Molecular mechanisms of insulin resistance.
1. Insulin stimulates tyrosine phosphorylation of the insulin receptor and of an endogenous substrate of approximately 185 kDa (insulin receptor substrate 1 or IRS-1). IRS-1 fulfills the criteria of a direct substrate of the insulin receptor, and tyrosine phosphorylation of IRS-1 leads to another step in insulin action, i.e., an association of phosphorylated IRS-1 with the enzyme PI3-kinase activating this enzyme. Using antipeptide antibodies to insulin receptor, to IRS-1 and to PI 3-kinase together with anti-phosphotyrosine antibodies it is possible to study insulin-stimulated insulin receptor phosphorylation, IRS-1 phosphorylation and the association/activation of IRS-1/PI 3-kinase. 2. In this review we describe alterations in these three early steps of insulin action after binding in animal models of insulin resistance, i.e., streptozotocin-induced diabetes (STZ diabetes), fasting, spontaneously hypertensive rats, the ob/ob mice, dexamethasone-treated rats, and the chronic effect of insulin on Fao cells in culture. 3. In states of insulin resistance with hypoinsulinemia (STZ diabetes and fasting) there is an increase in these early steps of insulin action. In animal models of insulin resistance with hyperinsulinemia there is a decrease in these steps of insulin action, indicating molecular post-receptor defects. Since we could reproduce the decrease in these three early steps of insulin action in cells in culture by chronic treatment with insulin, we postulate that these defects may be a consequence of the hyperinsulinemia of these animals.
Saad
M J
MJ
Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, SP, Brasil.
D000595:Amino Acid Sequence; D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D005215:Fasting / Q000378:metabolism; D007328:Insulin / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011972:Receptor, Insulin / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D014443:Tyrosine; D003907:Dexamethasone; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011972:Receptor, Insulin