Syt7-dependent　pancreatic　insulin　release　is　shown　to　be　mediated　by　5-IP7　in　response　to　parasympathetic　stimulation　of　the　GPCR　M3R.　5-diphosphoinositol　pentakisphosphate　(5-IP7)　is　a　signalling　metabolite　linked　to　various　cellular　processes.　How　extracellular　stimuli　elicit　5-IP7　signalling　remains　unclear.　Here　we　show　that　5-IP7　in　beta　cells　mediates　parasympathetic　stimulation　of　synaptotagmin-7　(Syt7)-dependent　insulin　release.　Mechanistically,　vagal　stimulation　and　activation　of　muscarinic　acetylcholine　receptors　triggers　G(alpha　q)-PLC-PKC-PKD-dependent　signalling　and　activates　IP6K1,　the　5-IP7　synthase.　Whereas　both　5-IP7　and　its　precursor　IP6　compete　with　PIP2　for　binding　to　Syt7,　Ca2+　selectively　binds　5-IP7　with　high　affinity,　freeing　Syt7　to　enable　fusion　of　insulin-containing　vesicles　with　the　cell　membrane.　beta-cell-specific　IP6K1　deletion　diminishes　insulin　secretion　and　glucose　clearance　elicited　by　muscarinic　stimulation,　whereas　mice　carrying　a　phosphorylation-mimicking,　hyperactive　IP6K1　mutant　display　augmented　insulin　release,　congenital　hyperinsulinaemia　and　obesity.　These　phenotypes　are　absent　in　mice　lacking　Syt7.　Our　study　proposes　a　new　conceptual　framework　for　inositol　pyrophosphate　physiology　in　which　5-IP7　acts　as　a　GPCR　second　messenger　at　the　interface　between　peripheral　nervous　system　and　metabolic　organs,　transmitting　G(q)-coupled　GPCR　stimulation　to　unclamp　Syt7-dependent,　and　perhaps　other,　exocytotic　events.