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Am J Physiol Endocrinol Metab 297: E67-E75, 2009. First published April 14, 2009; doi:10.1152/ajpendo.90945.2008
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Lipid and insulin infusion-induced skeletal muscle insulin resistance is likely due to metabolic feedback and not changes in IRS-1, Akt, or AS160 phosphorylation

Andrew J. Hoy,1 Amanda E. Brandon,1 Nigel Turner,1 Matthew J. Watt,2 Clinton R. Bruce,1,3 Gregory J. Cooney,1,4 and Edward W. Kraegen1,4

1Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Darlinghurst, and 4Faculty of Medicine, University of New South Wales, Sydney, New South Wales; 2Department of Physiology, Monash University, Clayton, and 3Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia

Submitted 23 November 2008 ; accepted in final form 10 April 2009

Type 2 diabetes is characterized by hyperlipidemia, hyperinsulinemia, and insulin resistance. The aim of this study was to investigate whether acute hyperlipidemia-induced insulin resistance in the presence of hyperinsulinemia was due to defective insulin signaling. Hyperinsulinemia (~300 mU/l) with hyperlipidemia or glycerol (control) was produced in cannulated male Wistar rats for 0.5, 1 h, 3 h, or 5 h. The glucose infusion rate required to maintain euglycemia was significantly reduced by 3 h with lipid infusion and was further reduced after 5 h of infusion, with no difference in plasma insulin levels, indicating development of insulin resistance. Consistent with this finding, in vivo skeletal muscle glucose uptake (31%, P < 0.05) and glycogen synthesis rate (38%, P < 0.02) were significantly reduced after 5 h compared with 3 h of lipid infusion. Despite the development of insulin resistance, there was no difference in the phosphorylation state of multiple insulin-signaling intermediates or muscle diacylglyceride and ceramide content over the same time course. However, there was an increase in cumulative exposure to long-chain acyl-CoA (70%) with lipid infusion. Interestingly, although muscle pyruvate dehydrogenase kinase 4 protein content was decreased in hyperinsulinemic glycerol-infused rats, this decrease was blunted in muscle from hyperinsulinemic lipid-infused rats. Decreased pyruvate dehydrogenase complex activity was also observed in lipid- and insulin-infused animals (43%). Overall, these results suggest that acute reductions in muscle glucose metabolism in rats with hyperlipidemia and hyperinsulinemia are more likely a result of substrate competition than a significant early defect in insulin action or signaling.

lipotoxicity; hyperlipidemia; in vivo metabolism; long-chain acyl-CoA; pyruvate dehydrogenase kinase 4


Address for reprint requests and other correspondence: A. J. Hoy, Biology of Lipid Metabolism Group, Dept. of Physiology, Bldg. 13F, Monash Univ., Clayton, Victoria 3800, Australia (e-mail: andrew.hoy{at}med.monash.edu.au)






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