Zhx2 maintains islet -cell mass and function by transcriptionally regulating Pax6

Emerging evidence shows that pancreatic beta-cell function and quality are key determinants in the progression of type 2 diabetes (T2D). The transcription factor zinc finger homeobox 2 (Zhx2) is involved in proliferation and development of multiple cells. However, the exact role of Zhx2 in beta-cells and T2D remains completely unknown. Here, we report that Zhx2 orchestrates beta-cell mass and function by regulating paired box protein pax-6 (Pax6). We found that beta-cell-specific knockout Zhx2 (Zhx2BKO) mice showed a decrease in beta-cell proliferation and glucose homeostasis. Under prediabetic and diabetic conditions, we discovered glucose intolerance in both Zhx2BKO-HFD mice and Zhx2BKO-db/db mice, with reduced beta-cell mass and insulin secretion. Mechanistically, we demonstrated that Zhx2 targeted the Pax6 promoter region (-1740 similar to-1563; -862 similar to-559; -251 similar to+75), enhanced promoter activity. Overall, Zhx2 maintains beta-cell function by transcriptionally regulating Pax6, which provides a therapeutic target for diabetes intervention.