Exp Mol Med.  2013 May;45(5):e25.

B-cell translocation gene 2 positively regulates GLP-1-stimulated insulin secretion via induction of PDX-1 in pancreatic beta-cells

• Hwang SL
• Kwon O
• Kim SG
• Lee IK
• Kim YD

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 beta-cells. GLP-1 treatment significantly increased BTG2, PDX-1 and insulin gene expression in pancreatic beta-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 beta-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 beta-cells.

Keyword

B-cell translocation gene 2; glucagon-like peptide-1; insulin; pancreatic duodenal homeobox-1

MeSH Terms

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