Kim-Muller Ja Young, Zhao Shangang, Srivastava Shekhar, Mugabo Yves, Noh Hye-Lim, Kim YoungJung R, Madiraju S R Murthy, Ferrante Anthony W, Skolnik Edward Y, Prentki Marc, Accili Domenico
Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY 10032, USA.
Molecular Nutrition Unit and Montreal Diabetes Research Center at the CRCHUM and Departments of Nutrition and Biochemistry, and Molecular Medicine, Université de Montréal, Montréal, QC H2X 0A9, Canada.
Cell Metab. 2014 Oct 7;20(4):593-602. doi: 10.1016/j.cmet.2014.08.012. Epub 2014 Sep 25.
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 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 β cell function and mass arise through FoxO-dependent mechanisms during diabetes progression.
2型糖尿病中胰腺β细胞功能衰竭与胰岛素分泌功能异常及β细胞数量减少有关。尚不清楚二者之间是如何相互影响的。我们已经表明，在不同的糖尿病模型中，β细胞数量的减少可归因于FoxO1功能受损。在此我们表明，在成熟β细胞中敲除三个FoxO基因（1、3a和4）会导致早发性、青少年发病的成年型糖尿病（MODY）样糖尿病，并伴有MODY相关网络Hnf4α、Hnf1α和Pdx1的异常。FoxO缺陷的β细胞代谢灵活性差，即它们优先利用脂质而非碳水化合物作为能量来源。这导致ATP生成受损和钙依赖性胰岛素分泌减少。目前的研究结果表明，在去分化之前，FoxO活性受损会导致分泌缺陷。我们认为，在糖尿病进展过程中，胰腺β细胞功能和数量的缺陷是通过FoxO依赖性机制产生的。
