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.
Highlights
The postprandial enhancement of insulin secretion by hormonal factors from the gut is called the incretin effect.[1,2] The incretin hormone, glucagon-like peptide-1 (GLP-1), is produced from the gut endocrine L-cells in a nutrientdependent manner and is secreted in pancreatic islets.[3]
GLP-1 induces insulin gene expression via B-cell translocation gene 2 (BTG2) induction in pancreatic b-cells Previous studies have shown that GLP-1 stimulates insulin gene transcription via a diverse network of transcription factors, such as pancreatic duodenal homeobox-1 (PDX-1), musculoaponeurotic fibrosarcoma oncogene family A (MafA) and BETA2.8,9,27 On the basis of these findings, we examined the biological relevance of BTG2 in GLP-1-induced insulin gene expression in pancreatic b-cells
In this study we have demonstrated that GLP-1 significantly elevated the BTG2 gene expression and that the overexpression of BTG2 using an adenoviral system (Ad-BTG2)-upregulated insulin gene expression and secretion via PDX-1 induction
Summary
The postprandial enhancement of insulin secretion by hormonal factors from the gut is called the incretin effect.[1,2] The incretin hormone, glucagon-like peptide-1 (GLP-1), is produced from the gut endocrine L-cells in a nutrientdependent manner and is secreted in pancreatic islets.[3] GLP-1 induces pancreatic b-cell neogenesis, proinsulin biosynthesis and glucose-stimulated insulin secretion, and it inhibits food intake, gastric emptying, acid secretion and glucagon secretion, both in normal subjects and in patients with type 2 diabetes.[2,4] The pancreatic b-cell growthpromoting action of GLP-1 acts as its insulinotropic activity through a G-protein-coupled receptor by interacting with a specific receptor, the GLP-1 receptor. GLP-1 regulates a diverse set of intracellular signals, such as cyclicAMP-dependent protein kinase A, calcium and Epac in pancreatic b-cells.[5,6,7] GLP-1 activates all the steps of insulin biosynthesis and gene expression, which enhances insulin secretion. Previous reports have shown that the transcriptional activity of the insulin gene is mainly mediated by a network of transcription factors, such as pancreatic duodenal homeobox-1 (PDX-1), b-cell E-box transcription factor (BETA2/NeuroD) and musculoaponeurotic fibrosarcoma oncogene family A (MafA), which are predominantly expressed in pancreatic b-cells.[8,9]
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