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37) enhances insulin action and alters lipid
metabolism in normal and insulin-resistant rats
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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