Glucagon-like peptide-1 prevents methylglyoxal-induced apoptosis of beta cells through improving mitochondrial function and suppressing prolonged AMPK activation
Journal
Scientific Reports
Journal Volume
6
Pages
23403
Date Issued
2016
Author(s)
Abstract
Accumulation of methylglyoxal (MG) contributes to glucotoxicity and mediates beta cell apoptosis. The molecular mechanism by which GLP-1 protects MG-induced beta cell apoptosis remains unclear. Metformin is a first-line drug for treating type 2 diabetes associated with AMPK activation. However, whether metformin prevents MG-induced beta cell apoptosis is controversial. Here, we explored the signaling pathway involved in the anti-apoptotic effect of GLP-1, and investigated whether metformin had an anti-apoptotic effect on beta cells. MG treatment induced apoptosis of beta cells, impaired mitochondrial function, and prolonged activation of AMP-dependent protein kinase (AMPK). The MG-induced pro-apoptotic effects were abolished by an AMPK inhibitor. Pretreatment of GLP-1 reversed MG-induced apoptosis, and mitochondrial dysfunction, and suppressed prolonged AMPK activation. Pretreatment of GLP-1 reversed AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR)-induced apoptosis, and suppressed prolonged AMPK activation. However, metformin neither leads to beta cell apoptosis nor ameliorates MG-induced beta cell apoptosis. In parallel, GLP-1 also prevents MG-induced beta cell apoptosis through PKA and PI3K-dependent pathway. In conclusion, these data indicates GLP-1 but not metformin protects MG-induced beta cell apoptosis through improving mitochondrial function, and alleviating the prolonged AMPK activation. Whether adding GLP-1 to metformin provides better beta cell survival and delays disease progression remains to be validated.
SDGs
Other Subjects
antidiabetic agent; cyclic AMP dependent protein kinase; glucagon like peptide 1; hydroxymethylglutaryl coenzyme A reductase kinase; metformin; methylglyoxal; phosphatidylinositol 3 kinase; animal; antagonists and inhibitors; apoptosis; cell survival; drug effects; metabolism; mitochondrion; pancreas islet beta cell; rat; signal transduction; tumor cell line; AMP-Activated Protein Kinases; Animals; Apoptosis; Cell Line, Tumor; Cell Survival; Cyclic AMP-Dependent Protein Kinases; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin-Secreting Cells; Metformin; Mitochondria; Phosphatidylinositol 3-Kinases; Pyruvaldehyde; Rats; Signal Transduction
Publisher
Nature Publishing Group
Type
journal article