title: A role of PLC/PKC-dependent pathway in GLP-1-stimulated insulin secretion.
abstract: Glucagon-like peptide-1 (GLP-1) is an endogenous glucose-lowering hormone and GLP-1 receptor agonists are currently being used as antidiabetic drugs clinically. The canonical signalling pathway (including cAMP, Epac2, protein kinase A (PKA) and KATPchannels) is almost universally accepted as the main mechanism of GLP-1-stimulated insulin secretion. This belief is based on in vitro studies that used nanomolar (1-100 nM) concentrations of GLP-1. Recently, it was found that the physiological concentrations (1-10 pM) of GLP-1 also stimulate insulin secretion from isolated islets, induce membrane depolarization and increase of intracellular [Ca2+] in isolated β cells/pancreatic islets. These responses were unaffected by PKA inhibitors and occurred without detectable increases in intracellular cAMP and PKA activity. These PKA-independent actions of GLP-1 depend on protein kinase C (PKC), involve activation of the standard GLP-1 receptor (GLP1R) and culminate in activation of phospholipase C (PLC), leading to an elevation of diacylglycerol (DAG), increased L-type Ca2+and TRPM4/TRPM5 channel activities. Here, we review these recent data and contrast them against the effects of nanomolar concentrations of GLP-1. The differential intracellular signalling activated by low and high concentrations of GLP-1 could provide a clue to explain how GLP-1 exerts different function in the central nervous system and peripheral organs.
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Old Road, Oxford, OX3 7LE, UK. shigeto@med.kawasaki-m.ac.jp.|Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan. shigeto@med.kawasaki-m.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Shigeto
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Old Road, Oxford, OX3 7LE, UK.
authors.forename: Chae Young
authors.initials: CY
authors.lastname: Cha
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Old Road, Oxford, OX3 7LE, UK.
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
authors.affiliation: Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Kaku
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D054086:KATP Channels / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D050053:TRPM Cation Channels / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D007004:Hypoglycemic Agents; D007328:Insulin; D054086:KATP Channels; D050053:TRPM Cation Channels; D050051:Transient Receptor Potential Channels; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; D011493:Protein Kinase C; D010738:Type C Phospholipases; D005947:Glucose
keywords: GLP-1; Insulin secretion; KATP channel; PKA; PKC; TRP channels