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Multilevel control of glucose homeostasis by adenylyl cyclase 8

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dc.contributor.authorRAOUX, Matthieu
dc.contributor.authorVACHER, Pierre
dc.contributor.authorPAPIN, Julien
dc.contributor.authorPICARD, Alexandre
dc.contributor.authorKOSTRZEWA, Elzbieta
dc.contributor.authorDEVIN, Anne
dc.contributor.authorGAITAN, Julien
dc.contributor.authorLIMON, Isabelle
dc.contributor.authorKAS, Martien J.
dc.contributor.authorMAGNAN, Christophe
dc.contributor.authorLANG, Jochen
dc.date.accessioned2020-09-03T08:01:56Z
dc.date.available2020-09-03T08:01:56Z
dc.date.issued2015
dc.identifier.issn0012-186X
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/10933
dc.description.abstractEnNutrient homeostasis requires integration of signals generated by glucose metabolism and hormones. Expression of the calcium-stimulated adenylyl cyclase ADCY8 is regulated by glucose and the enzyme is capable of integrating signals from multiple pathways. It may thus have an important role in glucose-induced signalling and glucose homeostasis. We used pharmacological and genetic approaches in beta cells to determine secretion and calcium metabolism. Furthermore, Adcy8 knockout mice were characterised. In clonal beta cells, inhibitors of adenylyl cyclases or their downstream targets reduced the glucose-induced increase in cytosolic calcium and insulin secretion. This was reproduced by knock-down of ADCY8, but not of ADCY1. These agents also inhibited glucose-induced increase in cytosolic calcium and electrical activity in primary beta cells and similar effects were observed after ADCY8 knock-down. Moreover, insulin secretion was diminished in islets from Adcy8 knockout mice. These mice were glucose intolerant after oral or intraperitoneal administration of glucose whereas their levels of glucagon-like peptide-1 remained unaltered. Finally, we knocked down ADCY8 in the ventromedial hypothalamus to evaluate the need for ADCY8 in the central regulation of glucose homeostasis. Whereas mice fed a standard diet had normal glucose levels, high-fat diet exacerbated glucose intolerance and knock-down mice were incapable of raising their plasma insulin levels. Finally we confirmed that ADCY8 is expressed in human islets. Collectively, our findings demonstrate that ADCY8 is required for the physiological activation of glucose-induced signalling pathways in beta cells, for glucose tolerance and for hypothalamic adaptation to a high-fat diet via regulation of islet insulin secretion.
dc.language.isoen
dc.title.enMultilevel control of glucose homeostasis by adenylyl cyclase 8
dc.typeArticle de revue
dc.subject.halChimie/Matériaux
bordeaux.journalDiabetologia
bordeaux.page749-757
bordeaux.volume58
bordeaux.hal.laboratoriesInstitut de Chimie & de Biologie des Membranes & des Nano-objets (CBMN) - UMR 5248*
bordeaux.hal.laboratoriesInstitut de Chimie & de Biologie des Membranes & des Nano-objets (CBMN, UMR 5248)
bordeaux.issue4
bordeaux.institutionUniversité de Bordeaux
bordeaux.institutionBordeaux INP
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