Preserving expression of Pdx1 improves ß-cell failure in diabetic mice.

ABSTRACT

Pdx1, a ß-cell-specific transcription factor, has been shown to play a crucial role in maintaining ß-cell function through transactivation of ß-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 ß-cell failure and generated the transgenic mouse that expressed Pdx1 conditionally and specifically in ß cells (ßPdx1) and crossed these mice with Ins2Akita diabetic mice. Whereas Pdx1 mRNA levels were reduced in Ins2Akita mice compared with their non-diabetic littermates, the mRNA levels of Pdx1 were significantly recovered in the islets of ßPdx1; Ins2Akita mice. The ßPdx1; Ins2Akita mice exhibited significantly improved glucose tolerance, compared with control Ins2Akita littermates, accompanied by increased insulin secretion after glucose loading. Furthermore, histological examination demonstrated that ßPdx1; Ins2Akita mice had improved localization of SLC2A2 (GLUT2), and quantitative RT-PCR showed the recovered expression of Mafa and Gck mRNAs in the islets of ßPdx1; Ins2Akita mice. These findings suggest that the sustained expression of Pdx1 improves ß-cell failure in Ins2Akita mice, at least partially through the preserving expression of ß-cell-specific genes as well as improved localization of GLUT2.