Inhibition of insulin gene expression by long-term exposure of pancreatic beta cells to palmitate is dependent on the presence of a stimulatory glucose concentration

Long-term exposure of pancreatic beta cells to elevated levels of fatty aci ds (FAs) impairs glucose-induced insulin secretion. However, the effects of FAs on insulin gene expression are controversial. We hypothesized that FAs adversely affect insulin gene expression only in the presence of elevated glucose concentrations. To test this hypothesis, isolated rat Islets were c ultured for up to 1 week in the presence of 2.8 or 16.7 mmol/L glucose with or without 0.5 mmol/L palmitate. Insulin release, insulin content, and ins ulin mRNA levels were determined at the end of each culture period. Palmita te increased insulin release tit each time point independently of the gluco se concentration. In contrast, insulin content was unchanged in the presenc e of palmitate at 2.8 mmol/L glucose, hut was markedly decreased in the pre sence of 0.5 mmol/L palmitate and 16.7 mmol/L glucose after 2 3, and 7 days of culture. In the presence of a basal concentration of glucose, insulin m RNA levels were transiently increased by palmitate at 24 hours but were unc hanged thereafter. In contrast, palmitate significantly inhibited the stimu latory effects of 16.7 mmol/L glucose on insulin mRNA levels after 2, 3, an d 7 days. To determine whether the inhibitory effect of palmitate on glucos e-stimulated insulin mRNA levels was associated with decreased insulin prom oter activity, HIT-T15 cells were cultured for 24 hours in 11.1 mmol/L gluc ose in the presence or absence of palmitate, and insulin gene promoter acti vity was measured in transient transfection experiments using the insulin p romoter-reporter construct INSLUC. INSLUC activity was decreased more than 2-fold after 24 hours of exposure to 0.5 mmol/L palmitate. We conclude that long-term exposure of pancreatic beta cells to palmitate decreases insulin gene expression only in the presence of elevated glucose concentrations. i n part through inhibition of insulin gene promoter activity. Copyright (C) 2000 by W.B. Saunders Company.