Type II Diabetes Mellitus Signaling


Pathway Description

Diabetes is a metabolic disorder characterized by elevated circulating blood glucose levels. Elevated blood glucose level triggers the secretion of insulin from the pancreatic beta-cells. Insulin has two major effects: stimulation of glucose uptake into cells and suppression of glucose production by the liver.Type II diabetes mellitus is caused by defects in both insulin secretion by beta-cells and insulin signaling in adipocytes, hepatocytes, and skeletal muscle cells.

Chronic hyperglycemia induces deleterious effects on beta-cells function. The mechanism of glucotoxicity is, at least in part, mediated by generation of chronic oxidative stress. In a chronic hyperglycemic state, glucose metabolism leads to large amount of reactive oxygen species (ROS), through various pathways (oxidative phosphorylation, PKC activation, autooxidation, glycation, hexosamine and sorbitol metabolism). Since the expression levels of antioxidant enzymes such as catalase, superoxide dismutase, and glutathione peroxidase are very low in beta-cells, these cells are particularly susceptible to oxidative stress, which in turn causes beta-cells apoptosis and down-regulation of several beta-cell specific genes (insulin, GLUT2 and glucokinase). High ROS levels decrease expression and activity of two transcription factors (PDX-1 and MafA), which are involved in insulin, GLUT2 and glugokinase expression, leading to an impaired insulin secretion.

Insulin signaling involves binding of insulin to its receptor (INSR), followed by the tyrosine phosphorylation and activation of insulin receptor substrate (IRS) proteins. IRS activation leads to the translocation of glucose transporter (GLUT4) from intracellular vesicles to the cell surface, allowing glucose uptake, and to the activation of downstream signaling cascades leading to glycogenesis and antilipolysis.

Negative modulation of insulin signaling is mediated via different pathways leading to insulin resistance. Insulin resistance is associated with obesity, in which levels of circulating free fatty acid (FFA) and TNFα are increased. FFA and TNFα have been shown to activate several IRS serine kinases (ERK, JNK, IKK, PKC, and mTOR). These kinases increase serine phosphorylation of IRS, reducing its ability to be activated by the insulin receptor, leading to negative regulation of insulin signaling. Adiponectin (ADIPO) is a protein hormone that signals via AMP kinase and regulates glucose uptake. Contrary to FFA and TNFα, adiponectin levels are decreased in visceral obesity, leading to inhibition of glucose uptake and insulin resistance.

Glucotoxicity leading to impaired beta-cell function and lipotoxicity leading to increased hepatic glucose production and decreased glucose transport in adipose tissue and muscle, both contribute to the progressive deterioration of glucose homeostasis observed in type II diabetes mellitus.