Preserving expression of Pdx1 improves β-cell failure in diabetic mice

Pdx1, a beta-cell-specific transcription factor, has been shown to play a crucial role in maintaining beta-cell function through transactivation of beta-cell-related genes. In addition, it has been reported that the expression levels of Pdx1 are compromised under diabetic conditions in human and rodent models. We therefore aimed to clarify the possible beneficial role of Pdx1 against beta-cell failure and generated the transgenic mouse that expressed Pdx1 conditionally and specifically in b cells (bPdx1) and crossed these mice with Ins2(Akita) diabetic mice. Whereas Pdx1 mRNA levels were reduced in Ins2(Akita) mice compared with their non-diabetic littermates, the mRNA levels of Pdx1 were significantly recovered in the islets of bPdx1; Ins2(Akita) mice. The bPdx1; Ins2(Akita) mice exhibited significantly improved glucose tolerance, compared with control Ins2(Akita) littermates, accompanied by increased insulin secretion after glucose loading. Furthermore, histological examination demonstrated that bPdx1; Ins2(Akita) mice had improved localization of SLC2A2 (GLUT2), and quantitative RT-PCR showed the recovered expression of Mafa and Gck mRNAs in the islets of bPdx1; Ins2(Akita) mice. These findings suggest that the sustained expression of Pdx1 improves beta-cell failure in Ins2(Akita) mice, at least partially through the preserving expression of bcell- specific genes as well as improved localization of GLUT2. (C) 2016 Elsevier Inc. All rights reserved.