Free Fatty Acids Block Glucose-Induced β-Cell Proliferation in Mice by Inducing Cell Cycle Inhibitors p16 and p18

Pancreatic beta-cell proliferation is infrequent in adult humans and is not increased in type 2 diabetes despite obesity and insulin resistance, suggesting the existence of inhibitory factors. Free fatty acids (FFAs) may influence proliferation. In order to test whether FFAs restrict beta-cell proliferation in vivo, mice were intravenously infused with saline, Liposyn II, glucose, or both, continuously for 4 days. Lipid infusion did not alter basal beta-cell proliferation, but blocked glucose-stimulated proliferation, without inducing excess beta-cell death. In vitro exposure to FFAs inhibited proliferation in both primary mouse beta-cells and in rat insulinoma (INS-1) cells, indicating a direct effect on beta-cells. Two of the fatty acids present in Liposyn II, linoleic acid and palmitic acid, both reduced proliferation. FFAs did not interfere with cyclin D2 induction or nuclear localization by glucose, but increased expression of inhibitor of cyclin dependent kinase 4 (INK4) family cell cycle inhibitors p16 and p18. Knockdown of either p16 or p18 rescued the antiproliferative effect of FFAs. These data provide evidence for a novel antiproliferative form of beta-cell glucolipotoxicity: FFAs restrain glucose-stimulated beta-cell proliferation in vivo and in vitro through cell cycle inhibitors p16 and p18. If FFAs reduce proliferation induced by obesity and insulin resistance, targeting this pathway may lead to new treatment approaches to prevent diabetes. Diabetes 61:632-641, 2012