Glucose activation of acetyl-CoA carboxylase in association with insulin secretion in a pancreatic beta-cell line.
Malonyl-CoA, which is the unique product of acetyl-CoA carboxylase (ACC), may serve as a metabolic coupler in glucose-stimulated insulin secretion by pancreatic beta-cells. Therefore we examined if and how ACC is affected by glucose in association with insulin secretion. Glucose induces a rapid increase in ACC activity which is closely related to insulin secretion in a dose- and time-dependent manner. The acute effect of glucose in increasing ACC activity is caused by dephosphorylation of existing ACC molecules, without the production of new enzyme. Inhibition of ACC dephosphorylation and activation by the use of okadaic acid led to diminished glucose-mediated insulin secretion. Likewise, when ACC phosphorylation and inactivation were induced by the use of 5-amino 4-imidazole-carboxamide ribotide, an AMP analog and activator of 5'-AMP protein kinase, the glucose-induced insulin secretion was virtually nil. In the long term, glucose induced ACC and increased insulin secretion. In beta-cells, ACC gene expression is controlled by promoter II and glucose activated promoter II expression. ACC promoter I is not expressed in beta-cells. Maximum activation of ACC and insulin secretion by glucose in the short term occurred at 5 mM glucose. On the other hand, activation of the expression of ACC promoter II occurred when the cells were exposed to high glucose concentrations for a long period of time. Thus, we have shown that ACC, the only enzyme that produces malonyl-CoA, is activated by glucose; activation of ACC is accomplished by dephosphorylation in the short term and by induction of ACC by gene activation in the long term.
D000103:Acetyl-CoA Carboxylase / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D004789:Enzyme Activation; D015870:Gene Expression; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000032:analysis / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic
D017931:DNA Primers; D007328:Insulin; D000103:Acetyl-CoA Carboxylase; D005947:Glucose