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

• Published in: Experimental & molecular medicine 2013-05, Vol.45 (5), p.e25-e25
• Main Authors: Hwang, Seung-Lark, Kwon, Okyun, Kim, Sun-Gyun, Lee, In-Kyu, Kim, Yong Deuk
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; 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; Medical Biochemistry; Mice; Mice, Inbred C57BL; Molecular Medicine; Original; original-article; Peptides - pharmacology; Promoter Regions, Genetic - genetics; Protein Binding - drug effects; Protein Binding - genetics; Rats; Stem Cells; Trans-Activators - genetics; Trans-Activators - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Venoms - pharmacology
• ISSN: 1226-3613; 2092-6413; 2092-6413
• DOI: 10.1038/emm.2013.47

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. Endocrinology: A controller of blood-sugar regulation revealed Scientists in Korea and the USA have uncovered an important ‘missing link’ in a physiological pathway that regulates insulin production. After a meal, the gut secretes a hormone called glucagon-like peptide-1 (GLP-1), which instructs pancreatic beta-cells to produce insulin. This complex, multi-step process is therefore of great interest to the diabetes research community. Led by Yong Deuk Kim of Yeungnam University, the scientists revealed that the protein encoded B-cell translocation gene 2 (BTG2) is a key intermediary in this process. They found that GLP-1 stimulates BTG2 production in beta cells, and that BTG2 in turn switches on genes responsible for insulin production. Accordingly, experimental interventions that eliminated BTG2 production essentially blocked the normal effects of GLP-1 on pancreatic cells. These findings could thus prove useful in ongoing efforts to manipulate GLP-1 pathways as treatment for metabolic disease.