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Pancreatic ß-cell hyper-O-GlcNAcylation leads to impaired glucose homeostasis in vivo.
Jo, Seokwon; Pritchard, Samantha; Wong, Alicia; Avula, Nandini; Essawy, Ahmad; Hanover, John; Alejandro, Emilyn U.
Afiliación
  • Jo S; Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, MN, United States.
  • Pritchard S; Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, MN, United States.
  • Wong A; Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, MN, United States.
  • Avula N; Department of Genetics, Cell Biology & Development, University of Minnesota, Minneapolis, MN, United States.
  • Essawy A; Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, MN, United States.
  • Hanover J; Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, MN, United States.
  • Alejandro EU; Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD, United States.
Front Endocrinol (Lausanne) ; 13: 1040014, 2022.
Article en En | MEDLINE | ID: mdl-36387851
Protein O-GlcNAcylation is a nutrient and stress-sensitive protein post-translational modification (PTM). The addition of an O-GlcNAc molecule to proteins is catalyzed by O-GlcNAc transferase (OGT), whereas O-GlcNAcase (OGA) enzyme is responsible for removal of this PTM. Previous work showed that OGT is highly expressed in the pancreas, and we demonstrated that hypo-O-GlcNAcylation in ß-cells cause severe diabetes in mice. These studies show a direct link between nutrient-sensitive OGT and ß-cell health and function. In the current study, we hypothesized that hyper-O-GlcNAcylation may confer protection from ß-cell failure in high-fat diet (HFD)-induced obesity. To test this hypothesis, we generated a mouse model with constitutive ß-cell OGA ablation (ßOGAKO) to specifically increase O-GlcNAcylation in ß-cells. Under normal chow diet, young male and female ßOGAKO mice exhibited normal glucose tolerance but developed glucose intolerance with aging, relative to littermate controls. No alteration in ß-cell mass was observed between ßOGAKO and littermate controls. Total insulin content was reduced despite an increase in pro-insulin to insulin ratio in ßOGAKO islets. ßOGAKO mice showed deficit in insulin secretion in vivo and in vitro. When young animals were subjected to HFD, both male and female ßOGAKO mice displayed normal body weight gain and insulin tolerance but developed glucose intolerance that worsened with longer exposure to HFD. Comparable ß-cell mass was found between ßOGAKO and littermate controls. Taken together, these data demonstrate that the loss of OGA in ß-cells reduces ß-cell function, thereby perturbing glucose homeostasis. The findings reinforce the rheostat model of intracellular O-GlcNAcylation where too much (OGA loss) or too little (OGT loss) O-GlcNAcylation are both detrimental to the ß-cell.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Intolerancia a la Glucosa / Células Secretoras de Insulina Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals Idioma: En Revista: Front Endocrinol (Lausanne) Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Intolerancia a la Glucosa / Células Secretoras de Insulina Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals Idioma: En Revista: Front Endocrinol (Lausanne) Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza