Multilevel control of glucose homeostasis by adenylyl cyclase 8.
OBJECTIVE
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.


METHODS
We used pharmacological and genetic approaches in beta cells to determine secretion and calcium metabolism. Furthermore, Adcy8 knockout mice were characterised.


RESULTS
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.


CONCLUSIONS
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.
Université de Bordeaux, CNRS UMR 5248, Chimie et Biologie des Membranes et Nano-objets, Batiment B14, Allée Geoffrey St Hilaire, CS90063, F-33615, Pessac, France.
Matthieu
M
Raoux
Pierre
P
Vacher
Julien
J
Papin
Alexandre
A
Picard
Elzbieta
E
Kostrzewa
Anne
A
Devin
Julien
J
Gaitan
Isabelle
I
Limon
Martien J
MJ
Kas
Christophe
C
Magnan
Jochen
J
Lang
D000262:Adenylyl Cyclases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005838:Genotype; D018149:Glucose Intolerance / Q000097:blood / Q000201:enzymology; D006706:Homeostasis; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000378:metabolism; D008564:Membrane Potentials; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014697:Ventromedial Hypothalamic Nucleus / Q000201:enzymology
D001786:Blood Glucose; D007328:Insulin; D000262:Adenylyl Cyclases; C118292:adenylyl cyclase 8; D002118:Calcium