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

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.