A connection between diet, obesity and diabetes exists in multiple species and is the basis of an escalating human health problem. The factors responsible provoke both insulin resistance and pancreatic beta cell dysfunction but remain to be fully identified. We report a combination of molecular events in human and mouse pancreatic beta cells, induced by elevated levels of free fatty acids or by administration of a high-fat diet with associated obesity, that comprise a pathogenic pathway to diabetes. Elevated concentrations of free fatty acids caused nuclear exclusion and reduced expression of the transcription factors FOXA2 and HNF1A in beta cells. This resulted in a deficit of GnT-4a glycosyltransferase expression in beta cells that produced signs of metabolic disease, including hyperglycemia, impaired glucose tolerance, hyperinsulinemia, hepatic steatosis and diminished insulin action in muscle and adipose tissues. Protection from disease was conferred by enforced beta cell–specific GnT-4a protein glycosylation and involved the maintenance of glucose transporter expression and the preservation of glucose transport. We observed that this pathogenic process was active in human islet cells obtained from donors with type 2 diabetes; thus, illuminating a pathway to disease implicated in the diet- and obesity-associated component of type 2 diabetes mellitus.
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This research was funded primarily by US National Institutes of Health (NIH) grant DK48247 with additional support from GM62116 and CA71932 (J.D.M.). Further funding was obtained from DK033651, DK074868, T32 DK007494, DK063491 and the Eunice Kennedy Shriver National Institute of Child Health and Human Development–NIH through cooperative agreement of U54 HD 012303-25 as part of the specialized Cooperative Centers Program in Reproduction and Infertility Research (J.M.O.) and the Japan Diabetes Foundation and Suntory Institute for Bioorganic Research (SUNBOR grant; K.O.).
The authors declare no competing financial interests.
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Ohtsubo, K., Chen, M., Olefsky, J. et al. Pathway to diabetes through attenuation of pancreatic beta cell glycosylation and glucose transport. Nat Med 17, 1067–1075 (2011). https://doi.org/10.1038/nm.2414
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