ChREBP Mediates Glucose-Stimulated Pancreatic β-cell Proliferation

Diabetes. 2012 Aug;61(8):2004-15. doi: 10.2337/db11-0802. Epub 2012 May 14.

Abstract

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, [(3)H]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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / biosynthesis
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / physiology*
  • Cell Cycle Proteins / physiology
  • Cell Proliferation / drug effects
  • Glucose / pharmacology*
  • Humans
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Insulinoma / metabolism
  • Mice
  • Nuclear Proteins / physiology*
  • Rats
  • Transcription Factors / physiology*

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Cell Cycle Proteins
  • MLXIPL protein, human
  • Mlxipl protein, mouse
  • Nuclear Proteins
  • Transcription Factors
  • Wbscr14 protein, rat
  • Glucose