Insulin resistance in rats harboring growth hormone-secreting tumors: decreased receptor number but increased kinase activity in liver.
Growth hormone (GH) is a potent antagonist of insulin action, and this resistance occurs primarily at a post-binding step(s). To elucidate the underlying mechanisms, the effects of chronic GH excess on the structure and function of insulin receptors partially purified from the liver were examined in rats harboring GH-secreting tumors. Insulin resistance was established in this animal model of GH hypersecretion by a hyperinsulinemic euglycemic clamp. Specific binding of 125I-insulin and receptor number were reduced in tumor animals by 40% and 62%, respectively, reflecting downregulation of the insulin receptor by hyperinsulinemia in these animals. Receptors from tumor animals showed a 50% increase in beta-subunit phosphorylation and in the kinase activity toward the synthetic polypeptide Glu4:Tyr1 when measured in vitro in the absence of insulin; however, the incremental stimulation by insulin (170 nmol/L) of the phosphorylation of either the beta-subunit or Glu4:Tyr1 was not different between control and experimental animals. There was no difference between the two groups in Glu4:Tyr1 phosphorylation measured after immunodepletion of receptors by antibodies to the insulin receptor, indicating that the observed alteration in the kinase activity of tumor animals was intrinsic to the insulin receptor. Exposure to chronic GH excess did not alter insulin receptor structure, as evidenced by electrophoretic mobility under reducing and nonreducing conditions. The enhanced basal kinase activity of the receptor from tumor animals may reflect a more highly phosphorylated state of the receptor (and hence elevated enzyme activity) in these animals due to elevated serum insulin levels. These results demonstrate that the hepatic insulin resistance in rats chronically exposed to GH excess is not due to impaired insulin receptor kinase activity.
Research Institute, Cedars-Sinai Medical Center, UCLA 90048.
N
N
Venkatesan
M B
MB
Davidson
D000818:Animals; D005260:Female; D013006:Growth Hormone / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000378:metabolism*; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism*; D051381:Rats; D011920:Rats, Inbred WF; D011972:Receptor, Insulin / Q000737:chemistry / Q000378:metabolism*
D007328:Insulin; D013006:Growth Hormone; D010770:Phosphotransferases; D011972:Receptor, Insulin