Metabolic inflexibility impairs insulin secretion and results in MODY-like diabetes in triple FoxO-deficient mice.
Ja Young Kim-Muller, Shangang Zhao, Shekhar Srivastava, Yves Mugabo, Hye-Lim Noh, YoungJung R Kim, S R Murthy Madiraju, Anthony W Ferrante, Edward Y Skolnik, Marc Prentki, Domenico Accili
Author Information
Ja Young Kim-Muller: Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY 10032, USA.
Shangang Zhao: 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.
Shekhar Srivastava: 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.
Yves Mugabo: 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.
Hye-Lim Noh: Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY 10032, USA.
YoungJung R Kim: Department of Genetics and Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University, New York, NY 10032, USA.
S R Murthy Madiraju: 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.
Anthony W Ferrante: Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY 10032, USA.
Edward Y Skolnik: 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.
Marc Prentki: 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.
Domenico Accili: Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY 10032, USA. Electronic address: da230@columbia.edu.
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.
