Current views on type 2 diabetes

Abstract

Type 2 diabetes mellitus (T2DM) affects a large population worldwide. T2DM is a complex heterogeneous group of metabolic disorders including hyperglycemia and impaired insulin action and/or insulin secretion. T2DM causes dysfunctions in multiple organs or tissues. Current theories of T2DM include a defect in insulin-mediated glucose uptake in muscle, a dysfunction of the pancreatic beta-cells, a disruption of secretory function of adipocytes, and an impaired insulin action in liver. The etiology of human T2DM is multifactorial, with genetic background and physical inactivity as two critical components. The pathogenesis of T2DM is not fully understood. Animal models of T2DM have been proved to be useful to study the pathogenesis of, and to find a new therapy for, the disease. Although different animal models share similar characteristics, each mimics a specific aspect of genetic, endocrine, metabolic, and morphologic changes that occur in human T2DM. The purpose of this review is to provide the recent progress and current theories in T2DM and to summarize animal models for studying the pathogenesis of the disease.

Figure 1

Insulin signaling pathways regulating GLUT4 translocation in mammalian skeletal muscle. Insulin activates tyrosine kinase activity of insulin receptor (IR) by binding with α-subunit of IR. Activated IR phosphorylates itself and insulin receptor substrate-1 (IRS1). Phosphorylated IRS1 binds to phosphatidylinositol 3-kinase (PI3-kinase), which is recruited to plasma membrane and converts phosphatidylinositols-4,5-bisphophate (PIP₂) to phospha-tidylinositols-3,4,5-trisphophate (PIP₃). Increased PIP₃ recruits phosphatidylinositol-dependent protein kinase-1 (PDK1) and AKT to plasma membrane where AKT is activated by PDK1-mediated phosphorylation. Activated AKT phosphorylates AS160/TBC1D1, which inhibits its Rab GTPase-activating protein (GAP) activity towards particular Rab isoform(s). Inhibition of GAP increases conversion of less active GDP-loaded Rab to more active GTP-loaded Rab. Increased active GTP-loaded Rab then allows GLUT4 storage vesicles to move to, dock, and fuse with plasma membrane. Four stages of GLUT4 translocation have been proposed. Vectorial transfer: GLUT4 vesicles are transported to the cell periphery, possibly along microtubules. Tethering: GLUT4 vesicles are retained near the cell periphery through remodeling actin cytoskeleton. Docking: GLUT4 vesicles bind to plasma membrane via interaction of VAMP2 with target-SNARE complexes. Fusion: irreversible incorporation of GLUT4 vesicles on to plasma membrane is enhanced through action of Munc18c on SNARE proteins.

Figure 2

Pathogenesis of T2DM. Current theories on T2DM include a defect in insulin-mediated glucose uptake in skeletal muscle, a disruption of secretory function of adipocytes, a dysfunction of pancreatic β-cells, impaired sensing and response to hyperglycemia in the CNS, an excessive accumulation of lipids, and impaired fatty acid oxidation due to obesity, physical inactivity, and genetic predisposition.