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 mumol/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.
Hettiarachchi
M
M
Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
Chalkley
S
S
Furler
S M
SM
Choong
Y S
YS
Heller
M
M
Cooper
G J
GJ
Kraegen
E W
EW
D000214:Acyl Coenzyme A / Q000378:metabolism*; D000682:Amyloid / Q000037:antagonists & inhibitors / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D015309:Glucose Clamp Technique; D005990:Glycerol / Q000097:blood; D019382:Human Growth Hormone / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D007333:Insulin Resistance; D058228:Islet Amyloid Polypeptide; D008099:Liver / Q000187:drug effects / Q000502:physiology*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D012044:Regression Analysis; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*
D000214:Acyl Coenzyme A; D000682:Amyloid; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments; D014280:Triglycerides; C109255:amylin (8-37); D019382:Human Growth Hormone; D005990:Glycerol