REDUCED INSULIN, GLUT2, AND IDX-1 IN BETA-CELLS AFTER PARTIAL PANCREATECTOMY

Reduction of GLUT2 is associated with loss of glucose-induced insulin secretion in genetic and chemical diabetes and in transplanted islets exposed to chronic hyperglycemia, To examine the mechanisms for this l oss of GLUT2 in normal islets exposed to hyperglycemia, we performed s tudies on Sprague Dawley rats 4 weeks after a 90% partial pancreatecto my (Px), a well-characterized model of hyperglycemia. GLUT2 immunofluo rescence in the beta-cell of Px rats was greatly reduced. Western blot analysis of homogenates of isolated Px islets also showed a reduction in GLUT2 protein; densitometry measurements were 36 +/- 3% of values from islets of sham-operated controls. Insulin protein levels were dec reased to a similar extent. Islet GLUT2 and insulin mRNA were measured with quantitative reverse transcriptase-polymerase chain reaction. Th e level of GLUT2 mRNA from Px islets was 24 +/- 4% of that of islets f rom sham-operated controls; similar results were obtained for insulin. Because both these beta-cell-specific messages mere reduced, we analy zed the Px islets for the pancreas-duodenum-specific transcription fac tor IDX-1 (IPF-1, STF-1, PDX-1) protein. It was markedly reduced (simi lar to 80%) in islets from the Px rats. These data suggest that 1) the loss of GLUT2 protein associated with hyperglycemia is at least parti ally explained by reduced levels of the GLUT2 gene transcripts; 2) the reduction of beta-cell insulin content during chronic hyperqlycemia m ay not be completely due to degranulation (reduced levels of gene tran scripts may play a role); and 3) the reduction in the transcription fa ctor IDX-1 raises the possibility that dysregulation of transcription factors may contribute to the abnormal beta-cell function found in sta tes of chronic hyperglycemia.