Recent advances in the molecular genetics of type 2 diabetes mellitus

Abstract

Type 2 diabetes mellitus (T2DM) is a complex disease in which both genetic and environmental factors interact in determining impaired β-cell insulin secretion and peripheral insulin resistance. Insulin resistance in muscle, liver and fat is a prominent feature of most patients with T2DM and obesity, resulting in a reduced response of these tissues to insulin. Considerable evidence has been accumulated to indicate that heredity is a major determinant of insulin resistance and T2DM. It is believed that, among individuals destined to develop T2DM, hyperinsulinemia is the mechanism by which the pancreatic β-cell initially compensates for deteriorating peripheral insulin sensitivity, thus ensuring normal glucose tolerance. Most of these people will develop T2DM when β-cells fail to compensate. Despite the progress achieved in this field in recent years, the genetic causes of insulin resistance and T2DM remain elusive. Candidate gene association, linkage and genome-wide association studies have highlighted the role of genetic factors in the development of T2DM. Using these strategies, a large number of variants have been identified in many of these genes, most of which may influence both hepatic and peripheral insulin resistance, adipogenesis and β-cell mass and function. Recently, a new gene has been identified by our research group, the HMGA1 gene, whose loss of function can greatly raise the risk of developing T2DM in humans and mice. Functional genetic variants of the HMGA1 gene have been associated with insulin resistance syndromes among white Europeans, Chinese individuals and Americans of Hispanic ancestry. These findings may represent new ways to improve or even prevent T2DM.

Keywords: Candidate gene; Genetic variants; Genome-wide association study; High-mobility group A1; Insulin resistant diabetes.

Figure 1

Overview of the pathogenic factors underlying development of type 2 diabetes mellitus. As a complex disease, T2DM is caused by a combination of genetic, environmental and lifestyle factors, all of which interact together to produce insulin resistance and β-cell dysfunction, leading to hyperglycemia, which is the clinical hallmark of diabetes. FFA: Free fatty acids.T2DM: Type 2 diabetes mellitus.

Figure 2

Schematic representation of the pancreatic β-cell. Reduced insulin secretion is shown in β-cells with gene variants linked to T2DM. Genes associated with defects in β-cell mass and/or function are indicated in white italic uppercase. T2DM: Type 2 diabetes mellitus.

Figure 3

Mechanisms of insulin resistance. The figure shows the mechanisms by which gene variants may impair insulin action in the insulin target tissues muscle, fat and liver. Peripheral insulin resistance in muscle and fat reduces cellular glucose uptake, whereas insulin resistance in liver results in a failure to suppress glucose production and gluconeogenesis. Genes whose variations can influence the risk of developing insulin resistance and T2DM are indicated in black italic uppercase. T2DM: Type 2 diabetes mellitus.

Figure 4

Model for the role of High Mobility Group A1 in type 2 diabetes mellitus. As a transcriptional regulator of the INSR gene, HMGA1 gene variants may lead to decreased INSR gene transcription. This loss of insulin receptor (INSR) underlies the resultant insulin resistance and T2D in affected individuals. T2D: Type 2 diabetes.