Somatostatin-28 regulates GLP-1 secretion via somatostatin receptor subtype 5 in rat intestinal cultures.
Five somatostatin receptors (SSTRs) bind somatostatin-14 (S-14) and somatostatin-28 (S-28), but SSTR5 has the highest affinity for S-28. To determine whether S-28 acting through SSTR5 mediates inhibition of glucagon-like peptide-1 (GLP-1), fetal rat intestinal cell cultures were treated with somatostatin analogs with relatively high specificity for SSTRs 2-5. S-28 dose-dependently inhibited GLP-1 secretion stimulated by gastrin-releasing peptide more potently than S-14 (EC(50) 0.01 vs. 5.8 nM). GLP-1 secretion was inhibited by an SSTR5 analog, BIM-23268, more potently than S-14 and nearly as effectively as S-28. The SSTR5 analog L-372,588 also suppressed GLP-1 secretion equivalent to S-28, but a structurally similar peptide, L-362,855 (Tyr to Phe at position 7), was ineffective. An SSTR2-selective analog was less effective than S-28, and an SSTR3 analog was inactive. Separate treatment with GLP-1-(7-36)-NH(2) increased S-28 and S-14 secretion by three- and fivefold; BIM-23268 abolished S-28 without altering S-14, whereas the SSTR2 analog was inactive. The results indicate that somatostatin regulation of GLP-1 secretion occurs via S-28 through activation of SSTR5. GLP-1-stimulated S-28 secretion is also autoregulated by SSTR5 activation, suggesting a feedback loop between GLP-1 and S-28 modulated by SSTR5.
Chisholm
Connie
C
Department of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada M5G 1X5.
Greenberg
Gordon R
GR
D000818:Animals; D002478:Cells, Cultured; D005333:Fetus; D005934:Glucagon / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1; D004763:Glucagon-Like Peptides; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology / Q000196:embryology; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D011498:Protein Precursors / Q000378:metabolism*; D051381:Rats; D017481:Receptors, Somatostatin / Q000502:physiology*; D013004:Somatostatin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D053561:Somatostatin-28
D010446:Peptide Fragments; D011498:Protein Precursors; D017481:Receptors, Somatostatin; C055453:glucagon-like peptide 1 (7-36)amide; D013004:Somatostatin; D004763:Glucagon-Like Peptides; D053561:Somatostatin-28; D052216:Glucagon-Like Peptide 1; C094573:somatostatin receptor 5; D005934:Glucagon