Ex vivo transcriptional profiling of human pancreatic islets following chronic exposure to monounsaturated fatty acids.
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/microg 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/microg 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 beta-cell insulin content, and inhibition of GSIS.
Bikopoulos
George
G
Department of Laboratory Medicine and Pathobiology, 1 King's College Circle, University of Toronto, Toronto, Canada.
da Silva Pimenta
Aurelio
A
Lee
Simon C
SC
Lakey
Jonathan R
JR
Der
Sandy D
SD
Chan
Catherine B
CB
Ceddia
Rolando Bacis
RB
Wheeler
Michael B
MB
Rozakis-Adcock
Maria
M
D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000503:physiopathology*; D005089:Exocytosis / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D009924:Organ Culture Techniques; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010195:Pancreatitis / Q000453:epidemiology / Q000503:physiopathology; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
D005229:Fatty Acids, Monounsaturated; D007328:Insulin; D005947:Glucose