Download PDF
Horm Metab Res 2004; 36(9): 595-600
DOI: 10.1055/s-2004-825921
Original Basic
© Georg Thieme Verlag KG Stuttgart · New York

Exendin-4 Dose-dependently Stimulates Somatostatin and Insulin Secretion in Perfused Rat Pancreas

E.  M.  Egido1 , R.  A.  Silvestre1 , R.  Hernández1 , J.  Marco1
  • 1Hospital Universitario Puerta de Hierro and Department of Physiology, Medical School, Universidad Autónoma de Madrid, San Martín de Porres 4, 28035 Madrid, Spain
Further Information

Publication History

Received 15 December 2003

Accepted after revision 6 May 2004

Publication Date:
05 October 2004 (online)

Also available at
    Permissions and Reprints

Abstract

We have investigated the effect of exendin-4, a GLP-1 analogue, on somatostatin and insulin secretion in perfused rat pancreas. At constant glucose concentration within the type 2 diabetic range (9 mM), exendin-4 stimulated somatostatin and insulin secretion in a dose-dependent manner. Dose-response curves were sigmoidal (R2 = 0.9954 and R2 = 0.9973, respectively; p < 0.01) and the EC50 was 4.3 nM for somatostatin secretion and 1.4 nM for insulin secretion. Exendin-4 stimulated somatostatin output at low (3.2 mM), normal (5.5 mM) and high (9 mM) glucose concentrations, while the insulinotropic effect of exendin-4 was not found at low glucose levels. On the other hand, exendin-4 potentiated somatostatin and insulin responses to an increase in perfusate glucose levels, and to arginine and carbachol. Finally, the insulinotropic effect of exendin-4 was maintained in the absence of a somatostatin response as induced by cysteamine pretreatment, indicating a direct effect of exendin-4 on the B-cell. In summary, exendin-4 behaves as a general stimulatory agent of both insulin and somatostatin release in the perfused rat pancreas. Given that exendin-4 has also been shown to increase gastric somatostatin secretion, it is tempting to speculate that exendin-4 might behave as a general stimulator of D-cell function in other tissues, a point worthy of further investigation.

