ChREBP Mediates Glucose-Stimulated Pancreatic β-Cell Proliferation
- Mallikarjuna R. Metukuri1,2,
- Pili Zhang1,
- Mahesh K. Basantani1,
- Connie Chin1,
- Rachel E. Stamateris1,
- Laura C. Alonso1,
- Karen K. Takane1,
- Roberto Gramignoli3,
- Stephen C. Strom3,
- Robert M. O’Doherty1,
- Andrew F. Stewart1,
- Rupangi C. Vasavada1,
- Adolfo Garcia-Ocaña1 and
- Donald K. Scott1⇓
- 1Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania
- 2Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
- 3Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
- Corresponding author: Donald K. Scott, .
Glucose stimulates rodent and human β-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 β-cells. We tested the hypothesis that ChREBP is required for glucose-stimulated β-cell proliferation. The relative expression of ChREBP was determined in liver and β-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 β-cells. Proliferation was measured by 5-bromo-2′-deoxyuridine incorporation, [3H]thymidine incorporation, and fluorescence-activated cell sorter analysis. In 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 β-cells isolated from ChREBP−/− mice, in INS-1–derived 832/13 cells, and in primary rat and human β-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 β-cells, with concomitant increases in cyclin gene expression. In conclusion, ChREBP mediates glucose-stimulated proliferation in pancreatic β-cells.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-0802/-/DC1.
- Received June 10, 2011.
- Accepted March 10, 2012.
- © 2012 by the American Diabetes Association.
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