ChREBP Mediates Glucose-Stimulated Pancreatic β-Cell Proliferation

Glucose stimulates rodent and human beta-cell replication, but the intracellular signaling mechanisms are poorly understood. Carbohydrate response element-binding protein (ChREBP) is a lipogenic glucose-sensing transcription factor with unknown functions in pancreatic beta-cells. We tested the hypothesis that ChREBP is required for glucose-stimulated beta-cell proliferation. The relative expression of ChREBP was determined in liver and beta-cells using quantitative RT-PCR (qRT-PCR), immunoblotting, and immunohistochemistry. Loss- and gain-of-function studies were performed using small interfering RNA and genetic deletion of ChREBP and adenoviral overexpression of ChREBP in rodent and human beta-cells. Proliferation was measured by 5-bromo-2'-deoxyuridine incorporation, [H-3]thymidine incorporation, and fluorescence-activated cell sorter analysis. hi addition, the expression of cell cycle regulatory genes was measured by qRT-PCR and immunoblotting. ChREBP expression was comparable with liver in mouse pancreata and in rat and human islets. Depletion of ChREBP decreased glucose-stimulated proliferation in beta-cells isolated from ChREBP(-/-) mice, in INS-1-derived 832/13 cells, and in primary rat and human beta-cells. Furthermore, depletion of ChREBP decreased the glucose-stimulated expression of cell cycle accelerators. Overexpression of ChREBP amplified glucose-stimulated proliferation in rat and human beta-cells, with concomitant increases in cyclin gene expression. In conclusion, ChREBP mediates glucose-stimulated proliferation in pancreatic beta-cells. Diabetes 61:2004-2015, 2012