Galenova T. Biochemical mechanisms of the insulin resistance development under type 2 diabetes mellitus.

The dissertation is devoted to study of biochemical mechanisms of the insulin resistance development under type 2 diabetes mellitus. The main components of the insulin signal cascade were analyzed in liver, muscle and adipose tissues of the control and diabetic animals under conditions of insulin stimulation and in its absence. The development of insulin resistance in peripheral tissues was established to be associated with the decrease of membrane insulin-stimulated tyrosine protein kinase activity. As it was demonstrated, such changes followed reduction of the surface insulin receptors number in cells of the investigated tissues while the decrease of the receptor affinity to its natural ligand wasn't involved in development of the present pathological condition. Besides defects on the receptor level, varieties of post-receptor disturbances in signal transduction were confirmed for the examined tissues of diabetic animals. The decrease of insulin-stimulated phosphatidylinositol 3-kinase and glycogen synthase activities as well as changes in hexokinases functioning was demonstrated in peripheral tissues under type 2 diabetes mellitus. It was established that insulin resistance development involves disorders associated with intracellular translocation processes of glucose transporter proteins in response to insulin action in insulin-dependent tissues of diabetic rats. The study of tyrosine protein phosphatase activity in various subcellular fractions of liver, muscle and adipose tissues of diabetic animals demonstrated that present enzymes were involved in negative regulation of insulin signal transduction under type 2 diabetes.