Key words

Exendin-4 · Pancreatic somatostatin secretion · Insulin secretion

References

  • 1 Eng J, Kleinman W A, Singh L, Singh G, Raufman J P. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas.  J Biol Chem. 1992;  267 7402-7405
    PubMedSearch in Google Scholar
  • 2 Göke R, Fehmann H C, Linn T, Schmidt H, Krause M, Eng J, Göke B. Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting B-cells.  J Biol Chem. 1993;  268 19 650-19 655
    PubMedSearch in Google Scholar
  • 3 Rodríguez-Gallardo J, Silvestre R A, Egido E M, Marco J. Insulin secretory pattern induced by exendin-4. Study in the perfused rat pancreas.  Diabetologia. 2000;  43 A138
    PubMedSearch in Google Scholar
  • 4 Parkes D G, Pittner R, Jodka C, Smith P, Young A. Insulinotropic actions of exendin-4 and glucagon-like peptide-1 in vivo and in vitro.  Metabolism. 2001;  50 583-589
    CrossrefPubMedSearch in Google Scholar
  • 5 Egan J M, Clocquet A R, Elahi D. The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes.  J Clin Endocrinol Metab. 2002;  87 1282-1290
    CrossrefPubMedSearch in Google Scholar
  • 6 Tourrel C, Bailbe D, Lacorne M, Meile M J, Kergoat M, Portha B. Persistent improvement of type 2 diabetes in the Goto-Kakizaki rat model by expansion of the beta-cell mass during the prediabetic period with glucagon-like peptide or exendin-4.  Diabetes. 2002;  51 1443-1452
    PubMedSearch in Google Scholar
  • 7 Chepurny O G, Hussain M A, Holz G G. Exendin-4 as a stimulator of rat insulin I gene promoter activity via bZIP/CRE interactions sensitive to serine/threonine protein kinase inhibitor Ro 31-8220.  Endocrinology. 2002;  143 2303-2313
    CrossrefPubMedSearch in Google Scholar
  • 8 Silvestre R A, Rodríguez-Gallardo J, Egido E M, Marco J. Interrelationship among insulin, glucagon and somatostatin secretory responses to exendin-4 in the perfused rat pancreas.  Eur J Pharmacol. 2003;  469 195-200
    CrossrefPubMedSearch in Google Scholar
  • 9 Gedulin B, Jodka L, Hoyt J. Exendin-4 (AC2993) decreases glucagon secretion during hyperglycemic clamps in diabetic fatty Zucker rats.  Diabetes. 1999;  48 A199
    PubMedSearch in Google Scholar
  • 10 Baron A, Fineman M, Young A, Gaines E, Prickett K. Synthetic exendin-4 (AC2993) reduces post-prandial glycaemia, glucagon levels and slows gastric emptying in subjects with type 2 diabetes.  Diabetologia. 2000;  43 A190
    PubMedSearch in Google Scholar
  • 11 Kolterman O, Gottlieb A, Prickett K, Gaines E, Young A. Dose-response for inhibition of glucagon secretion and gastric emptying by synthetic exendin-4 (AC2993) in subjects with type 2 diabetes.  Diabetes. 2000;  49 A114
    PubMedSearch in Google Scholar
  • 12 Parkes D G, Gedulin B, Smith P, Young A. Effect of exendin-4 on glucagon secretion in lean and obese Zucker (ZDF) rats.  Diabetes. 2001;  50 A313
    PubMedSearch in Google Scholar
  • 13 Rodríguez-Gallardo J, Egido E M, Gutiérrez E, Garcia P, Silvestre R A, Marco J. Evidence for a direct inhibitory effect of exendin-4 on alpha-cell secretion.  Diabetologia. 2002;  45 A214
    PubMedSearch in Google Scholar
  • 14 Greig N H, Holloway H W, De Ore K A. One-daily injection of exendin-4 to diabetic mice achieves long-term beneficial effects on blood glucose concentration.  Diabetologia. 1999;  42 45-50
    CrossrefPubMedSearch in Google Scholar
  • 15 Young A A, Gedulin B R, Bhavsar S, Bodkin N, Jodka C, Hanse B, Denaro M. Glucose-lowering and insulin sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta).  Diabetes. 1999;  48 1026-1034
    PubMedSearch in Google Scholar
  • 16 Szayna M, Doyle M E, Betkey J A, Holloway H N, Spencer R G, Greig N H, Egan J M. Exendin-4 decelerates food intake, weight gain, and fat deposition in Zucker rats.  Endocrinology. 2000;  141 1936-1941
    CrossrefPubMedSearch in Google Scholar
  • 17 Tourrel C, Bailbe D, Lacorne M, Meile M J, Kergoat M, Portha B. Persistent improvement of type 2 diabetes in the Goto-Kakizaki rat model by expansion of the beta-cell mass during the prediabetic period with glucagon-like peptide or exendin-4.  Diabetes. 2002;  51 1443-1452
    PubMedSearch in Google Scholar
  • 18 Egan J M, Meneilly G S, Elahi D. Effects of 1-mo bolus subcutaneaous administration of exendin-4 in type 2 diabetes.  Am J Physiol Endocrinol Metab. 2003;  284 E1072-1079
    PubMedSearch in Google Scholar
