title: Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas.
abstract: OBJECTIVE
  The glucose-lowering effect of glucagon-like peptide-1 (GLP-1) is based not only upon its potent insulinotropic actions but also on its ability to restrain glucagon secretion. Surprisingly, the closely related glucose-dependent insulinotropic peptide (GIP) stimulates glucagon release. We examined whether the islet hormone somatostatin, which strongly inhibits glucagon secretion, is involved in this divergent behaviour.
  
  
  METHODS
  At 1.5 mmol/l glucose and therefore minimal insulin secretion, the glucagon, insulin and somatostatin responses to 20 mmol/l glucose, GLP-1, GIP and somatostatin were studied in the presence of a high-affinity monoclonal somatostatin antibody and of a highly specific somatostatin receptor subtype 2 (SSTR2) antagonist (PRL-2903) in the isolated perfused rat pancreas.
  
  
  RESULTS
  In control experiments, GLP-1 at 1 and 10 nmol/l reduced glucagon secretion significantly to 59.0 +/- 6.3% (p < 0.004; n = 5; SSTR2 series; each vs pre-infusion level) and to 48.0 +/- 2.6% (p < 0.001; n = 6; somatostatin antibody series) respectively. During somatostatin antibody administration, GLP-1 still inhibited glucagon secretion significantly, but the effect was less pronounced than in control experiments (p < 0.018). Co-infusion of the SSTR2 antagonist completely abolished the GLP-1-induced suppression of glucagon secretion. In contrast, neither the GIP-induced stimulation of glucagon release nor its inhibition by 20 mmol/l glucose was altered by somatostatin antibody or SSTR2 antagonist administration.
  
  
  CONCLUSIONS
  We conclude that GLP-1 is capable of inhibiting glucagon secretion even in the absence of secretory products from the beta cell. It is highly likely that this is mediated via somatostatin interacting with SSTR2 on rat alpha cells. In contrast, GIP and glucose seem to influence the alpha cell independently of somatostatin secretion.
authors.affiliation: Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: de Heer
authors.forename: C
authors.initials: C
authors.lastname: Rasmussen
authors.forename: D H
authors.initials: DH
authors.lastname: Coy
authors.forename: J J
authors.initials: JJ
authors.lastname: Holst
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology; D005934:Glucagon / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D010179:Pancreas / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013004:Somatostatin / Q000276:immunology
chemical_list: D000906:Antibodies; D007328:Insulin; D017481:Receptors, Somatostatin; D013004:Somatostatin; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; C093733:somatostatin receptor 2
references.citation: Diabetes. 1997 May;46(5):785-91
references.pmid: 9133545
references.citation: Regul Pept. 1983 Apr;6(1):63-9
references.pmid: 6191365
references.citation: Horm Metab Res. 2004 Nov-Dec;36(11-12):747-54
references.pmid: 15655703
references.citation: J Clin Endocrinol Metab. 2007 Feb;92(2):673-80
references.pmid: 17105845
references.citation: Diabetes. 2000 Sep;49(9):1500-10
references.pmid: 10969834
references.citation: J Histochem Cytochem. 2004 Mar;52(3):391-400
references.pmid: 14966206
references.citation: J Clin Invest. 1990 Apr;85(4):983-7
references.pmid: 1969425
references.citation: Diabetes. 2005 Jun;54(6):1808-15
references.pmid: 15919803
references.citation: Biochem Biophys Res Commun. 1994 Nov 30;205(1):341-6
references.pmid: 7999046
references.citation: J Physiol. 2003 Jun 15;549(Pt 3):889-901
references.pmid: 12692184
references.citation: J Clin Invest. 1984 Dec;74(6):2296-9
references.pmid: 6392344
references.citation: Am J Physiol. 1992 Dec;263(6 Pt 1):G908-12
references.pmid: 1362042
references.citation: J Clin Endocrinol Metab. 2000 Nov;85(11):4053-9
references.pmid: 11095432
references.citation: Am J Physiol. 1983 Oct;245(4):G519-24
references.pmid: 6194694
references.citation: Br J Pharmacol. 1998 Nov;125(5):1081-7
references.pmid: 9846648
references.citation: Proc Natl Acad Sci U S A. 1979 Nov;76(11):5901-4
references.pmid: 118458
references.citation: Diabetes. 1992 Jan;41(1):93-7
references.pmid: 1345782
references.citation: Cell Metab. 2008 Jun;7(6):545-54
references.pmid: 18522835
references.citation: Endocrinology. 1978 Aug;103(2):610-5
references.pmid: 744105
references.citation: Nat Cell Biol. 2007 Apr;9(4):453-60
references.pmid: 17369816
references.citation: Diabetes. 2004 Dec;53 Suppl 3:S181-9
references.pmid: 15561909
references.citation: Science. 1974 Apr 26;184(4135):482-4
references.pmid: 4594711
references.citation: Diabetologia. 2007 Feb;50(2):370-9
references.pmid: 17136393
references.citation: Am J Anat. 1986 Jan;175(1):49-58
references.pmid: 3953470
references.citation: Lancet. 1973 Dec 8;2(7841):1299-301
references.pmid: 4127645
references.citation: Diabetologia. 1993 Aug;36(8):741-4
references.pmid: 8405741
references.citation: Diabetes. 1996 Feb;45(2):257-61
references.pmid: 8549871
references.citation: Diabetes. 2004 Apr;53(4):1038-45
references.pmid: 15047619
references.citation: J Clin Invest. 1977 Nov;60(5):1216-9
references.pmid: 908761
references.citation: Regul Pept. 1982 Jun;4(1):13-31
references.pmid: 6126917
references.citation: Front Neuroendocrinol. 1999 Jul;20(3):157-98
references.pmid: 10433861
references.citation: Diabetes. 1999 Jan;48(1):77-85
references.pmid: 9892225
references.citation: Acta Endocrinol (Copenh). 1982 Mar;99(3):416-21
references.pmid: 6122321
references.citation: J Med Chem. 1999 Jun 3;42(11):1863-71
references.pmid: 10354394
references.citation: Nat Cell Biol. 2003 Apr;5(4):330-5
references.pmid: 12640462
references.citation: Proc Natl Acad Sci U S A. 1977 May;74(5):2140-3
references.pmid: 325567
references.citation: Pflugers Arch. 1998 Apr;435(5):583-94
references.pmid: 9479010
references.citation: J Clin Invest. 1988 Jul;82(1):350-3
references.pmid: 2455737
references.citation: PLoS Biol. 2007 Jun;5(6):e143
references.pmid: 17503968
references.citation: Diabetes. 2007 Feb;56(2):438-43
references.pmid: 17259389
references.citation: J Clin Invest. 1991 Feb;87(2):415-23
references.pmid: 1991827
references.citation: Endocr Rev. 1995 Jun;16(3):390-410
references.pmid: 7671853
references.citation: Pancreas. 2001 Oct;23(3):302-8
references.pmid: 11590327
references.citation: Diabetes. 2003 May;52(5):1176-81
references.pmid: 12716749
references.citation: Metabolism. 1990 Sep;39(9 Suppl 2):55-60
references.pmid: 1976222
references.citation: Am J Physiol. 1995 Sep;269(3 Pt 1):E469-77
references.pmid: 7573424
references.citation: Endocrinology. 2000 Jan;141(1):111-7
references.pmid: 10614629
references.citation: Diabetologia. 2003 Jun;46(6):798-801
references.pmid: 12764578