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 loss of GLUT2 in normal islets exposed to
hyperglycemia, we performed studies on Sprague Dawley rats 4 weeks after a 90% partial
pancreatectomy (Px), a well-characterized model of
hyperglycemia. GLUT2 immunofluorescence 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 decreased to a similar extent. Islet GLUT2 and
insulin mRNA were measured with quantitative
reverse transcriptase-polymerase chain reaction. The level of GLUT2
mRNA from Px islets was 24 +/- 4% of that of islets from
sham-operated controls; similar results were obtained for
insulin. Because both these beta-cell-specific messages were reduced, we analyzed the Px islets for the pancreas-duodenum-specific
transcription factor IDX-1(IPF-1, STF-1, PDX-1)
protein. It was markedly reduced (approximately 80%) in islets from the Px rats. These data suggest that 1) the loss of
GLUT2 protein associated with
hyperglycemia is at least partially explained by reduced levels of the GLUT2 gene transcripts; 2) the reduction of beta-cell
insulin content during chronic
hyperglycemia may not be completely due to degranulation (reduced levels of gene transcripts may play a role); and 3) the reduction in the
transcription factor IDX-1 raises the possibility that dysregulation of
transcription factors may contribute to the abnormal beta-cell function found in states of chronic
hyperglycemia.