GLUT2 IN PANCREATIC-ISLETS - CRUCIAL TARGET MOLECULE IN DIABETES-INDUCED WITH MULTIPLE LOW-DOSES OF STREPTOZOTOCIN IN MICE

In mice, diabetes can be induced by multiple low doses of streptozotoc in (MLD-STZ), i.e., 40 mg/kg body wt on each of 5 consecutive days. In this model, diabetes develops only when STZ induces both beta-cell to xicity and T-cell-dependent immune reactions. The target molecule(s) o f MLD-STZ-induced beta-cell toxicity are not known, however. In this s tudy, we report that GLUT2 is a target molecule for MLD-STZ toxicity. Ex vivo, a gradual decrement of both GLUT2 protein and mRNA expression was found in pancreatic islets isolated from MLD-STZ-treated C57BL/6 male mice, whereas mRNA expression of beta-actin, glucokinase, and pro insulin remained unaffected. Significant reduction of both GLUT2 prote in and mRNA expression was first noted 1 day after the third STZ injec tion, clearly preceding the onset of hyperglycemia. The extent of redu ction increased with the number of STZ injections administered and inc reased over time, after the last, i.e., fifth, STZ injection. The STZ- induced reduction of GLUT2 protein and mRNA was not due to an essentia l toss of beta-cells, because ex vivo, not only the total RNA yield an d protein content in isolated islets, but also proinsulin mRNA express ion, failed to differ significantly in the differently treated groups. Furthermore, islets isolated from MLD-STZ-treated donors responded to the nonglucose secretagogue arginine in a pattern similar to that of solvent-treated donors. Interestingly, the MLD-STZ-induced reduction o f both GLUT2 protein and mRNA was prevented by preinjecting mice with 5-thio-D-glucose before each STZ injection. Apparently, GLUT2 is a cru cial target molecule of MLD-STZ toxicity, and this toxicity seems to p recede the immune reactions against beta-cells.