Chronic treatment with exendin(9–39)amide indicates a minor role for endogenous glucagon-like peptide-1 in metabolic abnormalities of obesity-related diabetes in ob/ob mice

Abstract

Glucagon-like peptide-1 (GLP-1) is a potent insulinotropic hormone proposed to play a role in both the pathophysiology and treatment of type 2 diabetes. This study has employed the GLP-1 receptor antagonist, exendin-4(9-39)amide (Ex(9-39)) to evaluate the role of endogenous GLP-1 in genetic obesity-related diabetes and related metabolic abnormalities using ob/ob and normal mice. Acute in vivo antagonistic potency of Ex(9-39) was confirmed in ob/ob mice by blockade of the insulinreleasing and anti-hyperglycaemic actions of intraperitoneal GLP-1. In longer term studies, ob/ob mice were given once daily injections of Ex(9-39) or vehicle for 11 days. Feeding activity, body weight, and both basal and glucosestimulated insulin secretion were not significantly affected by chronic Ex(9-39) treatment. However, significantly elevated basal glucose concentrations and impaired glucose tolerance were evident at 11 days. These disturbances in glucose homeostasis were independent of changes of insulin sensitivity and reversed by discontinuation of the Ex(9-39) for 9 days. Similar treatment of normal mice did not affect any of the parameters measured. These findings illustrate the physiological extrapancreatic glucoselowering actions of GLP-1 in ob/ob mice and suggest that the endogenous hormone plays a minor role in the metabolic abnormalities associated with obesity-related diabetes.

Osteocalcin Induces Release of Glucagon-Like Peptide-1 and Thereby Stimulates Insulin Secretion in Mice

“…We first confirmed that exendin(9–39) acted as a GLP-1 receptor antagonist in our experiments. Exendin-4 binds to and activates GLP-1 receptors [22], [23], and we found that intraperitoneal administration of exendin-4 increased the serum insulin concentration in mice in a manner sensitive to prior injection of exendin(9–39) at a dose (25 nmol/kg) previously shown [24] to fully antagonize GLP-1 signaling in mice (Fig. 4A).…”

GLP-1 and related peptides cause concentration-dependent relaxation of rat aorta through a pathway involving KATP and cAMP

“…Exendin-4 (1-39) is a peptide isolated from the salivary glands of the Gila monster lizard which possesses 53% sequence homology to GLP-1 and is a potent GLP-1 receptor agonist [21]. Exendin (9-39) is a well characterised antagonist of the GLP-1 receptor which has been demonstrated on numerous occasions to block the biological actions of both GLP-1(7-36)amide and exendin-4 (1-39) [20,21,23,[25][26][27]. Indeed, a previous study on the ex vivo vascular actions of GLP-1 reported that exendin (9-39) significantly inhibited GLP-1-induced relaxations in rat femoral artery [16].…”

Novel Glucagon-Like Peptide-1 (GLP-1) Analog (Val8)GLP-1 Results in Significant Improvements of Glucose Tolerance and Pancreatic β-Cell Function after 3-Week Daily Administration in Obese Diabetic (ob/ob) Mice

“…The extent to which this reflects possible long-term exposure to the truncated metabolite GLP-1-(9 -36) amide that acts as a weak antagonist at the GLP-1 receptor (Green et al, 2004c) is unknown. However, daily administration of the GLP-1 receptor antagonist, exendin(9 -39) amide mildly impaired glucose homeostasis in normal mice due to changes of insulin secretion (Green et al, 2005). It remains to be seen whether DPP IV processing of GLP-1 to this degradation fragment results in any alterations of metabolism in obese-diabetic ob/ob mice.…”