Diabetes mellitus: Metabolic effects and oxidative stress

Diabetes mellitus is a complex polygenic pathology, which is characterized by numerous metabolic disorders. Progressive hyperglycemia developing during this disease causes clinically significant tissue damage and is considered as a main risk factor of micro- and macrovascular complications leading to retinopathy, nephropathy, and neuropathy. Hyperglycemia-depended oxidative stress and impairments in nitric oxide bioavailability play an essential role in the pathogenesis of diabetes and its complications. Homeostasis of glucose maintained by metabolic effects of insulin includes an increase of glucose uptake by skeletal muscles and suppression of glucose production by the liver. M. Brownlee (2005) put forward a hypothesis assuming that oxidative stress is the main mechanism of diabetic tissue damages. According to this hypothesis, mitochondrial dysfunction and superoxide anion radical hyperproduction by mitochondria is the principal mechanism of activation of four pathways of hyperglycemia-induced impairments under diabetes. Two cell signaling cascades regulate the glucose homeostasis: insulin-mediated glucose uptake (IMGU) in skeletal muscles, liver, and heart and glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells. In addition to nonspecific irreversible oxidative damage of DNA, protein and lipid molecules reactive oxygen and nitrogen species induce cell and tissue damage, activating a number of cell stress-sensitive signaling cascades. Stress-dependent serine phosphorylation of insulin receptor substrate (IRS) proteins decreases its capacity for tyrosine phosphorylation and may accelerate degradation of IRS. This process underlies the molecular mechanism of oxidative stress-induced insulin resistance.