Differential stimulation of insulin secretion by GLP-1 and Kisspeptin-10

• Published in: PloS one 2014-11, Vol.9 (11), p.e113020-e113020
• Main Authors: Schwetz, Tara A, Reissaus, Christopher A, Piston, David W
• Format: Article
• Language: English
• Subjects: Animals; Biology and Life Sciences; Blood Glucose - drug effects; Calcium; Calcium (intracellular); Calcium - metabolism; Calcium Signaling - drug effects; Electrode potentials; Endocrinology; G protein-coupled receptors; Gene expression; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide 1 - pharmacology; Glucose; Glucose metabolism; GTP-Binding Protein alpha Subunits - metabolism; GTP-Binding Protein beta Subunits - metabolism; GTP-Binding Protein gamma Subunits - metabolism; Homeostasis; Humans; Insulin; Insulin - biosynthesis; Insulin secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Islets of Langerhans; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Kiss1 protein; Kisspeptins - pharmacology; Ligands; Male; Medicine and Health Sciences; Metabolism; Mice; Oxidation-Reduction - drug effects; Pancreas; Peptides; Physiology; Proteins; Receptors; Redox potential; Rodents; Secretion; Signal transduction; Signal Transduction - drug effects; Signaling; Stimulation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0113020

β-cells in the pancreatic islet respond to elevated plasma glucose by secreting insulin to maintain glucose homeostasis. In addition to glucose stimulation, insulin secretion is modulated by numerous G-protein coupled receptors (GPCRs). The GPCR ligands Kisspeptin-10 (KP) and glucagon-like peptide-1 (GLP-1) potentiate insulin secretion through Gq and Gs-coupled receptors, respectively. Despite many studies, the signaling mechanisms by which KP and GLP-1 potentiate insulin release are not thoroughly understood. We investigated the downstream signaling pathways of these ligands and their affects on cellular redox potential, intracellular calcium activity ([Ca(2+)]i), and insulin secretion from β-cells within intact murine islets. In contrast to previous studies performed on single β-cells, neither KP nor GLP-1 affect [Ca(2+)]i upon stimulation with glucose. KP significantly increases the cellular redox potential, while no effect is observed with GLP-1, suggesting that KP and GLP-1 potentiate insulin secretion through different mechanisms. Co-treatment with KP and the Gβγ-subunit inhibitor gallein inhibits insulin secretion similar to that observed with gallein alone, while co-treatment with gallein and GLP-1 does not differ from GLP-1 alone. In contrast, co-treatment with the Gβγ activator mSIRK and either KP or GLP-1 stimulates insulin release similar to mSIRK alone. Neither gallein nor mSIRK alter [Ca(2+)]i activity in the presence of KP or GLP-1. These data suggest that KP likely alters insulin secretion through a Gβγ-dependent process that stimulates glucose metabolism without altering Ca(2+) activity, while GLP-1 does so, at least partly, through a Gα-dependent pathway that is independent of both metabolism and Ca(2+).