B-cell Translocation Gene 2 Positively Regulates GLP-1-stimulated Insulin Secretion via Induction of PDX-1 in Pancreatic β-cells

Exp Mol Med. 2013 May 24;45(5):e25. doi: 10.1038/emm.2013.47.

Abstract

Glucagon-like peptide-1 (GLP-1) is a potent glucoincretin hormone and an important agent for the treatment of type 2 diabetes. Here we demonstrate that B-cell translocation gene 2 (BTG2) is a crucial regulator in GLP-1-induced insulin gene expression and insulin secretion via upregulation of pancreatic duodenal homeobox-1 (PDX-1) in pancreatic β-cells. GLP-1 treatment significantly increased BTG2, PDX-1 and insulin gene expression in pancreatic β-cells. Notably, adenovirus-mediated overexpression of BTG2 significantly elevated insulin secretion, as well as insulin and PDX-1 gene expression. Physical interaction studies showed that BTG2 is associated with increased PDX-1 occupancy on the insulin gene promoter via a direct interaction with PDX-1. Exendin-4 (Ex-4), a GLP-1 agonist, and GLP-1 in pancreatic β-cells increased insulin secretion through the BTG2-PDX-1-insulin pathway, which was blocked by endogenous BTG2 knockdown using a BTG2 small interfering RNA knockdown system. Finally, we revealed that Ex-4 and GLP-1 significantly elevated insulin secretion via upregulation of the BTG2-PDX-1 axis in pancreatic islets, and this phenomenon was abolished by endogenous BTG2 knockdown. Collectively, our current study provides a novel molecular mechanism by which GLP-1 positively regulates insulin gene expression via BTG2, suggesting that BTG2 has a key function in insulin secretion in pancreatic β-cells.

MeSH terms

  • Animals
  • Exenatide
  • Gene Expression Regulation / drug effects
  • Glucagon-Like Peptide 1 / pharmacology*
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism*
  • Insulin / genetics
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Peptides / pharmacology
  • Promoter Regions, Genetic / genetics
  • Protein Binding / drug effects
  • Protein Binding / genetics
  • Rats
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Venoms / pharmacology

Substances

  • BTG2 protein, rat
  • Btg2 protein, mouse
  • Homeodomain Proteins
  • Immediate-Early Proteins
  • Insulin
  • Peptides
  • Trans-Activators
  • Tumor Suppressor Proteins
  • Venoms
  • pancreatic and duodenal homeobox 1 protein
  • Glucagon-Like Peptide 1
  • Exenatide