Abstract
Type 2 diabetes is a disorder of dysregulated glucose homeostasis. Normal glucose homeostasis is a complex process involving several interacting mechanisms, such as insulin secretion, insulin sensitivity, glucose production, and glucose uptake. The dysregulation of one or more of these mechanisms due to environmental and/or genetic factors, can lead to a defective glucose homeostasis. Hyperglycemia is managed by augmenting insulin secretion and/or interaction with hepatic glucose production, as well as by decreasing dietary caloric intake and raising glucose metabolism through exercise. Although these interventions can delay disease progression and correct blood glucose levels, they are not able to cure the disease or stop its progression entirely. Better management of type 2 diabetes is sorely needed. Advances in genotyping techniques and the availability of large patient cohorts have made it possible to identify common genetic variants associated with type 2 diabetes through genome-wide association studies (GWAS). So far, genetic variants on 19 loci have been identified. Most of these loci contain or lie close to genes that were not previously linked to diabetes and they may thus harbor targets for new drugs. It is also hoped that further genetic studies will pave the way for predictive genetic screening. The newly discovered type 2 diabetes genes can be classified based on their presumed molecular function, and we discuss the relation between these gene classes and current treatments. We go on to consider whether the new genes provide opportunities for developing alternative drug therapies.
Highlights
The last few decades have witnessed a dramatic increase in the prevalence of type 2 diabetes mellitus, due to changes in food intake combined with less physical exercise, a lifestyle often referred to as Western
To explore the functions of the newly discovered genes, various studies have investigated their roles in determining sub-phenotypes of type 2 diabetes, such as peripheral insulin sensitivity and -cell insulin secretion, and the genetic variants identified in genome-wide association studies (GWAS) [32,33,34,35,36]
Type 2 diabetes genes that are presumed to play a role in cell cycle regulation (JAZF1, CDKN2A, and CDC123), apoptosis (THADA and WFS1), or pancreas development and growth (TCF7L2, TCF2, HHEX / IDE, IGF2BP2, CDKAL1, and NOTCH2) have not yet been studied well enough to predict whether interference with their products could be used in managing diabetes
Summary
The last few decades have witnessed a dramatic increase in the prevalence of type 2 diabetes mellitus, due to changes in food intake combined with less physical exercise, a lifestyle often referred to as Western. Genetic variants in three (KCNJ11, TCF2, WFS1) out of four replicated genes for type 2 diabetes found by candidatebased genetic association studies are related to decreased -cell function. To explore the functions of the newly discovered genes, various studies have investigated their roles in determining sub-phenotypes of type 2 diabetes, such as peripheral insulin sensitivity and -cell insulin secretion, and the genetic variants identified in GWAS (except KCNQ1 because variants in this gene have only recently been identified) [32,33,34,35,36].
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