Multilevel control of glucose homeostasis by adenylyl cyclase 8 - Biological Adaptation and Ageing Accéder directement au contenu
Article Dans Une Revue Diabetologia Année : 2015

Multilevel control of glucose homeostasis by adenylyl cyclase 8

Matthieu Raoux
Pierre Vacher
Julien Papin
  • Fonction : Auteur
Alexandre Picard
  • Fonction : Auteur
Elzbieta Kostrzewa
  • Fonction : Auteur
Anne Devin
  • Fonction : Auteur
Julien Gaitan
  • Fonction : Auteur
Martien J. Kas
  • Fonction : Auteur
Christophe Magnan
Jochen Lang
  • Fonction : Auteur
  • PersonId : 1061965
  • IdHAL : jochen-lang

Résumé

Nutrient 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.

Dates et versions

hal-01545427 , version 1 (22-06-2017)

Identifiants

Citer

Matthieu Raoux, Pierre Vacher, Julien Papin, Alexandre Picard, Elzbieta Kostrzewa, et al.. Multilevel control of glucose homeostasis by adenylyl cyclase 8. Diabetologia, 2015, 58 (4), pp.749-757. ⟨10.1007/s00125-014-3445-z⟩. ⟨hal-01545427⟩
141 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More