Type 2 diabetes mellitus

Abstract

Type 2 diabetes mellitus (T2DM) is an expanding global health problem, closely linked to the epidemic of obesity. Individuals with T2DM are at high risk for both microvascular complications (including retinopathy, nephropathy and neuropathy) and macrovascular complications (such as cardiovascular comorbidities), owing to hyperglycaemia and individual components of the insulin resistance (metabolic) syndrome. Environmental factors (for example, obesity, an unhealthy diet and physical inactivity) and genetic factors contribute to the multiple pathophysiological disturbances that are responsible for impaired glucose homeostasis in T2DM. Insulin resistance and impaired insulin secretion remain the core defects in T2DM, but at least six other pathophysiological abnormalities contribute to the dysregulation of glucose metabolism. The multiple pathogenetic disturbances present in T2DM dictate that multiple antidiabetic agents, used in combination, will be required to maintain normoglycaemia. The treatment must not only be effective and safe but also improve the quality of life. Several novel medications are in development, but the greatest need is for agents that enhance insulin sensitivity, halt the progressive pancreatic β-cell failure that is characteristic of T2DM and prevent or reverse the microvascular complications. For an illustrated summary of this Primer, visit: http://go.nature.com/V2eGfN.

Adipose Tissue and Inflammation

“…Insulin resistance is characterized by a series of alterations at the intracellular level, such as a decrease in the concentration of the receptor and its kinase activity, the concentration and phosphorylation of IRS-1 and IRS-2, PI3K activity, translocation to the membrane of the GLUT4 and the activity of intracellular enzymes [91]. Insulin resistance has been associated mainly with a state of obesity and physical inactivity, as well as a genetic predisposition, the stress on the β cells, causing an alteration in the function of these cells and a progressive decrease in the secretion of insulin [92]. IR can be divided into two types: hepatic IR or peripheral RI.…”

“…There is also evidence that adipose tissue plays an important role in the development of insulin resistance, and this tissue can regulate the metabolism of glucose in the body, through the regulation of free fatty acids, the secretion of adipokines, since it acts as an endocrine organ [97]. The ectopic accumulation of lipids in muscle and liver induces insulin resistance through the increase in the levels of diacylglycerol (DAG), and its accumulation promotes the translocation and activation of the protein kinase (PK)-C in the tissues, the PKC-θ in the muscle, and in the liver the PKC-δ and PKC-ε, which are involved in inhibiting the kinase activity of the receptor to insulin and thus inhibit insulin signaling [92]. The phosphorylation of IRS-1 at the residue of Serine-1101 by PKC-θ showed a blockade of the insulin-stimulated IRS-1 tyrosine phosphorylation [98]; this determines the signaling of insulin ( Figure 6B).…”

Association Between SLC30A8 Gene rs3802177 Polymorphism and T2DM in Asian Population-a Meta-Analysis

“…As suggested by Thakkinstian [9], the optimal model was selected through pairwise comparison among genotypes (CC vs TT , OR 1 Discussion T2DM is a disease caused by multiple genes and environmental factors that contribute to insulin resistance or insufficient insulin secretion [15]. SLC30A8 encodes the Zn 2+ transporter ZnT8, which is responsible for the Zinc supply in pancreatic β cells [4], therefore mutations in this gene sequence may affect the function of β cells and thus increase the risk of T2DM.…”

Circulating Betatrophin and Hepatocyte Growth Factor in Type 2 Diabetic Patients: Their Relationship With Disease Prognosis

“…In the major type 2 diabetes mellitus (T2DM), improper blood glucose metabolism is caused by impaired insulin secretion and/or insulin resistance (IR). The progressive decline in insulin production by the pancreatic β cells ultimately leading to T2DM is instigated by obesity-associated IR [1,2]. Actually, T2DM is a magnitude of diseases since it involves abnormalities in 57 genes and 136 single nucleotide polymorphisms that afflict insulin secretion, resistance, signaling, and β-cell dysfunction, along with epigenetic changes due to environmental factors encompassing ethnicity, nutrition, intrauterine surroundings, and obesity.…”