Abstract
Acetyl-CoA carboxylase (ACC) catalyzes the production of malonyl-CoA which may act as a metabolic coupling factor in nutrient-induced insulin release. We have studied the long term regulation of ACC by nutrients using the cell line INS-1. Glucose, from 5 to 20 mM, elicited a 15-fold increase in ACC mRNA. The effect was detected after 4 h and reached a maximum by 24 h. ACC protein accumulation followed that of ACC mRNA, and glucose did not modify the half-life of the ACC transcript. Glucose caused a dose-dependent rise in the glucose 6-phosphate content of INS-1 cells. 2-Deoxyglucose, which is phosphorylated by glucokinase but is not further metabolized, induced ACC mRNA. The effect of glucose was blocked by the glucokinase inhibitors mannoheptulose and glucosamine and was not mimicked by the 3-O-methyl or 6-deoxy analogues of glucose, which are not phosphorylated. Activation of the Ca2+, cAMP, and C-kinase pathways with high K+, forskolin, and phorbol 12-myristate 13 acetate, respectively, caused insulin release but not ACC mRNA induction. Basal insulin release, at 5 mM glucose, correlated with the ACC protein content of INS-1 cells preincubated for 24 h at various glucose concentrations. In conclusion, glucose is a potent inducer of the ACC gene, and glucose 6-phosphate may mediate its effect. Different signaling systems mediate the action of glucose on insulin release and ACC gene expression. The data strengthen the view that ACC plays a pivotal role in nutrient-induced insulin release.
Highlights
Acetyl-coA carboxylase (ACC)catalyzes the produc- of some key regulatory enzymes of intermediate metabolism tion of malonyl-CoAwhichmay act as a metabolic are modulated by this carbohydrate in the0-cell
As a first step toward a better understandingof the action of various nutrients on the expression of metabolic enzymes involved in the pathway of malonyl-CoA formation from glucose, a pathway we believe plays important role in P-cell fuel sensing [13,14,15,26],we chose tostudythe action of glucose on acetyl-coA carboxylase (ACC) gene expression
Using INS-1cells as a model, we show that glucose in the physiological range is a major regulator of the ACC gene in @-cellsand that the signal transductionsystems implicated in ACC induction are entirely different from those involved in insulin secretion
Summary
Glucose has pleiotropic actions on the pancreatic &cell. An elevation in plasma glucose promotes the release of insulin [1, 2] and activates insulin gene transcription [3]and proinsulin mRNA translation [3]. Various insulin secreting cell lines that have been used to date do not show biological actions of glucose in the physiologicalrange and may not be appropriate models forstudies of the long term effects of glucose on the pancreatic &cell. Glucose in the physiological range promotes insulin secretion [23] and increases the cellular redox state [24] at least in partthrough Ca” activation of mitochondrial glycerol-phosphatedehydrobe hereby marked “advertisement” in accordance with 18 U.S.C. genase [25]. This cell line may provide an interesting.
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