Recent advances in the molecular genetics of type 2 diabetes mellitus

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.

Expression of matrix metalloproteinase-11 is increased under conditions of insulin resistance

AIM To investigate matrix metalloproteinase-11(MMP-11) expression in adipose tissue dysfunction, using in vitro and in vivo models of insulin resistance.METHODS Culture of mouse 3T3-L1 preadipocytes were induced to differentiation into mature 3T3-L1 adipocytes. Cellular insulin resistance was induced by treating differentiated cultured adipocytes with hypoxia and/or tumor necrosis factor(TNF)-α, and transcriptional changes were analyzed in each condition thereafter. For the in vivo studies, MMP-11 expression levels were measured in white adipose tissue(WAT) from C57BL/6J mice that underwent low fat diet or high-fat feeding in order to induce obesity and obesity-related insulin resistance. Statistical analysis was carried out with GraphP ad Prism Software.RESULTS MMP-11 m RNA expression levels were significantly higher in insulin resistant 3T3-L1 adipocytes compared to control cells(1.46±0.49vs0.83±0.21, respectively;P<0.00036). The increase in MMP-11 expression was observed even in the presence of TNF-α alone(3.79±1.11vs1±0.17, P<0.01) or hypoxia alone(1.79±0.7vs0.88±0.1, P<0.00023). The results obtained in in vitro experiments were confirmed in the in vivo model of insulin resistance. In particular, MMP-11 m RNA was upregulated in WAT from obese mice compared to lean mice(5.5±2.8vs1.1±0.7, respectively; P<3.72E-08). The increase in MMP-11 levels in obese mice was accompanied by the increase in typical markers of fibrosis, such as collagen type Ⅵ alpha 3(Col6_α3), and fibroblast-specific protein 1.CONCLUSION Our results indicate that dysregulation of MMP-11 expression is an early process in the adipose tissue dysfunction, which leads to obesity and obesity-related insulin resistance.

Pharmacogenetics of type 2 diabetes mellitus: An example of success in clinical and translational medicine

The pharmacological interventions currently available to control type 2 diabetes mellitus(T2DM) show a wide interindividual variability in drug response, emphasizing the importance of a personalized, more effective medical treatment for each individual patient. In this context, a growing interest has emerged in recent years and has focused on pharmacogenetics, a discipline aimed at understanding the variability in patients' drug response, making it possible to predict which drug is best for each patient and at what doses. Recent pharmacological and clinical evidences indicate that genetic polymorphisms(or genetic variations) of certain genes can adversely affect drug response and therapeutic efficacy of oral hypoglycemic agents in patients with T2 DM, through pharmacokinetic- and/or pharmacodynamic-based mechanisms that may reduce the therapeutic effects or increase toxicity. For example, genetic variants in genes encoding enzymes of the cytochrome P-450 superfamily, or proteins of the ATP-sensitive potassium channel on the beta-cell of the pancreas, are responsible for the interindividual variability of drug response to sulfonylureas in patients with T2 DM. Instead, genetic variants in the genes that encode for the organic cation transporters of metformin have been related to changes in both pharmacodynamic and pharmacokinetic responses to metformin in metformin-treated patients. Thus, based on the individual's genotype, the possibility, in these subjects, of a personalized therapy constitutes the main goal of pharmacogenetics, directly leading to the development of the right medicine for the right patient. Undoubtedly, this represents an integral part of the translational medicine network.