title: Kisspeptin stimulation of insulin secretion: mechanisms of action in mouse islets and rats.
abstract: OBJECTIVE
  Kisspeptin is a novel peptide identified as an endogenous ligand of the G-protein-coupled receptor 54 (GPR-54), which plays a crucial role in puberty and reproductive function. High levels of GPR-54 and kisspeptin have been reported in the pancreas and we have previously shown that kisspeptin potentiates glucose-induced insulin release from isolated islets, although the mechanisms underlying this effect were unclear.
  
  
  METHODS
  Insulin secretion from isolated mouse islets was measured to characterise the effects of kisspeptin. The effects of kisspeptin on both p42/44 mitogen-activated protein kinase (MAPK) phosphorylation and intracellular Ca(2+)([Ca(2+)](i)) in mouse islets were also investigated. Furthermore, kisspeptin was administered to rats in vivo and effects on plasma insulin levels measured.
  
  
  RESULTS
  In the current study, kisspeptin induced a concentration-dependent potentiation of glucose-induced (20 mmol/l) insulin secretion from mouse islets, with maximal effects at 1 micromol/l, but had no effect on insulin secretion at a substimulatory concentration of glucose (2 mmol/l). Activation of GPR-54 by kisspeptin also caused reversible increases in [Ca(2+)](i) in Fura-2 loaded dispersed islet cells. The kisspeptin-induced potentiation of glucose-induced insulin secretion was completely abolished by inhibitors of phospholipase C and p42/44 MAPK, but not by inhibitors of protein kinase C or p38 MAPK. Intravenous administration of kisspeptin into conscious, unrestrained rats caused an increase in circulating insulin levels, whilst central administration of kisspeptin had no effect, indicating a peripheral site of action.
  
  
  CONCLUSIONS
  These observations suggest that neither typical protein kinase C isoforms nor p38 MAPK are involved in the potentiation of glucose-induced insulin release by kisspeptin, but intracellular signalling pathways involving phospholipase C, p42/44 MAPK and increased [Ca(2+)](i) are required for the stimulatory effects on insulin secretion. The observation that kisspeptin is also capable of stimulating insulin release in vivo supports the conclusion that kisspeptin is a regulator of beta cell function.
authors.affiliation: Division of Reproduction and Endocrinology, School of Biomedical and Health Sciences, King's College London, London, UK. james.bowe@kcl.ac.uk
authors.forename: J E
authors.initials: JE
authors.lastname: Bowe
authors.forename: A J
authors.initials: AJ
authors.lastname: King
authors.forename: J S
authors.initials: JS
authors.lastname: Kinsey-Jones
authors.forename: V L
authors.initials: VL
authors.lastname: Foot
authors.forename: X F
authors.initials: XF
authors.lastname: Li
authors.forename: K T
authors.initials: KT
authors.lastname: O'Byrne
authors.forename: S J
authors.initials: SJ
authors.lastname: Persaud
authors.forename: P M
authors.initials: PM
authors.lastname: Jones
mesh_terms: D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D059648:Kisspeptins; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011493:Protein Kinase C / Q000378:metabolism; D011506:Proteins / Q000494:pharmacology*; D051381:Rats; D025521:Tumor Suppressor Proteins / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D007328:Insulin; C491407:Kiss1 protein, mouse; C491406:Kiss1 protein, rat; D059648:Kisspeptins; D011506:Proteins; D025521:Tumor Suppressor Proteins; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose