Insulin and angiotensin II are hormones that play pivotal roles in the control of two vital and closely related systems, the metabolic and the circulatory systems, respectively. A failure in the proper action of each of these hormones results, to a variable degree, in the development of two highly prevalent and commonly overlapping diseases--diabetes mellitus and hypertension. In recent years, a series of studies has revealed a tight connection between the signal transduction pathways that mediate insulin and angiotensin II actions in target tissues. This molecular cross-talk occurs at multiple levels and plays an important role in phenomena that range from the action of anti-hypertensive drugs to cardiac hypertrophy and energy acquisition by the heart. At the extracellular level, the angiotensin-converting enzyme controls angiotensin II synthesis but also interferes with insulin signaling through the proper regulation of angiotensin II and through the accumulation of bradykinin. At an early intracellular level, angiotensin II, acting through JAK-2/IRS-1/PI3-kinase, JNK and ERK, may induce the serine phosphorylation and inhibition of key elements of the insulin-signaling pathway. Finally, by inducing the expression of the regulatory protein SOCS-3, angiotensin II may impose a late control on the insulin signal. We studied insulin sensitivity in lean and obese non-diabetic baboons and examine the underlying cellular/molecular mechanisms responsible for impaired insulin action in order to characterize a baboon model of insulin resistance. 20 baboons received a hyperinsulinemic euglycemic clamp, with skeletal muscle, visceral adipose and liver tissue biopsies at baseline, 30 and 120 min after insulin. Genes and protein expression of key molecules involved in the insulin signaling cascade (insulin receptor, IRS-1, p85, PI3 kinase, Akt1, Akt2, AS160, Glut1 and Glut 4) were sequenced and insulin-mediated changes were analyzed. The genes and protein sequences analyzed were found to have ~98% identity to those of man. Insulin-mediated changes in key signaling molecules were impaired both in muscle and adipose tissue in obese insulin-resistant compared to lean insulin-sensitive baboons. The baboon is a pertinent non-human primate model to examine the underlying cellular/molecular mechanisms responsible for insulin resistance and for the study of beta cell dysfunction and death and very early therapeutic interventions in T2DM.
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