Inhibition by cyclosporine of insulin secretion--a beta cell-specific alteration of islet tissue function.
We have reported the potent inhibitory effect of cyclosporine on glucose-induced insulin release in in vitro perfused pancreases. Suppression of both phases of release indicates inhibition of secretion and synthesis. Further studies were performed to examine the effect of high extracellular Ca2+ (4.875 mM). High Ca2+ failed to potentiate release in CsA-treated pancreases, thus we are focusing on the integrity of Ca(2+)-dependent signals in the beta cell. In this study, four groups of pancreases were perfused at 16.7 mM glucose: Control +/- somatostatin (SRIF) and CsA-treated +/- SRIF (60 nM). In control rats, the total 2-hr release decreased 40% with SRIF, from 42.7 +/- 5.5 to 25.5 +/- 3.9 micrograms/300 g body weight (P less than .05). In CsA-treated rats, release decreased 55% with SRIF, from 8.9 +/- 1.1 to 4.0 +/- 0.6 micrograms/300 g body weight. Further, at every time point of these CsA-treated rats, there was approximately 15% greater inhibition by SRIF than in controls. Pancreatic insulin contents were determined, indicating marked depletion of insulin stores in CsA-treated rats (190 +/- 9 vs. 76 +/- 5 micrograms/300 g body weight, P less than .01). Arginine-stimulated secretion of insulin and glucagon was also examined in control and CsA-treated pancreases. CsA exerted no effect on arginine-stimulated glucagon release, yet inhibited insulin approximately 50%. From these studies, we conclude that normal SRIF inhibitory mechanisms must be at least partially intact in CsA-treated pancreases during glucose-induced insulin release, and that CsA inhibition is specific for insulin release, as glucagon stores and arginine-stimulated glucagon release are unaffected by CsA.
Department of Physiological Sciences, University of California, Davis 95616.
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Gillison
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Bartlett
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Curry
D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D005934:Glucagon / Q000378:metabolism; D005947:Glucose; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009929:Organ Size; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D013004:Somatostatin / Q000494:pharmacology; D013997:Time Factors
D007328:Insulin; D013004:Somatostatin; D016572:Cyclosporine; D005934:Glucagon; D001120:Arginine; D005947:Glucose; D002118:Calcium