| First Author | Kim-Muller JY | Year | 2014 |
| Journal | Cell Metab | Volume | 20 |
| Issue | 4 | Pages | 593-602 |
| PubMed ID | 25264246 | Mgi Jnum | J:215526 |
| Mgi Id | MGI:5605590 | Doi | 10.1016/j.cmet.2014.08.012 |
| Citation | Kim-Muller JY, et al. (2014) Metabolic inflexibility impairs insulin secretion and results in MODY-like diabetes in triple FoxO-deficient mice. Cell Metab 20(4):593-602 |
| abstractText | Pancreatic beta cell failure in type 2 diabetes is associated with functional abnormalities of insulin secretion and deficits of beta cell mass. It's unclear how one begets the other. We have shown that loss of beta 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 beta cells results in early-onset, maturity-onset diabetes of the young (MODY)-like diabetes, with abnormalities of the MODY networks Hnf4alpha, Hnf1alpha, and Pdx1. FoxO-deficient beta 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 beta cell function and mass arise through FoxO-dependent mechanisms during diabetes progression. |
