Alteration of the malonyl-CoA/carnitine palmitoyltransferase I interaction in the beta-cell impairs glucose-induced insulin secretion.
Carnitine palmitoyltransferase I, which is expressed in the pancreas as the liver isoform (LCPTI), catalyzes the rate-limiting step in the transport of fatty acids into the mitochondria for their oxidation. Malonyl-CoA derived from glucose metabolism regulates fatty acid oxidation by inhibiting LCPTI. To examine directly whether the availability of long-chain fatty acyl-CoA (LC-CoA) affects the regulation of insulin secretion in the beta-cell and whether malonyl-CoA may act as a metabolic coupling factor in the beta-cell, we infected INS(832/13) cells and rat islets with an adenovirus encoding a mutant form of LCPTI (Ad-LCPTI M593S) that is insensitive to malonyl-CoA. In Ad-LCPTI M593S-infected INS(832/13) cells, LCPTI activity increased sixfold. This was associated with enhanced fatty acid oxidation, at any glucose concentration, and a 60% suppression of glucose-stimulated insulin secretion (GSIS). In isolated rat islets in which LCPTI M593S was overexpressed, GSIS decreased 40%. The impairment of GSIS in Ad-LCPTI M593S-infected INS(832/13) cells was not recovered when cells were incubated with 0.25 mmol/l palmitate, indicating the deep metabolic influence of a nonregulated fatty acid oxidation system. At high glucose concentration, overexpression of a malonyl-CoA-insensitive form of LCPTI reduced partitioning of exogenous palmitate into lipid esterification products and decreased protein kinase C activation. Moreover, LCPTI M593S expression impaired K(ATP) channel-independent GSIS in INS(832/13) cells. The LCPTI M593S mutant caused more pronounced alterations in GSIS and lipid partitioning (fat oxidation, esterification, and the level of nonesterified palmitate) than LCPTI wt in INS(832/13) cells that were transduced with these constructs. The results provide direct support for the hypothesis that the malonyl-CoA/CPTI interaction is a component of a metabolic signaling network that controls insulin secretion.
Herrero
Laura
L
Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, Diagonal 643, E-08028 Barcelona, Spain.
Rubí
Blanca
B
Sebastián
David
D
Serra
Dolors
D
Asins
Guillermina
G
Maechler
Pierre
P
Prentki
Marc
M
Hegardt
Fausto G
FG
D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008316:Malonyl Coenzyme A / Q000378:metabolism* / Q000494:pharmacology; D010190:Pancreatic Neoplasms; D051381:Rats
D007328:Insulin; D008316:Malonyl Coenzyme A; D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose