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

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 (R (2) = 0.9954 and R (2) = 0.9973, respectively; p < 0.01) and the EC (50) 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.

[1]  J. Egan,et al.  Effects of 1-mo bolus subcutaneous administration of exendin-4 in type 2 diabetes. , 2003, American journal of physiology. Endocrinology and metabolism.

[2]  R. Silvestre,et al.  Interrelationship among insulin, glucagon and somatostatin secretory responses to exendin-4 in the perfused rat pancreas. , 2003, European journal of pharmacology.

[3]  M. Hussain,et al.  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. , 2002, Endocrinology.

[4]  B. Portha,et al.  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-1 or exendin-4. , 2002, Diabetes.

[5]  J. Egan,et al.  The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes. , 2002, The Journal of clinical endocrinology and metabolism.

[6]  A. Young,et al.  Pharmacokinetic actions of exendin‐4 in the rat: Comparison with glucagon‐like peptide‐1 , 2001 .

[7]  A. Young,et al.  Insulinotropic actions of exendin-4 and glucagon-like peptide-1 in vivo and in vitro. , 2001, Metabolism: clinical and experimental.

[8]  N. Greig,et al.  Exendin-4 decelerates food intake, weight gain, and fat deposition in Zucker rats. , 2000, Endocrinology.

[9]  J. Habener,et al.  The glucagon-like peptides. , 1999, Endocrine reviews.

[10]  A. Young,et al.  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). , 1999, Diabetes.

[11]  J. Habener,et al.  Insulinotropic Glucagon-Like Peptide I Receptor Expression in Glucagon-Producing α-Cells of the Rat Endocrine Pancreas , 1997, Diabetes.

[12]  R. Pederson,et al.  Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. , 1995, Endocrinology.

[13]  Shaoping Deng,et al.  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 , 1993, Diabetes.

[14]  B. Göke,et al.  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 beta-cells. , 1993, The Journal of biological chemistry.

[15]  B. Gallwitz,et al.  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. , 1993, European journal of biochemistry.

[16]  J. Habener,et al.  Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7-37) , 1993, Nature.

[17]  B. Thorens.  Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[18]  D. Bataille,et al.  Glucagon-like peptide-1(7–36)amide, oxyntomodulin and glucagon interact with a common receptor in a somatostatin-secreting cell line , 1992, Regulatory Peptides.

[19]  J. Raufman,et al.  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. , 1992, The Journal of biological chemistry.

[20]  J. Habener,et al.  Functional receptors for the insulinotropic hormone glucagon‐like peptide‐I(7–37) on a somatostatin secreting cell line , 1991, FEBS letters.

[21]  J. Conlon,et al.  Characterization of the receptor for glucagon-like peptide-1(7-36)amide on plasma membranes from rat insulinoma-derived cells by covalent cross-linking. , 1989, Journal of molecular endocrinology.

[22]  V. Marks,et al.  The order of islet microvascular cellular perfusion is B----A----D in the perfused rat pancreas. , 1988, The Journal of clinical investigation.

[23]  D. Drucker,et al.  Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[24]  R. Silvestre,et al.  Somatostatin, insulin and glucagon secretion by the perfused pancreas from the cysteamine-treated rat. , 1986, Biochemical and biophysical research communications.

[25]  V. Herbert,et al.  Coated charcoal immunoassay of insulin. , 1965, The Journal of clinical endocrinology and metabolism.

[26]  B. Göke,et al.  Rat gastric somatostatin and gastrin release: interactions of exendin-4 and truncated glucagon-like peptide-1 (GLP-1) amide. , 1994, Life sciences.

[27]  C. Orskov.  Glucagon-like peptide-1, a new hormone of the entero-insular axis. , 1992, Diabetologia.

[28]  W. Malaisse,et al.  Stimulus-secretion coupling of arginine-induced insulin release. Uptake of metabolized and nonmetabolized cationic amino acids by pancreatic islets. , 1989, Endocrinology.