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Endocrinology Vol. 140, No. 3 1141-1150
Copyright © 1999 by The Endocrine Society

ARTICLES

In Vivo Insulin Signaling in the Myocardium of Streptozotocin-Diabetic Rats: Opposite Effects of Diabetes on Insulin Stimulation of Glycogen Synthase and c-Fos1

Ping H. Wang2, Abdulraof Almahfouz3, Francesco Giorgino4, Karen C. McCowen and Robert J. Smith

Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: Robert J. Smith, M.D., Research Division, Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02215. E-mail: smithr{at}joslab.harvard.edu

Diabetes induced by streptozotocin (STZ) in laboratory rats leads to impaired glucose metabolism in the heart and changes in myocardial contractile protein isoform expression and cardiac function. The purpose of this study was to investigate in vivo insulin signaling responses in the myocardium of STZ-diabetic rats. Insulin rapidly stimulated tyrosine phosphorylation of the insulin receptor, insulin receptor substrate-1 (IRS-1) and, to a lesser extent, IRS-2 in normal and diabetic myocardium. In diabetic rats, there was 2-fold higher insulin receptor content and insulin-stimulated receptor tyrosine phosphorylation in comparison with control rats. IRS-1 tyrosine phosphorylation also increased in STZ diabetes in spite of a decrease in IRS-1 content, resulting in a 4-fold higher ratio of phosphorylated to total IRS-1. This was associated with 2-fold higher IRS-1 precipitable phosphatidylinositide 3-kinase activity in diabetic animals. Insulin stimulation of glycogen synthase activity was significantly diminished in STZ diabetes, consistent with resistance to insulin in a step downstream from phosphatidylinositide 3-kinase activation. Under the same experimental conditions, there was a marked increase in insulin stimulation of myocardial c-fos messenger RNA content in diabetic animals in comparison with controls. These data demonstrate altered early steps in insulin signaling in STZ-diabetic rat myocardium. Consequent oppositely directed disturbances in growth regulatory and glucose regulatory responses to insulin may contribute to the development of myocardial functional abnormalities in this model of diabetes.




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