GLUCOSE REGULATES ACETYL-COA CARBOXYLASE GENE-EXPRESSION IN A PANCREATIC BETA-CELL LINE (INS-1)

Acetyl-CoA carboxylase (ACC) catalyzes the production of malonyl-CoA w hich may act as a metabolic coupling factor in nutrient-induced insuli n release. We have studied the long term regulation of ACC by nutrient s using the cell line INS-1. Glucose, from 5 to 20 mm, elicited a 15-f old increase in ACC mRNA. The effect was detected after 4 h and reache d a maximum by 24 h. ACC protein accumulation followed that of ACC mRN A, and glucose did not modify the half-life of the ACC transcript. Glu cose caused a dose-dependent rise in the glucose 6-phosphate content o f INS-1 cells. 2-Deoxyglucose, which is phosphorylated by glucokinase but is not further metabolized, induced ACC mRNA. The effect of glucos e was blocked by the glucokinase inhibitors mannoheptulose and glucosa mine and was not mimicked by the 3-O-methyl or 6-deoxy analogues of gl ucose, which are not phosphorylated. Activation of the Ca2+, cAMP, and C-kinase pathways with high K+, forskolin, and phorbol 12-myristate 1 3 acetate, respectively, caused insulin release but not ACC mRNA induc tion. Basal insulin release, at 5 mm glucose, correlated with the ACC protein content of INS-1 cells preincubated for 24 h at various glucos e concentrations. In conclusion, glucose is a potent inducer of the AC C gene, and glucose 6-phosphate may mediate its effect. Different sign aling systems mediate the action of glucose on insulin release and ACC gene expression. The data strengthen the view that ACC plays a pivota l role in nutrient-induced insulin release.