Ex vivo transcriptional profiling of human pancreatic islets following chronic exposure to monounsaturated fatty acids

Theaimofthisstudywastoassesstheeffectsofchronicfreefatty acid(FFA)exposureongeneexpressionandthefunctionalstate 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 (466G82 vs 234G57 ng/m gD NA,P!0 . 05). OA treatment also led to reduction in total insulin content of the islets (17 609G3816 vs 10 599G3876 ng insulin/mg 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,individualanalysisofgeneclustersfromtheisletsof all donors revealed the induction of genes involved in inflammation and immunity, which provides further evidence thatFFA are risk factorsfor the developmentof type2 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 b-cell insulin content, and inhibition of GSIS.