title: Malonyl coenzyme A and the regulation of functional carnitine palmitoyltransferase-1 activity and fat oxidation in human skeletal muscle.
abstract: Physiological hyperglycemia with hyperinsulinemia reduces fat oxidation in skeletal muscle. The mechanism responsible for this decrease in fat oxidation in human muscle is not known and may contribute to the development of insulin resistance. We hypothesized that the transfer of long-chain fatty acids (LCFAs) into the mitochondria via carnitine palmitoyltransferase-1 (CPT-1) is inhibited by increased malonyl coenzyme A (malonyl-CoA) (a known potent inhibitor of CPT-1) in human muscle during hyperglycemia with hyperinsulinemia. We studied six healthy subjects after an overnight fast and during an induced 5-hour period of hyperglycemia with hyperinsulinemia. Muscle fatty acid oxidation was calculated using stable isotope methodology combined with blood sampling from the femoral artery and vein of one leg. Muscle functional CPT-1 activity was assessed by concurrently infusing an LCFA tracer and a CPT-independent medium-chain fatty acid tracer. Muscle biopsies were obtained from the vastus lateralis after the periods of fasting and hyperglycemia with hyperinsulinemia. Hyperglycemia with hyperinsulinemia decreased LCFA oxidation, but had no effect on LCFA uptake or medium-chain fatty acid oxidation across the leg. Malonyl-CoA concentration significantly increased from 0.13 +/- 0.01 to 0.35 +/- 0.07 nmol/g during hyperglycemia with hyperinsulinemia. We conclude that hyperglycemia with hyperinsulinemia increases malonyl-CoA, inhibits functional CPT-1 activity, and shunts LCFA away from oxidation and toward storage in human muscle.
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas, USA. blakeras@usc.edu
authors.forename: Blake B
authors.initials: BB
authors.lastname: Rasmussen
authors.forename: Ulf C
authors.initials: UC
authors.lastname: Holmbäck
authors.forename: Elena
authors.initials: E
authors.lastname: Volpi
authors.forename: Beatrice
authors.initials: B
authors.lastname: Morio-Liondore
authors.forename: Douglas
authors.initials: D
authors.lastname: Paddon-Jones
authors.forename: Robert R
authors.initials: RR
authors.lastname: Wolfe
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism*; D001824:Body Constitution; D002153:Calorimetry, Indirect / Q000379:methods; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D005227:Fatty Acids / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology; D006946:Hyperinsulinism / Q000503:physiopathology; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D012016:Reference Values; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D014280:Triglycerides; D008316:Malonyl Coenzyme A; D002784:Cholesterol; D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose