Metabolic Inflexibility Impairs Insulin Secretion And Results In MODY-like Diabetes In Triple FoxO-deficient Mice

ABSTRACT: Pancreatic b-cell failure in type 2 diabetes is associated with functional abnormalities of insulin secretion and deficits of b-cell mass. It’s unclear how one begets the other. We have shown that loss of b-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 b-cells results in early-onset, maturity onset diabetes of the young (MODY)-like diabetes, with signature abnormalities of the MODY networks of Hnf4a, Hnf1a, and Pdx1. Transcriptome and functional analyses reveal that FoxO-deficient b-cells are metabolically inflexible, i.e., they preferentially utilize lipids rather than carbohydrates as source of acetyl-CoA for mitochondrial oxidative phosphorylation. This results in impaired

ORGANISM(S): Mus musculus

SUBMITTER: Domenico Accili 

PROVIDER: E-GEOD-60505 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress