Glucagon-like Peptide-1 Prevents Beta Cell Glucolipotoxicity

Buteau J, El-Assaad W, Rhodes CJ, Rosenberg L, Joly E, Prentki M. Diabetologia. 2004;47:806-815.

Glucagon-like peptide-1 (GLP-1) is a gluco-incretin hormone secreted by intestinal L-cells that has been shown to increase glucose secretion among people with impaired glucose tolerance or type 2 diabetes.[1,2] The purpose of this study was to determine if GLP-1 prevents pancreatic β-cell glucolipotoxicity and to elucidate the mechanism by which this occurs. DNA fragmentation and chromatin condensation were used to evaluate apoptosis in human islet and INS832/13 cells. Cells were exposed to glucose concentrations of 5 or 25 mmol/L for 24 hours with or without 0.4 mmol/L palmitate and 10 nmol/L GLP-1. GLP-1 was found to protect cells from apoptosis in the presence of elevated concentrations of glucose (glucotoxicity), palmitate (lipotoxicity), and both glucose and palmitate (glucolipotoxicity). Wild type and protein kinase B (PKB) mutant INS832/13 cells infected with adenoviral constructs were used to show that this effect is mediated by activation of PKB. GLP-1 is also thought to enhance binding activity of nuclear factor-κB (NF-κB), the downstream target of PKB, as assessed using an electrophoretic mobility shift assay (EMSA). β-cell apoptosis due to glucolipotoxicity is thought to be one of the mechanisms involved in the development of obesity-associated type 2 diabetes. Given the protective, anti-apoptotic role of GLP-1 in pancreatic β-cells, GLP-1 may play both a preventive and therapeutic role in type 2 diabetes.

References

1. Gutniak M, Orskov C, Holst JJ, Ahren B, Efendic S. Antidiabetogenic effect of glucagon-like peptide-1 (7-36) amide in normal subjects and patients with diabetes mellitus. N Engl J Med. 1992;326:1316-1322.

2. Holst JJ. Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1. Diabetes Metab Res Rev. 2002;18:430-441.