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This Article Full Text Full Text (PDF) All Versions of this Article: 290/3/E471    most recent 00316.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (13) Citing Articles via Google Scholar Google Scholar Articles by Kraegen, E. W. Articles by Ruderman, N. B. Search for Related Content PubMed PubMed Citation Articles by Kraegen, E. W. Articles by Ruderman, N. B.

Increased malonyl-CoA and diacylglycerol content and reduced AMPK activity accompany insulin resistance induced by glucose infusion in muscle and liver of rats

¹Garvan Institute of Medical Research, Sydney; ²Faculty of Medicine, University of New South Wales, New South Wales, Australia; and ³Boston University School of Medicine, Boston, Massachusetts

Submitted 13 July 2005 ; accepted in final form 12 October 2005

Glucose infusion in rats for 1–4 days results in insulin resistance and increased triglyceride, whole tissue long-chain fatty acyl-CoA (LCA-CoA), and malonyl-CoA content in red skeletal muscle. Despite this, the relation between these alterations and the onset of insulin resistance has not been defined. We aimed to 1) identify whether the changes in these lipids and of diacylglycerol (DAG) precede or accompany the onset of insulin resistance in glucose-infused rats, 2) determine whether the insulin resistance is associated with alterations in AMP-activated protein kinase (AMPK), and 3) assess whether similar changes occur in liver and in muscle. Hyperglycemia (17–18 mM) was maintained by intravenous glucose infusion in rats for 3 or 5 h; then euglycemia was restored and a 2-h hyperinsulinemic clamp was performed. Significant (P < 0.01) muscle and liver insulin resistance first appeared in red quadriceps and liver of the glucose-infused group at 5 h and was associated with a twofold increase in DAG and malonyl-CoA content and a 50% decrease in AMPK and acetyl-CoA carboxylase (ACC) phosphorylation and AMPK activity. White quadriceps showed qualitatively similar changes but without decreases in AMPK or ACC phosphorylation. Triglyceride mass was increased at 5 h only in liver, and whole tissue LCA-CoA content was not increased in liver or either muscle type. We conclude that the onset of insulin resistance induced by glucose oversupply correlates temporally with increases in malonyl-CoA and DAG content in all three tissues and with reduced AMPK phosphorylation and activity in red muscle and liver. In contrast, it was not associated with increased whole tissue LCA-CoA content in any tissue or triglyceride in muscle, although both are observed at later times.

adenosine monophosphate-activated protein kinase; hyperglycemia; glucose clamp; triglyceride; long-chain acyl-coenzyme A; glucotoxicity

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