Glucose-induced preproinsulin gene expression is inhibited by the free fatty acid palmitate

Prolonged exposure to elevated FFA levels has been shown to induce peripher al insulin resistance and to alter the beta-cell secretory response to gluc ose. To investigate the effects of FFAs on preproinsulin gene expression, w e measured insulin release, cell content, and messenger RNA (mRNA) levels i n rat islets after a 24-h exposure to 1 mM palmitate. Insulin release incre ased at all glucose concentrations studied; in contrast, preproinsulin mRNA levels were specifically reduced by palmitate at high glucose with a decre ase in insulin stores, suggesting that palmitate inhibits the glucose-stimu lated increase in preproinsulin gene expression. The mechanisms by which palmitate affects preproinsulin gene expression imp licate both preproinsulin mRNA stability and transcription, as suggested by an actinomycin D decay assay, quantification of primary preproinsulin tran scripts, and transient transfection experiments in Min6 cells. Metabolism o f palmitate is not required to obtain these effects, inasmuch as they can b e reproduced by 2-bromopalmitate. However, oleate and linoleate did not sig nificantly influence preproinsulin mRNA levels. We conclude that insulin re lease and preproinsulin gene expression are not coordinately regulated by p almitate and that chronically elevated FFA levels may interfere with beta-c ell function and be implicated in the development of noninsulin-dependent d iabetes.