Time-dependent stimulation of insulin exocytosis by 3',5'-cyclic adenosine monophosphate in the rat islet beta-cell.
Isolated rat islets were exposed to cAMP-elevating agents and/or nutrients. Insulin exocytosis subsequently triggered by a depolarizing concentration of K(+) or a stimulatory concentration of glucose was employed as an index of time-dependent potentiation (TDP). Stimulatory concentrations (>or=5.5 mM) of glucose caused TDP, and 6 micro M forskolin (an activator of adenylyl cyclase) significantly enhanced it (3.1-fold at most). Forskolin produced an 8.0-fold increase in islet cell cAMP; however, it returned to the baseline after washout by the time of stimulation of exocytosis. Two millimoles of dibutyryl cAMP (a cAMP analog), 0.1 mM isobutylmethylxanthine (a phosphodiesterase inhibitor), and 100 nM glucagon-like peptide-1 (an incretin hormone) also enhanced glucoseinduced TDP. The time-dependent effect of cAMP was not attenuated by protein kinase A inhibitors (200 micro M adenosine 3',5'-cyclic monophosphothioate, Rp isomer, and 10 micro M H89). Although glucose-induced TDP was attenuated by NaN(3) (a mitochondrial poison) and cerulenin (an inhibitor of protein acylation), cAMP enhancement of it was unaffected by these agents. In conclusion, cAMP time-dependently stimulates insulin exocytosis, provided the extracellular glucose concentration is equivalent to or higher than ambient plasma levels. Protein kinase A, mitochondrial metabolism, and protein acylation are not involved in this cAMP action. Incretin stimulation of insulin exocytosis may occur in part via this mechanism.
Yamada
Satoko
S
Department of Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, 371-8512, Japan.
Komatsu
Mitsuhisa
M
Sato
Yoshihiko
Y
Yamauchi
Keishi
K
Kojima
Itaru
I
Aizawa
Toru
T
Hashizume
Kiyoshi
K
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002569:Cerulenin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000032:analysis / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005089:Exocytosis / Q000187:drug effects*; D005934:Glucagon / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011498:Protein Precursors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D002569:Cerulenin; D005576:Colforsin; D003994:Bucladesine; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D005947:Glucose; D011188:Potassium; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine