Free fatty acid-induced inhibition of glucose and insulin-like growth factor I-induced deoxyribonucleic acid synthesis in the pancreatic beta-cell line INS-1

Pancreatic beta -cell mitogenesis is increased by insulin-like growth facto r I(IGF-I) in a glucose-dependent manner. In this study it was found that a lternative beta -cell nutrient fuels to glucose, pyruvate, and glutamine/le ucine independently induced and provided a platform for IGF-I to induce INS -1 cell DNA synthesis in the absence of serum. In contrast, long chain FFA (greater than or equal toC(12)) inhibited 15 mM glucose-induced [H-3]thymid ine incorporation (+/-10 nM IGF-I) by 95% or more within 24 h above 0.2 mM FFA complexed to 1% BSA (K-0.5 for palnitate/1% BSA = 65-85 muM for 24 h; t (0.5) for 0.2 mM palmitate/1% BSA = similar to6 h). FFA-mediated inhibition of glucose/IGF-I-induced beta -cell DNA synthesis was reversible, and FFA oxidation did not appear to he required, nor did FFA interfere with glucose metabolism in INS-1 cells. An examination of mitogenic signal transduction pathways in INS-1 cells revealed that glucose/IGF-I induction of early sig naling elements in SH2-containing protein (Shc)- and insulin receptor subst rate-1/2-mediated pathways leading to downstream mitogen-activated protein kinase and phosphoinositol 3'-kinase activation, were unaffected by FFA. Ho wever, glucose-/IGF-I-induced activation of protein kinase B (PKB) was sign ificantly inhibited, and protein kinase C-zeta was chronically activated by FFA. It is possible that FFA-mediated inhibition of beta -cell mitogenesis contributes to the reduction of beta -cell mass and the subsequent failure to compensate for peripheral insulin resistance in vivo that is key to the pathogenesis of obesity-linked diabetes.