内分泌学
内科学
葡萄糖稳态
平衡
生物
基因剔除小鼠
葡萄糖激酶
蛋白激酶A
细胞凋亡
β细胞
糖尿病
细胞生物学
激酶
受体
胰岛素抵抗
医学
小岛
生物化学
作者
Shona Pfeiffer,Luise Halang,Heiko Düßmann,Maria Byrne,Jochen H. M. Prehn
标识
DOI:10.1038/cddiscovery.2015.41
摘要
Abstract Heterozygous loss-of-function mutations in the hepatocyte nuclear factor 1 α (HNF-1 α ) gene can lead to diminished amounts of functional HNF-1 α , resulting in the onset of a particularly severe form of maturity-onset diabetes of the young (MODY). We have previously shown that induction of a dominant-negative mutant of HNF-1 α (DNHNF-1 α ) results in the activation of the bioenergetic stress sensor AMP-activated protein kinase (AMPK), preceding the onset of apoptosis and the induction of pro-apoptotic Bcl-2 homology domain-3-only protein Bmf (Bcl-2-modifying factor) as a mediator of DNHNF-1 α -induced apoptosis. Through the knockout of bmf in a transgenic mouse model with DNHNF-1 α suppression of HNF-1 α function in pancreatic beta-cells, this study aimed to examine the effect of loss-of-function of this BH3-only protein on the disease pathology and progression, and further elucidate the role of Bmf in mediating DNHNF-1 α -induced beta-cell loss. Morphological analysis revealed an attenuation in beta-cell loss in bmf -deficient diabetic male mice and preserved insulin content. Surprisingly, bmf deficiency was found to exacerbate hyperglycemia in both diabetic male and hyperglycemic female mice, and ultimately resulted in a decreased glucose-stimulated insulin response, implicating a role for Bmf in glucose homeostasis regulation independent of an effect on beta-cell loss. Collectively, our data demonstrate that Bmf contributes to the decline in beta-cells in a mouse model of HNF1A-MODY but is also required for the maintenance of glucose homeostasis in vivo .
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