A role for malonyl-CoA in glucose-stimulated insulin secretion from clonal pancreatic beta-cells.
To gain insight into the relationship between acyl coenzyme A (CoA) esters and glucose-induced insulin release, acyl-CoA profiles were determined in clonal pancreatic beta-cells (HIT). A high sensitivity high performance liquid chromatography method was used to measure malonyl, succinyl, beta-hydroxy beta-methylglutaryl and acetyl-CoA esters and free CoASH. Malonyl-CoA content increased more than 3-fold following exposure of HIT cells to 10 mM glucose. The rise in malonyl-CoA, which preceded insulin secretion, was evident 2 min after exposure to glucose and was sustained for at least 30 min. The increase in malonyl-CoA was associated with inhibition of fatty acid oxidation, increased de novo lipid synthesis and a rise in diacylglycerol content. Succinyl-CoA levels, which may reflect anaplerotic influx into the citric acid cycle, were elevated in the presence of glucose. The concentration of acetyl-CoA and the ratio of free CoASH to acetyl-CoA was unchanged. The data are consistent with a metabolic model in which malonyl-CoA mediates the switch from fatty acid catabolism to lipid synthesis during glucose stimulation of beta-cells. We suggest that these changes in lipid metabolism, by leading to increased diacylglycerol synthesis or protein acylation could play a pivotal role in the regulation of the sustained phase of insulin secretion.
Corkey
B E
BE
Department of Biochemistry, Boston University School of Medicine, Massachusetts 02118.
Glennon
M C
MC
Chen
K S
KS
Deeney
J T
JT
Matschinsky
F M
FM
Prentki
M
M
D000214:Acyl Coenzyme A / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002999:Clone Cells; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D050356:Lipid Metabolism; D008316:Malonyl Coenzyme A / Q000378:metabolism*; D008954:Models, Biological; D019308:Palmitic Acid; D010169:Palmitic Acids / Q000378:metabolism
D000214:Acyl Coenzyme A; D007328:Insulin; D010169:Palmitic Acids; D019308:Palmitic Acid; D008316:Malonyl Coenzyme A; D005947:Glucose