title: Pathway to diabetes through attenuation of pancreatic beta cell glycosylation and glucose transport.
abstract: 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.
authors.affiliation: Center for Nanomedicine, Sanford-Burnham Medical Research Institute, University of California-Santa Barbara, Santa Barbara, California, USA.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Ohtsubo
authors.forename: Mark Z
authors.initials: MZ
authors.lastname: Chen
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
authors.forename: Jamey D
authors.initials: JD
authors.lastname: Marth
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001774:Blood Chemical Analysis; D001786:Blood Glucose / Q000378:metabolism; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D005822:Genetic Vectors; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism; D006031:Glycosylation; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008659:Metabolic Diseases / Q000150:complications / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D019308:Palmitic Acid / Q000494:pharmacology; D016133:Polymerase Chain Reaction
chemical_list: D001786:Blood Glucose; D017931:DNA Primers; C496502:FOXA2 protein, human; D005230:Fatty Acids, Nonesterified; D051246:Glucose Transport Proteins, Facilitative; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D007328:Insulin; D051542:Hepatocyte Nuclear Factor 3-beta; D019308:Palmitic Acid; C508256:Mgat14 protein, mouse; D017351:N-Acetylglucosaminyltransferases