RAT AMYLIN-(8-37) ENHANCES INSULIN ACTION AND ALTERS LIPID-METABOLISMIN 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-re sistant, human growth hormone (hGH)-infused rats. Fasting conscious ra ts were infused with saline or hGH, each with and without amylin-(8-37 ) (0.125 mu mol/h), over 5.75 h. At 3.75 h, a hyperinsulinemic (100 mU /l) clamp with bolus 2-deoxy-D-[H-3]glucose and [C-14]glucose was star ted. 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 insu lin sensitivity (P < 0.05) in both saline-and hGH-infused rats. Amylin -(8-37) corrected hGH-induced liver insulin resistance, increased basa l plasma triglycerides and lowered plasma nonesterified fatty acids in both groups, and reduced muscle triglyceride and total long-chain acy l-CoA content in saline-treated rats (P < 0.05). In isolated soleus mu scle, amylin-(8-37) blocked amylin-induced inhibition of glycogen synt hesis but had no effect in the absence of amylin. Thus 1) hyperamyline mia accompanies insulin resistance induced by hGH infusion; 2) amylin- (8-37) increases whole body and muscle insulin sensitivity and consist ently reduces basal insulin levels in normal and hGH-induced insulin-r esistant rats; and 3) amylin-(8-37) elicits a significant alteration o f 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.