Matsuoka Taka-aki, Kaneto Hideaki, Kawashima Satoshi, Miyatsuka Takeshi, Tochino Yoshihiro, Yoshikawa Atsushi, Imagawa Akihisa, Miyazaki Jun-ichi, Gannon Maureen, Stein Roland, Shimomura Iichiro
From the Department of Metabolic Medicine,
From the Department of Metabolic Medicine.
J Biol Chem. 2015 Mar 20;290(12):7647-57. doi: 10.1074/jbc.M114.595579. Epub 2015 Feb 2.
The murine Mafa transcription factor is a key regulator of postnatal islet β-cell activity, affecting insulin transcription, insulin secretion, and β-cell mass. Human MAFA expression is also markedly decreased in islet β-cells of type 2 diabetes mellitus (T2DM) patients. Moreover, levels are profoundly reduced in db/db islet β-cells, a mouse model of T2DM. To examine the significance of this key islet β-cell-enriched protein to glycemic control under diabetic conditions, we generated transgenic mice that conditionally and specifically produced Mafa in db/db islet β-cells. Sustained expression of Mafa resulted in significantly lower plasma glucose levels, higher plasma insulin, and augmented islet β-cell mass. In addition, there was increased expression of insulin, Slc2a2, and newly identified Mafa-regulated genes involved in reducing β-cell stress, like Gsta1 and Gckr. Importantly, the levels of human GSTA1 were also compromised in T2DM islets. Collectively, these results illustrate how consequential the reduction in Mafa activity is to islet β-cell function under pathophysiological conditions.
小鼠Mafa转录因子是出生后胰岛β细胞活性的关键调节因子，影响胰岛素转录、胰岛素分泌和β细胞量。在2型糖尿病（T2DM）患者的胰岛β细胞中，人MAFA的表达也显著降低。此外，在T2DM小鼠模型db/db胰岛β细胞中，其水平大幅降低。为了研究这种关键的富含胰岛β细胞的蛋白在糖尿病条件下对血糖控制的重要性，我们构建了在db/db胰岛β细胞中条件性且特异性产生Mafa的转基因小鼠。Mafa的持续表达导致血浆葡萄糖水平显著降低、血浆胰岛素水平升高以及胰岛β细胞量增加。此外，胰岛素、Slc2a2以及新发现的参与减轻β细胞应激的Mafa调控基因（如Gsta1和Gckr）的表达增加。重要的是，在T2DM胰岛中，人GSTA1的水平也受到影响。总体而言，这些结果说明了在病理生理条件下Mafa活性降低对胰岛β细胞功能的影响有多大。
