title: Genetic manipulations of fatty acid metabolism in beta-cells are associated with dysregulated insulin secretion.
abstract: Triacylglyceride (TG) accumulation in pancreatic beta-cells is associated with impaired insulin secretion, which is called lipotoxicity. To gain a better understanding of the pathophysiology of lipotoxicity, we generated three models of dysregulated fatty acid metabolism in beta-cells. The overexpression of sterol regulatory element binding protein-1c induced lipogenic genes and TG accumulation. Under these conditions, we observed a decrease in glucose oxidation and upregulation of uncoupling protein-2, which might be causally related to the decreased glucose-stimulated insulin secretion. The overexpression of AMP-activated protein kinase was accompanied by decreased lipogenesis, increased fatty acid oxidation, and decreased glucose oxidation; insulin secretions to glucose and depolarization stimuli were decreased, probably because of the decrease in glucose oxidation and cellular insulin content. It was notable that the secretory response to palmitate was blunted, which would suggest a role of the fatty acid synthesis pathway, but not its oxidative pathway in palmitate-stimulated insulin secretion. Finally, we studied islets of PPAR-gamma(+/-) mice that had increased insulin sensitivity and low TG content in white adipose tissue, skeletal muscle, and liver. On a high-fat diet, glucose-stimulated insulin secretion was decreased in association with increased TG content in the islets, which might be mediated through the elevated serum free fatty acid levels and their passive transport into beta-cells. These results revealed some aspects about the mechanisms by which alterations of fatty acid metabolism affect beta-cell functions.
authors.affiliation: Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Eto
authors.forename: Tokuyuki
authors.initials: T
authors.lastname: Yamashita
authors.forename: Junji
authors.initials: J
authors.lastname: Matsui
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Noda
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000263:Adenylate Kinase / Q000502:physiology; D017667:Adipocytes / Q000166:cytology; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism*; D005821:Genetic Techniques; D005947:Glucose / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000502:physiology
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D004041:Dietary Fats; D005227:Fatty Acids; D007328:Insulin; D018160:Receptors, Cytoplasmic and Nuclear; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D000263:Adenylate Kinase; D005947:Glucose