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

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)593-602
Number of pages10
JournalCell Metabolism
Volume20
Issue number4
DOIs
StatePublished - Oct 7 2014
Externally publishedYes

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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