LONG-TERM EXPOSURE OF BETA-INS CELLS TO HIGH GLUCOSE-CONCENTRATIONS INCREASES ANAPLEROSIS, LIPOGENESIS, AND LIPOGENIC GENE-EXPRESSION

Chronic exposure of pancreatic beta-cells to high glucose has pleiotro pic action on beta-cell function. In particular, it induces key glycol ytic genes, promotes glycogen deposition, and causes beta-cell prolife ration and altered insulin secretion characterized by sensitization to low glucose. Postglycolytic events, in particular, anaplerosis and li pid signaling, are thought to be implicated in beta-cell activation by glucose. To understand the biochemical nature of the beta-cell adapti ve process to hyperglycemia, we studied the regulation by glucose of l ipogenic genes in the beta-cell line INS-1. A 3-day exposure of cells to elevated glucose (5-25 mmol/l) increased the enzymatic activities o f fatty acid synthase 3-fold, acetyl-CoA carboxylase 30-fold, and mali c enzyme 1.3-fold. Pyruvate carboxylase and citrate lyase expression r emained constant. Similar observations mere made at the protein and mR NA levels except for malic enzyme mRNA, which did not vary. Metabolic gene expression changes mere associated with chronically elevated leve ls of citrate, malate, malonyl-CoA, and conversion of glucose carbon i nto lipids, even in cells that mere subsequently exposed to low glucos e. Similarly, fatty acid oxidation was suppressed and phospholipid and triglyceride synthesis was enhanced independently of the external glu cose concentration in cells preexposed to high glucose. The results su ggest that a coordinated induction of glycolytic and lipogenic genes i n conjunction with glycogen and triglyceride deposition, as well as in creased anaplerosis and altered lipid partitioning, contribute to the adaptive process to hyperglycemia and glucose sensitization of the bet a-cell.