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Free Fatty Acid-Induced Inhibition of Glucose and Insulin-Like Growth Factor I-Induced Deoxyribonucleic Acid Synthesis in the Pancreatic ß-Cell Line INS-1¹

Pacific Northwest Research Institute, and Department of Pharmacology, University of Washington, Seattle, Washington 98122; and Research Division, Joslin Diabetes Center (M.G.M.), Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: Christopher J. Rhodes, Ph.D., Pacific Northwest Research Institute, 720 Broadway, Seattle, Washington 98122. E-mail: cjr{at}pnri.org

Pancreatic ß-cell mitogenesis is increased by insulin-like growth factor I (IGF-I) in a glucose-dependent manner. In this study it was found that alternative ß-cell nutrient fuels to glucose, pyruvate, and glutamine/leucine 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 (C₁₂) inhibited 15 mM glucose-induced [³H]thymidine 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 palmitate/1% BSA = 65–85 µM for 24 h; t_0.5 for 0.2 mM palmitate/1% BSA = 6 h). FFA-mediated inhibition of glucose/IGF-I-induced ß-cell DNA synthesis was reversible, and FFA oxidation did not appear to be 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 signaling elements in SH2-containing protein (Shc)- and insulin receptor substrate-1/2-mediated pathways leading to downstream mitogen-activated protein kinase and phosphoinositol 3'-kinase activation, were unaffected by FFA. However, glucose-/IGF-I-induced activation of protein kinase B (PKB) was significantly inhibited, and protein kinase C was chronically activated by FFA. It is possible that FFA-mediated inhibition of ß-cell mitogenesis contributes to the reduction of ß-cell mass and the subsequent failure to compensate for peripheral insulin resistance in vivo that is key to the pathogenesis of obesity-linked diabetes.

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