title: Endogenous GLP-1 as a key self-defense molecule against lipotoxicity in pancreatic islets.
abstract: The number of pro-α cells is known to increase in response to β cell injury and these cells then generate glucagon-like peptide-1 (GLP-1), thus attenuating the development of diabetes. The aim of the present study was to further examine the role and the mechanisms responsible for intra-islet GLP-1 production as a self-protective response against lipotoxicity. The levels of the key enzyme, prohormone convertase 1/3 (PC1/3), as well as the synthesis and release of GLP-1 in models of lipotoxicity were measured. Furthermore, islet viability, apoptosis, oxidative stress and inflammation, as well as islet structure were assessed after altering GLP-1 receptor signaling. Both prolonged exposure to palmitate and a high-fat diet facilitated PC1/3 expression, as well as the synthesis and release of GLP-1 induced by β cell injury and the generation of pro-α cells. Prolonged exposure to palmitate increased reactive oxygen species (ROS) production, and the antioxidant, N-acetylcysteine (NAC), partially prevented the detrimental effects induced by palmitate on β cells, resulting in decreased GLP-1 levels. Furthermore, the inhibition of GLP-1 receptor (GLP-1R) signaling by treatment with exendin‑(9-39) further decreased cell viability, increased cell apoptosis and caused a stronger inhibition of the β cell-specific transcription factor, pancreatic duodenal homeobox 1 (PDX1). Moreover, treatment with the GLP-1R agonist, liraglutide, normalized islet structure and function, resulting in a decrease in cell death and in the amelioration of β cell marker expression. Importantly, liraglutide maintained the oxidative balance and decreased inflammatory factor and p65 expression. Overall, our data demonstrate that an increase in the number of pro-α cells and the activation of the intra-islet GLP-1 system comprise a self-defense mechanism for enhancing β cell survival to combat lipid overload, which is in part mediated by oxidative stress and inflammation.
authors.affiliation: Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
authors.forename: Chenghu
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
authors.forename: Shuyi
authors.initials: S
authors.lastname: Cao
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D059305:Diet, High-Fat; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000037:antagonists & inhibitors; D050416:Glucagon-Secreting Cells / Q000166:cytology*; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors; D007249:Inflammation / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D000069450:Liraglutide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000502:physiology; D010168:Palmitates / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D045664:Proprotein Convertase 1 / Q000096:biosynthesis / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000037:antagonists & inhibitors; D051996:Transcription Factor RelA / Q000096:biosynthesis; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D018398:Homeodomain Proteins; D010168:Palmitates; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C498144:Rela protein, mouse; D015534:Trans-Activators; D051996:Transcription Factor RelA; C084010:pancreatic and duodenal homeobox 1 protein; C083773:exendin (9-39); D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D045664:Proprotein Convertase 1; D000111:Acetylcysteine; D000097789:Glucagon-Like Peptide-1 Receptor Agonists