title: Understanding Genetic Heterogeneity in Type 2 Diabetes by Delineating Physiological Phenotypes: SIRT1 and its Gene Network in Impaired Insulin Secretion.
abstract: Type 2 diabetes (T2D) is a chronic metabolic disease which shows an exponential increase in all parts of the world. However, the disease is controllable by early detection and modified lifestyle. A series of factors have been associated with the pathogenesis of diabetes, and genes are considered to play a critical role. The individual risk of developing T2D is determined by an altered genetic background of the en-zymes involved in several metabolism-related biological mechanisms, including glucose homeostasis, insulin metab-olism, the glucose and ion transporters involved in glucose uptake, transcription factors, signaling intermediates of insulin signaling pathways, insulin production and secretion, pancreatic tissue development, and apoptosis. However, many candidate genes have shown heterogeneity of associations with the disease in different populations. A possible approach to resolving this complexity and under-standing genetic heterogeneity is to delineate the physiological phenotypes one by one as studying them in combination may cause discrepancies in association studies. A systems biology approach involving regulatory proteins, transcription factors, and microRNAs is one way to understand and identify key factors in complex diseases such as T2D. Our earlier studies have screened more than 100 single nucleotide polymorphisms (SNPs) belonging to more than 60 globally known T2D candidate genes in the Indian population. We observed that genes invariably involved in the activity of pancreatic β-cells provide susceptibility to type 2 diabetes (T2D). Encouraged by these results, we attempted to delineate in this review one of the commonest physiological phenotypes in T2D, namely impaired insulin secretion, as the cause of hyperglycemia. This review is also intended to explain the genetic basis of the pathophysiology of insulin secretion in the context of variations in the SIRT1 gene, a major switch that modulates insulin secretion, and a set of other genes such as HHEX, PGC-α, TCF7L2, UCP2, and ND3 which were found to be in association with T2D. The review aims to look at the genotypic and transcriptional regulatory relationships with the disease phenotype.
authors: National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi-110067, India.
authors: Shafat
authors: S
authors: Ali
authors: National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi-110067, India.
authors: Shazia
authors: S
authors: Nafis
authors: National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi-110067, India.
authors: Ponnusamy
authors: P
authors: Kalaiarasan
authors: Human Genetics Research Group, Department of Biotechnology, Shri Mata Vaishno Devi University, Katra, 182320, India.
authors: Ekta
authors: E
authors: Rai
authors: Human Genetics Research Group, Department of Biotechnology, Shri Mata Vaishno Devi University, Katra, 182320, India.
authors: Swarkar
authors: S
authors: Sharma
authors: National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi-110067, India.
authors: Rameshwar N
authors: RN
authors: Bamezai
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics*; D000078790:Insulin Secretion; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D056564:Sirtuin 1 / Q000235:genetics*
chemical_list: D007328:Insulin; D056564:Sirtuin 1