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Am J Physiol Endocrinol Metab 273: E859-E867, 1997;
0193-1849/97 $5.00
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Vol. 273, Issue 5, E859-E867, November 1997

Rat amylin-(8---37) enhances insulin action and alters lipid metabolism in normal and insulin-resistant rats

M. Hettiarachchi1, S. Chalkley1, S. M. Furler1, Y.-S. Choong2, M. Heller2, G. J. S. Cooper2,3, and E. W. Kraegen1

1 Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; and 2 School of Biological Sciences and 3 Department of Medicine, School of Medicine, University of Auckland, Auckland 1, New Zealand

To clarify roles of amylin, we investigated metabolic responses to rat amylin-(8---37), a specific amylin antagonist, in normal and insulin-resistant, human growth hormone (hGH)-infused rats. Fasting conscious rats were infused with saline or hGH, each with and without amylin-(8---37) (0.125 µmol/h), over 5.75 h. At 3.75 h, a hyperinsulinemic (100 mU/l) clamp with bolus 2-deoxy-D-[3H]glucose and [14C]glucose was started. hGH infusion led to prompt (2- to 3-fold) basal hyperamylinemia (P < 0.02) and hyperinsulinemia. Amylin-(8---37) reduced plasma insulin (P < 0.001) and enhanced several measures of whole body and muscle insulin sensitivity (P < 0.05) in both saline- and hGH-infused rats. Amylin-(8---37) corrected hGH-induced liver insulin resistance, increased basal plasma triglycerides and lowered plasma nonesterified fatty acids in both groups, and reduced muscle triglyceride and total long-chain acyl-CoA content in saline-treated rats (P < 0.05). In isolated soleus muscle, amylin-(8---37) blocked amylin-induced inhibition of glycogen synthesis but had no effect in the absence of amylin. Thus 1) hyperamylinemia accompanies insulin resistance induced by hGH infusion; 2) amylin-(8---37) increases whole body and muscle insulin sensitivity and consistently reduces basal insulin levels in normal and hGH-induced insulin-resistant rats; and 3) amylin-(8---37) elicits a significant alteration of in vivo lipid metabolism. These findings support a role of amylin in modulating insulin action and suggest that this could be mediated by effects on lipid metabolism.

human growth hormone; euglycemic clamp; muscle; liver; triglycerides; long-chain acyl-CoA


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