Regulation of islet somatostatin secretion and gene expression: selective effects of adenosine 3',5'-monophosphate and phorbol esters in normal islets of Langerhans and in a somatostatin-producing rat islet clonal cell line 1027 B2.
To investigate cAMP-dependent regulation of somatostatin secretion and gene expression in the islets of Langerhans, we have correlated the effects of forskolin, theophylline, and (Bu)2cAMP (dbcAMP) on the secretion of somatostatin-like immunoreactivity (SLI), cAMP generation, and somatosatin mRNA (S-mRNA) accumulation by cultured rat islet cells and a rat somatostatin-producing islet tumor cell line (1027 B2). Additionally, we have compared these effects with those of phorbol esters. Forskolin induced large acute increases in cAMP levels in islet cells, whereas theophylline produced modest sustained elevations in cAMP. During 4-h exposure to islets cells, forskolin, theophylline, and dbcAMP produced time- and dose-related increases of up to 14-fold in SLI release and up to 5-fold in S-mRNA levels. The rate of increase in S-mRNA paralleled secretion and occurred with the following order of potency: forskolin greater than dbcAMP greater than theophylline. The analog 1,9-dideoxyforskolin, which is unable to activate adenylyl cyclase, produced a small increase in SLI release without affecting S-mRNA. The effects of short term increases in islet cAMP levels and SLI release on long term changes in S-mRNA accumulation were investigated in a 48-h study with forskolin. Pretreatment of islet cells for 30 min with forskolin evoked large acute increases in cAMP levels and SLI release. S-mRNA rose in a biphasic pattern, with an acute increase at 30 min followed by a secondary increase at 12-48 h. In 1027B2 cells, forskolin and theophylline generated large increases in cAMP levels. Despite this, the two agents as well as dbcAMP produced only slight (20-35%) stimulation of SLI release and S-mRNA accumulation. Phorbol 12-myristate 13-acetate and phorbol 12,13-dibutyrate evoked dose-dependent stimulation of SLI secretion of up to 4-fold from islet cells without altering S-mRNA. Both secretion and S-mRNA were unresponsive to phorbol esters in 1027 B2 cells.(ABSTRACT TRUNCATED AT 400 WORDS)
Patel
Y C
YC
McGill University, Department of Medicine, Royal Victoria Hospital, Quebec, Canada.
Papachristou
D N
DN
Zingg
H H
HH
Farkas
E M
EM
D007516:Adenoma, Islet Cell / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D003994:Bucladesine / Q000008:administration & dosage / Q000494:pharmacology; D005576:Colforsin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005934:Glucagon / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D010703:Phorbol Esters / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013004:Somatostatin / Q000235:genetics / Q000378:metabolism*; D013806:Theophylline / Q000008:administration & dosage / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D007328:Insulin; D010703:Phorbol Esters; D012333:RNA, Messenger; D005576:Colforsin; D013004:Somatostatin; D003994:Bucladesine; D005934:Glucagon; D013806:Theophylline; D000242:Cyclic AMP; C047983:1,9-dideoxyforskolin