Muscle lipid accumulation and protein kinase C activation in the insulin-resistant chronically glucose-infused rat.
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.
Laybutt
D R
DR
Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
Schmitz-Peiffer
C
C
Saha
A K
AK
Ruderman
N B
NB
Biden
T J
TJ
Kraegen
E W
EW
D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose; D005947:Glucose / Q000494:pharmacology*; D006943:Hyperglycemia / Q000378:metabolism; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D007527:Isoenzymes / Q000032:analysis / Q000378:metabolism*; D050356:Lipid Metabolism; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism; D018482:Muscle, Skeletal / Q000201:enzymology*; D011493:Protein Kinase C / Q000032:analysis / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D000074121:Protein Kinase C-theta; D051381:Rats; D017208:Rats, Wistar; D013347:Subcellular Fractions / Q000201:enzymology
D000214:Acyl Coenzyme A; D001786:Blood Glucose; D007328:Insulin; D007527:Isoenzymes; D008316:Malonyl Coenzyme A; C497260:Prkcd protein, rat; C497257:Prkce protein, rat; C489591:Prkcq protein, rat; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D000074121:Protein Kinase C-theta; D005947:Glucose