Metabolic inflexibility impairs insulin secretion and results in MODY-like diabetes in triple FoxO-deficient mice.

ABSTRACT: Pancreatic ? cell failure in type 2 diabetes is associated with functional abnormalities of insulin secretion and deficits of ? cell mass. It's unclear how one begets the other. We have shown that loss of ? 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 ? cells results in early-onset, maturity-onset diabetes of the young (MODY)-like diabetes, with abnormalities of the MODY networks Hnf4?, Hnf1?, and Pdx1. FoxO-deficient ? 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 ? cell function and mass arise through FoxO-dependent mechanisms during diabetes progression.

SUBMITTER: Kim-Muller JY 

PROVIDER: S-EPMC4192072 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature