Genetic Variation and the Pathogenesis of Type 2 diabetes

Type 2 diabetes is a common metabolic disorder that arises out of a complex interaction between genes and the environment. It is preceded by pre-diabetes where affected subjects have elevated fasting or postprandial glucose concentrations but do not fulfill the criteria for the diagnosis of diabetes. Individuals with prediabetes are at high risk of progression to diabetes. To date about 20 genetic loci have been reliably associated with type 2 diabetes predisposition. However, it is uncertain how these these genes interact and how they influence predisposition and progression to diabetes.

TCF7L2 is a transcription factor that may modulate signaling pathways necessary for blood glucose homeostasis. It has been shown that individuals with the disease-associated variant(s) of this gene secrete less insulin during an oral glucose tolerance test (OGTT). However, despite the reproducible association of this genetic locus with type 2 diabetes, there is very little knowledge of how variation in this locus affects glucose homeostasis in humans with and without impaired fasting glucose and / or impaired glucose tolerance and ultimately how this gene contributes to the development of diabetes. The product of TCF7L2 is an important constituent of the wnt-signaling cascade that regulates proglucagon gene expression. The protein product of proglucagon is differentially processed in intestinal L cells to produce glucagon-like peptide-1 (GLP-1), an incretin hormone that is a potent insulin secretagogue. Defective secretion of GLP-1 has been associated with type 2 diabetes and impaired glucose tolerance.

This hormonal pathway is harnessed by various therapeutic interventions designed to improve glucose homeostasis in people with type 2 diabetes. The effect of GLP-1 on whole body glucose metabolism and how common genetic variation in TCF7L2 and other loci may alter response to GLP-1 is an area of active investigation in our laboratory.