Defects of insulin's signal transduction in old rat livers.
Aging is associated with a postbinding defect in insulin action, leading to increased glucose intolerance and occasional diabetes. To determine whether defects in insulin receptor kinase (IRK) activity or in the phosphorylation of its physiological substrates underlie this age-related phenomenon, young (2-3 months old) and old (24-27 months old) Wistar rats were studied. When assayed in vitro, the hepatic IRK activities of noninjected old and young rats were comparable. Thirty seconds after the injection of insulin, the hepatic IRK activity of young rats increased 7- to 10-fold in a dose-dependent manner, with maximal effects obtained in rats injected with 20 mg insulin. By contrast, old animals exhibited impaired in vivo activation, with a mean 50% reduction in maximal IRK activity. When the rats were grouped into animals with mild (20%), moderate (50%), and severe (80%) reductions in maximal IRK activity, it was found that the mild and moderate defects could be reversed once the receptors were subjected to extensive autophosphorylation in vitro. The severe form of the defect was essentially irreversible and could not be corrected by phosphorylation in vitro. Immunoblotting with anti P-Tyr antibodies revealed that the reduced IRK activity in the old animals correlated with reduced intrahepatic tyrosine phosphorylation of the beta-subunit of the insulin receptor and pp180, a putative substrate of IRK. We, therefore, conclude that glucose intolerance in aging could be attributed at least in part to acquired defects in the in vivo activation of the hepatic IRK, which results in reduced phosphorylation of its putative substrate pp180.
Nadiv
O
O
Department of Chemical Immunology, Weizmann Institute of Science, Rehovot, Israel.
Cohen
O
O
Zick
Y
Y
D000375:Aging / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D005947:Glucose / Q000494:pharmacology; D015151:Immunoblotting; D007275:Injections, Intravenous; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000201:enzymology / Q000502:physiology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D011972:Receptor, Insulin; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism
D007328:Insulin; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D005947:Glucose