THE LOSS OF GLUT2 EXPRESSION IN THE PANCREATIC BETA-CELLS OF DIABETICDB DB MICE IS ASSOCIATED WITH AN IMPAIRED DNA-BINDING ACTIVITY OF ISLET-SPECIFIC TRANS-ACTING FACTORS/

GLUT2 expression is reduced in the pancreatic beta-cells of several di abetic animals. The transcriptional control of the gene in beta-cells involves at least two islet-specific DNA-binding proteins, GTIIa and P DX-1, which also transactivates the insulin, somatostatin and glucokin ase genes. In this report, we assessed the DNA-binding activities of G TIIa and PDX-1 to their respective cis-elements of the GLUT2 promoter using nuclear extracts prepared from pancreatic islets of 12 week old db/db diabetic mice. We show that the decreased GLUT2 mRNA expression correlates with a decrease of the GTIIa DNA-binding activity, whereas the PDX-1 binding activity is increased. In these diabetic animals, in sulin mRNA expression remains normal. The adjunction of dexamethasone to isolated pancreatic islets, a treatment previously shown to decreas e PDX-1 expression in the insulin-secreting HIT-T15 cells, has no effe ct on the GTIIa and PDX-1 DNA-binding activities. These data suggest t hat the decreased activity of GTIIa, in contrast to PDX-1, may be a ma jor initial step in the development of the beta-cell dysfunction in th is model of diabetes. (C) 1997 Elsevier Science Ireland Ltd.