  • 19 Eissele R, Bothe-Sandfort E, Göke B, Eng J, Arnold R, Koop H. Rat gastric somatostatin and gastrin release: interactions of exendin-4 and truncated glucagon-like peptide-1 (GLP-1) amide.  Life Sci. 1994;  55 629-634
    CrossrefPubMedSearch in Google Scholar
  • 20 Silvestre R A, Miralles P, Moreno P, Villanueva M L, Marco J. Somatostatin, insulin and glucagon secretion by the perfused rat pancreas from the cysteamine-treated rats.  Biochem Biophys Res Commun. 1986;  134 1291-1297
    CrossrefPubMedSearch in Google Scholar
  • 21 Herbert V, Lau K S, Gottlieb C W, Bleicher S J. Coated charcoal immunoassay of insulin.  J Clin Endocrinol Metab. 1965;  25 1375-1384
    CrossrefPubMedSearch in Google Scholar
  • 22 Kieffer T J, McIntosh C HS, Pederson R A. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV.  Endocrinology. 1995;  136 3585-3596
    CrossrefPubMedSearch in Google Scholar
  • 23 Mentlein R, Gallwitz B, Schmidt W E. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum.  Eur J Biochem. 1993;  214 829-835
    CrossrefPubMedSearch in Google Scholar
  • 24 Parkes D G, Jodka C, Smith P, Nayak S, Rinehart L, Gingerich R, Chen K, Young A. Pharmacokinetic actions of exendin-4 in the rat: comparison with glucagon-like peptide-1.  Drug Dev Res. 2001;  53 260-267
    CrossrefPubMedSearch in Google Scholar
  • 25 Drucker D J. Glucagon-like peptides.  Diabetes. 1998;  47 159-169
    CrossrefPubMedSearch in Google Scholar
  • 26 Ørskov C. Glucagon-like peptide-1, a new hormone of the entero-insular axis.  Diabetologia. 1992;  35 701-711
    PubMedSearch in Google Scholar
  • 27 Holz G G, Kühtreiber W M, Habener J F. Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1 (7-37).  Nature. 1993;  361 362-365
    CrossrefPubMedSearch in Google Scholar
  • 28 Drucker D J, Phillippe J, Mojsov S, Chick W L, Haberner J F. Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line.  Proc Natl Acad Sci USA. 1987;  84 3434-3438
    PubMedSearch in Google Scholar
  • 29 Blachier F, Mourtada A, Sener A, Malaisse A J. Stimulus-secretion coupling of arginine-induced insulin release. Uptake of metabolized and nonmetabolized cationic amino acids by pancreatic islets.  Endocrinology. 1989;  124 134-141
    CrossrefPubMedSearch in Google Scholar
  • 30 Zawalich W S. Regulation of insulin secretion by phosphoinositide-specific phospholipase V and protein kinase C activation.  Diabetes Review. 1996;  4 160-176
    PubMedSearch in Google Scholar
  • 31 Samols E, Stagner J I, Ewart R BL, Marks V. The order of islet microvascular cellular perfusion is B>A>D in the perfused rat pancreas.  Clin J Invest. 1988;  82 350-353
    PubMedSearch in Google Scholar
  • 32 Thorens B, Porret A, Bühler L, Deng S P, Morel P, Widmann C. Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor.  Diabetes. 1993;  42 1678-1682
    CrossrefPubMedSearch in Google Scholar
  • 33 Fehmann H C, Haberner J F. Functional receptors for the insulinotropic hormone glucagon-like peptide-I-(7-37) on a somatostatin secreting cell line.  FEBS Lett. 1991;  279 335-340
    CrossrefPubMedSearch in Google Scholar
  • 34 Gros L, Thorens B, Bataille D, Kervran A. Glucagon-like peptide-1-(7-36) amide, oxyntomodulin, and glucagon interact with a common receptor in a somatostatin-secreting cell line.  Endocrinology. 1993;  133 631-638
    CrossrefPubMedSearch in Google Scholar
  • 35 Göke R, Cole T, Conlon J M. Characterization of the receptor for glucagon-like peptide-1 (7-36) amide on plasma membranes from rat insulinoma-cells by covalent cross-linking.  J Mol Endocrinol. 1989;  2 93-98
    PubMedSearch in Google Scholar
  • 36 Heller R S, Kieffer T J, Habener J F. Insulinotropic glucagon-like peptide I receptor expression in glucagon-producing alpha-cells of the rat endocrine pancreas.  Diabetes. 1997;  46 785-791
    PubMedSearch in Google Scholar
  • 37 Horsck D, Göke R, Eissele R, Michel B, Göke B. Repriprocal cellular distribution of glucagon-like peptide-1 (GLP-1) immunoreactivity and GLP-1 receptor mRNA in pancreatic islet of rat.  Pancreas. 1997;  14 290-294
    PubMedSearch in Google Scholar
  • 38 Thorens N. Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1.  Proc Natl Acad Sci USA. 1992;  89 8641-8645
    CrossrefPubMedSearch in Google Scholar

R. A. Silvestre, Ph. D.

Hospital Universitario Puerta de Hierro and Department of Physiology, Medical School, Universidad Autónoma de Madrid

San Martín de Porres, 4 · 28035 Madrid · Spain

Phone: +34 (91) 316 22 40, Ext. 5463

Fax: +34 (91) 373 76 67

Email: rsilvestre.hpth@salud.madrid.org