were higher as compared to bb genotype. Our results suggest that eNOS genotypes 27VNTR carrying "aa" genotype is an independent protective factor for DR and is associated with low risk of DR.

Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease, including diabetic neuropathy (DNP). Endothelial-derived nitric oxide synthase (eNOS) gene polymorphisms affect eNOS activity and are associated with endothelial dysfunction. Studies examining association of eNOS gene polymorphism in type 2 diabetic patients (T2DM) with DNP and without DNP are lacking in Asian Indians. Thus, we investigated the association and interaction between two potentially functional single nucleotide polymorphisms (SNPs) of the eNOS gene (T-786C, G894T) and one repeat polymorphism (27VNTR) with DNP using validated PCR-RFLP assays in 1258 T2DM subjects belonging to two independent cohorts from north Indian Origin and also, we replicated our study in a 3 rd independent cohort from south Indian population having T2DM. We also measured serum Nitric Oxide (NO) levels in these subjects and examined its correlation with DNP and eNOS genotypes. We observed that eNOS genotype carrying 'aa' genotype of 27VNTR (a/b) and eNOS haplotype C-a-G and C-aT (allele of T-786C, 27VNTR a/b and G894T) carrying 'a' allele of 27VNTR (a/b) were associated with increased risk of DNP, in all the three cohorts. We also observed lower serum NO levels in T2DM subjects (both cases and controls) carrying ba+aa genotypes. Our study suggest that 27VNTR (a/b) eNOS polymorphism carrying 'a' allele alone and in association with T-786C and G894T eNOS polymorphism is associated with increased risk of DNP in Asian Indians T2DM patients.

No abstract