DIFFERENTIATION OF GLUCOSE TOXICITY FROM BETA-CELL EXHAUSTION DURING THE EVOLUTION OF DEFECTIVE INSULIN GENE-EXPRESSION IN THE PANCREATIC-ISLET CELL-LINE, HIT-T15

Chronic exposure of HIT-TIS cells to supraphysiologic glucose concentr ation diminishes insulin gene expression and decreased binding of two critical insulin gene transcription factors, STF-1 and RIPE-3b1 activa tor. To distinguish whether these changes are caused by glucose toxici ty or beta cell exhaustion, HIT-TIS cells grown from passage 75 throug h 99 in media containing 11.1 mM glucose were switched to 0.8 mM gluco se at passage 100. They regained binding of STF-1 and RDPE-3b1 activat or and had a partial but minimal return of insulin mRNA expression. In a second study, inclusion of somatostatin in the media-containing 11. 1 mM glucose inhibited insulin secretion; however, despite this protec tion against beta cell exhaustion, dramatic decreases in insulin gene expression, STF-1 and RTPE-3b1 binding, and insulin gene promoter acti vity still occurred. These data indicate that the glucotoxic effects c aused by chronic exposure to supraphysiologic concentration of glucose are only minimally reversible and that they are not due simply to bet a cell exhaustion. These observations carry with them the clinical imp lication that Type II diabetic patients who remain hyperglycemic for p rolonged periods may have secondary glucose toxic effects on the beta cell that could lead to defective insulin gene expression and worsenin g of hyperglycemia.