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Department of Laboratory Medicine and Pathobiology, 1 King's College Circle, University of Toronto, Toronto, Canada M5S 1A8¹ School of Kinesiology and Health Science, York University, Ontario, Canada M3J1 P3² Department of Physiology, 1 King's College Circle, University of Toronto, Toronto, Canada M5S 1A8³ Clinical Islet Transplant Program, Department of Transplant Services, University of Alberta Hospital, Edmonton, Alberta, Canada T6G 2C8⁴ Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2E1

(Correspondence should be addressed to M B Wheeler; Email: michael.wheeler{at}utoronto.ca; M Rozakis-Adcock; Email: maria.rozakis{at}utoronto.ca)

The aim of this study was to assess the effects of chronic free fatty acid (FFA) exposure on gene expression and the functional state of human pancreatic islets. Chronic exposure of islets to oleate (OA) resulted in a significant reduction in glucose-stimulated insulin secretion (GSIS) compared with control (466±82 vs 234±57 ng/µg DNA, P<0.05). OA treatment also led to reduction in total insulin content of the islets (17 609±3816 vs 10 599±3876 ng insulin/µg DNA) and to an increase in the rate of reactive oxygen species (ROS) generation. Interestingly, the suppressive effects of OA on biosynthesis and secretion of insulin were accompanied by alteration in the expression of 40 genes, as determined by microarray analysis and subsequent qPCR validation. The majority of genes regulated by OA encoded metabolic enzymes. The expression of enzymes involved in oxidative defense was elevated, indicating a link between ROS generation and antioxidant defense activation. Additionally, pretreatment of human islets with OA led to a significant increase (30%) in the rate of oxidation of this fatty acid and to a significant decrease (75%) in glucose oxidation. Importantly, individual analysis of gene clusters from the islets of all donors revealed the induction of genes involved in inflammation and immunity, which provides further evidence that FFA are risk factors for the development of type 2 diabetes. In summary, our data indicate that chronic exposure of human islets to FFA activates inflammatory and metabolic pathways that lead to oxidative stress, reduced β-cell insulin content, and inhibition of GSIS.