TY - JOUR
T1 - Metabolic inflexibility impairs insulin secretion and results in MODY-like diabetes in triple FoxO-deficient mice
AU - Kim-Muller, Ja Young
AU - Zhao, Shangang
AU - Srivastava, Shekhar
AU - Mugabo, Yves
AU - Noh, Hye Lim
AU - Kim, Youngjung R.
AU - Madiraju, S. R.Murthy
AU - Ferrante, Anthony W.
AU - Skolnik, Edward Y.
AU - Prentki, Marc
AU - Accili, Domenico
N1 - Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2014/10/7
Y1 - 2014/10/7
N2 - 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 Ca2+-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.
AB - 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 Ca2+-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.
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U2 - 10.1016/j.cmet.2014.08.012
DO - 10.1016/j.cmet.2014.08.012
M3 - Article
C2 - 25264246
AN - SCOPUS:84907994036
SN - 1550-4131
VL - 20
SP - 593
EP - 602
JO - Cell Metabolism
JF - Cell Metabolism
IS - 4
ER -