Effects of free fatty acids on beta-cell functions: A possible involvementof peroxisome proliferator-activated receptors alpha or pancreatic/duodenal homeobox

It is well known that acute administration of fatty acids enhances insulin release from beta cells, although chronic exposure to fatty acids inhibits insulin release (lipotoxicity). The mechanism for these reciprocal effects of fatty acids on insulin release remains to be elucidated. The present stu dy was performed to investigate the effects of fatty acids on gene expressi on related to glucose metabolism or insulin biosynthesis. In islets culture d with palmitate for 8 hours, glucose-induced insulin release was enhanced together with increment of pyruvate carboxylase (PC) mRNA or peroxisome pro liferator-activated receptors (PPAR)alpha. In contrast, by extending the cu lture period up to 48 hours, glucose-induced insulin release or islet insul in content was significantly impaired by the coexistence of palmitate. Conc omitantly, PC, PPAR alpha, GLUT-2, glucokinase (GK), preproinsulin, or panc reatic/duodenal homeobox-1 (PDX-1) mRNA were significantly suppressed in th ose islets cultured for 48 hours with palmitate. These data may imply that during short-term culture period palmitate promotes PPARa gene expression, which enhances PC mRNA expression leading to the enhancement of insulin rel ease, whereas during long-term culture period, palmitate rather inhibits PP AR alpha mRNA, which reduces PC mRNA expression. Furthermore, palmitate red uces GLUT-2. GK, or preproinsulin mRNA expression probably through the inhi bition of PDX-1 mRNA. Copyright (C) 2001 by W.B. Saunders Company.