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Am J Physiol. 1999 Dec;277(6):E1070-6. doi: 10.1152/ajpendo.1999.277.6.E1070.

Muscle lipid accumulation and protein kinase C activation in the insulin-resistant chronically glucose-infused rat.

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1
Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

Abstract

Chronic glucose infusion results in hyperinsulinemia and causes lipid accumulation and insulin resistance in rat muscle. To examine possible mechanisms for the insulin resistance, alterations in malonyl-CoA and long-chain acyl-CoA (LCA-CoA) concentration and the distribution of protein kinase C (PKC) isozymes, putative links between muscle lipids and insulin resistance, were determined. Cannulated rats were infused with glucose (40 mg. kg(-1). min(-1)) for 1 or 4 days. This increased red quadriceps muscle LCA-CoA content (sum of 6 species) by 1.3-fold at 1 day and 1.4-fold at 4 days vs. saline-infused controls (both P < 0.001 vs. control). The concentration of malonyl-CoA was also increased (1.7-fold at 1 day, P < 0.01, and 2.2-fold at 4 days, P < 0.001 vs. control), suggesting an even greater increase in cytosolic LCA-CoA. The ratio of membrane to cytosolic PKC-epsilon was increased twofold in the red gastrocnemius after both 1 and 4 days, suggesting chronic activation. No changes were observed for PKC-alpha, -delta, and -theta. We conclude that LCA-CoAs accumulate in muscle during chronic glucose infusion, consistent with a malonyl-CoA-induced inhibition of fatty acid oxidation (reverse glucose-fatty acid cycle). Accumulation of LCA-CoAs could play a role in the generation of muscle insulin resistance by glucose oversupply, either directly or via chronic activation of PKC-epsilon.

[Indexed for MEDLINE]

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