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1 Garvan Institute of Medical Research, Sydney, NSW, Australia; Faculty of Medicine, University of NSW, Sydney, NSW, Australia
2 School of Medicine, Boston University, Boston, MA, USA
3 Garvan Institute of Medical Research, Sydney, NSW, Australia
* To whom correspondence should be addressed. E-mail: e.kraegen{at}garvan.org.au.
Glucose infusion in rats for 1-4 days results in insulin resistance and increased triglyceride, whole-tissue long chain fatty acyl CoA (LCACoA), and malonyl CoA content in red skeletal muscle. Despite this, the relationship 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 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 iv glucose infusion in rats for 3 or 5h; then euglycemia was restored and a 2h 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 5h, and was associated with a twofold increase in diacylglycerol (DAG) and malonyl CoA content and a 50% decrease in AMPK and ACC phosphorylation and AMPK activity. White quadriceps showed qualitatively similar changes but without decreases in AMPK or ACC phosphorylation. Triglyceride mass was increased at 5h only in liver and whole-tissue LCACoA 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 LCACoA content in any tissue or triglyceride in muscle, although both are observed at later times.
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