Glucose-induced cyclic AMP oscillations regulate pulsatile insulin secretion.
Cyclic AMP (cAMP) and Ca(2+) are key regulators of exocytosis in many cells, including insulin-secreting beta cells. Glucose-stimulated insulin secretion from beta cells is pulsatile and involves oscillations of the cytoplasmic Ca(2+) concentration ([Ca(2+)](i)), but little is known about the detailed kinetics of cAMP signaling. Using evanescent-wave fluorescence imaging we found that glucose induces pronounced oscillations of cAMP in the submembrane space of single MIN6 cells and primary mouse beta cells. These oscillations were preceded and enhanced by elevations of [Ca(2+)](i). However, conditions raising cytoplasmic ATP could trigger cAMP elevations without accompanying [Ca(2+)](i) rise, indicating that adenylyl cyclase activity may be controlled also by the substrate concentration. The cAMP oscillations correlated with pulsatile insulin release. Whereas elevation of cAMP enhanced secretion, inhibition of adenylyl cyclases suppressed both cAMP oscillations and pulsatile insulin release. We conclude that cell metabolism directly controls cAMP and that glucose-induced cAMP oscillations regulate the magnitude and kinetics of insulin exocytosis.
Dyachok
Oleg
O
Department of Medical Cell Biology, Uppsala University, Biomedical Centre, Box 571, SE-751 23 Uppsala, Sweden.
Idevall-Hagren
Olof
O
Sågetorp
Jenny
J
Tian
Geng
G
Wuttke
Anne
A
Arrieumerlou
Cécile
C
Akusjärvi
Göran
G
Gylfe
Erik
E
Tengholm
Anders
A
D000818:Animals; D002118:Calcium; D000242:Cyclic AMP / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005089:Exocytosis; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008856:Microscopy, Fluorescence; D015290:Second Messenger Systems
D007328:Insulin; D000242:Cyclic AMP; D005947:Glucose; D002118:Calcium