Mechanisms of synergism between glucose and cAMP on stimulation of insulin release.
The mechanism of synergism between glucose and adenosine 3',5'-cyclic monophosphate (cAMP) on insulin release has been studied. Synergism may result from 1) inhibition of Na+-Ca2+ exchange by glucose and 2) a cAMP-induced sensitization of the release machinery to Ca2+. To distinguish between these two possibilities, isolated rat pancreatic islets were perifused with agents that raise intracellular levels of cAMP [3-isobutyl-1-methylxanthine (IBMX) and forskolin] and others that increase intracellular concentrations of Ca2+ either by blocking Na2+-Ca2+ exchange (ouabain and choline-Ringer solution) or by causing increased Ca2+ influx (KCl, carbachol, and 10 mM Ca2+). The results indicate that both the combination of cAMP and increased Ca2+ influx or blocked Na2-Ca2+ exchange and increased Ca2+ influx potentiated insulin release. When the relative potentiating abilities of cAMP and blocked Na2+-Ca2+ exchange were compared by determining the individual effects of IBMX and 1 mM ouabain (a concentration that causes similar inhibition of 45C2+ efflux as 16.7 mM glucose) in the presence of carbachol, cAMP was only 1.4 times more potent as a potentiating agent than blocked Na+-Ca2+ exchange. The greatest potentiation of insulin release was observed when Na+-Ca2+ exchange was blocked in the presence of increased levels of intracellular cAMP.
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001696:Biomechanical Phenomena; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002794:Choline / Q000494:pharmacology; D005576:Colforsin; D000242:Cyclic AMP / Q000502:physiology*; D004224:Diterpenes / Q000494:pharmacology; D004357:Drug Synergism; D005947:Glucose / Q000502:physiology*; D007328:Insulin / Q000378:metabolism*; D007474:Ion Exchange; D007515:Islets of Langerhans / Q000378:metabolism; D007552:Isotonic Solutions / Q000494:pharmacology; D008297:Male; D010042:Ouabain / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D000077331:Ringer's Solution; D012964:Sodium / Q000378:metabolism; D013268:Stimulation, Chemical; D014700:Verapamil / Q000494:pharmacology
D004224:Diterpenes; D007328:Insulin; D007552:Isotonic Solutions; D005576:Colforsin; D010042:Ouabain; D011189:Potassium Chloride; D000077331:Ringer's Solution; D002217:Carbachol; D012964:Sodium; D014700:Verapamil; D000242:Cyclic AMP; D005947:Glucose; D002794:Choline; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine