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  • Diabetes mellitus is a syndrome characterized by elevated levels of glucose in the plasma. The American Diabetes Association has recently proposed revised criteria for the diagnosis of diabetes: (a) a fasting plasma glucose level >126 mg/dl, or (b) a plasma glucose level >200 mg/dl at 2 h after the ingestion of oral glucose (75 g), or (c) random plasma glucose >200 mg/dl.

  • Diabetes is a heterogeneous clinical syndrome with multiple etiologies. Type 1 diabetes is caused by destruction of pancreatic beta cells, most often by autoimmune mechanisms. Type 2 diabetes (the most common form of diabetes, accounting for >90 percent of patients) is caused by a combination of two physiological defects: resistance to the action of insulin combined with a deficiency in insulin secretion. Although the molecular basis of the common form of type 2 diabetes has not been elucidated, it is thought to result from genetic defects that cause both insulin resistance and insulin deficiency. Type 2 diabetes generally has onset after the age of 40. Unlike type 1 diabetes, type 2 diabetes is usually associated with relatively mild hyperglycemia, and ketoacidosis seldom develops. Gestational diabetes mellitus is a form of diabetes that has its initial onset during pregnancy, and resolves after the end of the pregnancy.

  • Insulin exerts multiple effects upon target cells—especially skeletal muscle, liver, and adipose tissue. In general, insulin promotes storage of fuels (e.g., glycogen and triglyceride), and inhibits the breakdown of stored fuel. To accomplish these general physiological functions, insulin exerts multiple specific actions upon target cells. For example, insulin promotes recruitment of glucose transporters from intracellular vesicles to the plasma membrane, thereby stimulating glucose transport into skeletal muscle and adipocytes. Insulin also regulates many metabolic enzymes, either by increasing or decreasing the level of protein phosphorylation. In addition, insulin regulates the level of intracellular metabolites that regulate enzyme activity by allosteric mechanisms. Finally, insulin regulates the level of gene expression—inducing the expression of some genes (e.g., hepatic glucokinase) and inhibiting expression of other genes (e.g., phosphoenolpyruvate carboxykinase).

  • The biologic actions of insulin are mediated by a cell surface receptor. The receptor possesses an extracellular domain that binds insulin, and an intracellular domain that possesses tyrosine-specific protein kinase activity. Insulin binding activates the receptor tyrosine kinase, leading to autophosphorylation of the receptor as well as phosphorylation of several intracellular proteins (e.g., insulin receptor substrates -1, -2, -3, and -4). Insulin-stimulated tyrosine phosphorylation ultimately leads to the activation of multiple downstream signaling pathways. Among these, activation of phosphatidylinositol 3-kinase is the most important in mediating the metabolic actions of insulin. Increasing the cellular content of phosphatidylinositol 3,4,5-trisphosphate activates phosphoinositide-dependent protein kinases (e.g., PDK-1). PDK-1 phosphorylates and activates multiple downstream protein kinases, including protein kinase B, atypical protein kinase C, and p70 S6 kinase. Activation of these protein kinases is responsible for mediating many of the ultimate metabolic actions of insulin, including translocation of GLUT4, activation of glycogen synthesis, and suppressing gluconeogenesis by inhibiting transcription of the gene ...

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