title: Metabolic inflexibility impairs insulin secretion and results in MODY-like diabetes in triple FoxO-deficient mice.
abstract: Pancreatic β cell failure in type 2 diabetes is associated with functional abnormalities of insulin secretion and deficits of β cell mass. It's unclear how one begets the other. We have shown that loss of β cell mass can be ascribed to impaired FoxO1 function in different models of diabetes. Here we show that ablation of the three FoxO genes (1, 3a, and 4) in mature β cells results in early-onset, maturity-onset diabetes of the young (MODY)-like diabetes, with abnormalities of the MODY networks Hnf4α, Hnf1α, and Pdx1. FoxO-deficient β cells are metabolically inflexible, i.e., they preferentially utilize lipids rather than carbohydrates as an energy source. This results in impaired ATP generation and reduced Ca(2+)-dependent insulin secretion. The present findings demonstrate a secretory defect caused by impaired FoxO activity that antedates dedifferentiation. We propose that defects in both pancreatic β cell function and mass arise through FoxO-dependent mechanisms during diabetes progression.
authors.affiliation: Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Ja Young
authors.initials: JY
authors.lastname: Kim-Muller
authors.affiliation: Molecular Nutrition Unit and Montreal Diabetes Research Center at the CRCHUM and Departments of Nutrition and Biochemistry, and Molecular Medicine, Université de Montréal, Montréal, QC H2X 0A9, Canada.
authors.forename: Shangang
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Division of Nephrology, The Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute for Biomolecular Medicine, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Shekhar
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Molecular Nutrition Unit and Montreal Diabetes Research Center at the CRCHUM and Departments of Nutrition and Biochemistry, and Molecular Medicine, Université de Montréal, Montréal, QC H2X 0A9, Canada.
authors.forename: Yves
authors.initials: Y
authors.lastname: Mugabo
authors.affiliation: Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Hye-Lim
authors.initials: HL
authors.lastname: Noh
authors.affiliation: Department of Genetics and Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University, New York, NY 10032, USA.
authors.forename: YoungJung R
authors.initials: YR
authors.lastname: Kim
authors.affiliation: Molecular Nutrition Unit and Montreal Diabetes Research Center at the CRCHUM and Departments of Nutrition and Biochemistry, and Molecular Medicine, Université de Montréal, Montréal, QC H2X 0A9, Canada.
authors.forename: S R Murthy
authors.initials: SR
authors.lastname: Madiraju
authors.affiliation: Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Ferrante
authors.affiliation: Division of Nephrology, The Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute for Biomolecular Medicine, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Edward Y
authors.initials: EY
authors.lastname: Skolnik
authors.affiliation: Molecular Nutrition Unit and Montreal Diabetes Research Center at the CRCHUM and Departments of Nutrition and Biochemistry, and Molecular Medicine, Université de Montréal, Montréal, QC H2X 0A9, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Prentki
authors.affiliation: Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY 10032, USA. Electronic address: da230@columbia.edu.
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics*; D020869:Gene Expression Profiling; D005951:Glucose Tolerance Test; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D020746:Calcium Channels, L-Type; D018797:Cell Cycle Proteins; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C525394:FoxO4 protein, mouse; C467200:Foxo1 protein, mouse; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; C496488:Hnf1a protein, mouse; C496593:Hnf4a protein, mouse; D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D002118:Calcium