What is the role of the metabolite generated by DPP-4 cleavage of intact GLP-1, GLP-1(9-36)amide in physiological control of glucose homeostasis?

Although some studies have suggested that GLP-1 (9-36)amide may be an antagonist of GLP-1 action at the known GLP-1 receptor Glucagon-like peptide-1-(9-36) amide is a major metabolite of glucagon-like peptide-1-(7-36) amide after in vivo administration to dogs, and it acts as an antagonist on the pancreatic receptor. Eur J Pharmacol. 1996 Dec 30;318(2-3):429-35, other studies have failed to demonstrate the same antagonist properties of this GLP-1 degradation product. Experiments in pigs carried out in the presence of a DPP-4 inhibitor show a modest but significant independent effect of GLP-1 (9-36)amide on glucose clearance through an as yet unidentified mechanism of action. See GLP-1-(9-36) amide reduces blood glucose in anesthetized pigs by a mechanism that does not involve insulin secretion. Am J Physiol Endocrinol Metab. 2002 Apr;282(4):E873-9. Critically however, studies examining the biological activity of GLP-1 (9-36)amide in healthy human volunteers failed to demonstrate an effect of this metabolite on glucose clearance or insulin secretion as outlined in Effects of GLP-1-(7-36)NH2, GLP-1-(7-37), and GLP-1- (9-36)NH2 on intravenous glucose tolerance and glucose-induced insulin secretion in healthy humans. J Clin Endocrinol Metab. 2003 Apr;88(4):1772-9.

Analysis of the ratio of biologically intact GLP-1(7-36)amide versus GLP-1(9-36)amide in patients with type 2 diabetes following GLP-1 infusion with or without concomitant administration of a DPP-4 inhibitor found no evidence that levels of GLP-1(9-36)amide were correlated with changes in plasma glucose The metabolite generated by dipeptidyl-peptidase 4 metabolism of glucagon-like peptide-1 has no influence on plasma glucose levels in patients with type 2 diabetes. Diabetologia. 2005 Dec 30:1-6.

In contrast, administration of GLP-1(9-36)amide into fasting healthy human male subjects for 390 minutes, in the presence of a test meal, modestly but significantly reduced the rise in postprandial hyperglycemia, without effects on gastric emptying or on plasma levels of insulin, or glucagon, perhaps through effects on glucose disposal  The glucagon-like peptide 1 metabolite GLP-1 (9-36)amide reduces postprandial glycemia independently of gastric emptying and insulin secretion in humans. Am J Physiol Endocrinol Metab. 2006 Jan 10; [Epub ahead of print]

GLP-1 (9-36amide): Agonist, antagonist, or biologically inactive degradation product?

DPP-4 inhibitors prevent or attenuate the normal degradation of GLP-1(7-36)amide to GLP-1(9-36)amide. Several studies have raised the possibility that GLP-1(9-36) amide, which is proportionately more abundant than the full length bioactive peptide, may not simply represent an inert cleavage product, but may function either as an endogenous GLP-1R antagonist or a weak agonist (Glucagon-like peptide-1-(9-36) amide is a major metabolite of glucagon-like peptide-1-(7-36) amide after in vivo administration to dogs, and it acts as an antagonist on the pancreatic receptor. Eur J Pharmacol. 1996 Dec  30;318(2-3):429-35 and The inhibitory effect of glucagon-like peptide-1 (7-36)amide on antral motility is antagonized by its N-terminally truncated primary metabolite GLP-1 (9-36)amide. Peptides. 1998;19(5):877-82 and High potency antagonists of the pancreatic glucagon-like peptide-1 receptor. J Biol Chem. 1997 Aug 22;272(34):21201-6, or as a unique agonist with insulin-independent glucose-lowering properties, as hypothesized in GLP-1-(9-36) amide reduces blood glucose in anesthetized pigs by a mechanism that does not involve insulin secretion. Am J Physiol Endocrinol Metab. 2002 Apr;282(4):E873-9.

The importance of GLP-1(9-36)amide has been assessed in healthy humans, where elegant studies have shown no effect of this peptide on insulin secretion or glucose clearance, as shown in Effects of GLP-1-(7-36)NH(2), GLP-1-(7-37), and GLP-1- (9-36)NH(2) on Intravenous Glucose Tolerance and Glucose-Induced Insulin Secretion in Healthy Humans. J Clin Endocrinol Metab. 2003 Apr;88( 4): 1772-9

 Cardiovascular biology of GLP-1(9-36)amide

Remarkably, improvements in dog cardiovascular function in a canine model of pacing induced LV dysfunction have also been demonstrated using the truncated peptide GLP-1(9-36)amide, raising the possibility that a second functional receptor for GLP-1(9-36)amide may be critical for the cardiovascular actions of native GLP-1. See Active Metabolite of GLP-1 Mediates Myocardial Glucose Uptake and Improves Left Ventricular Performance in Conscious Dogs with Dilated Cardiomyopathy. Am J Physiol Heart Circ Physiol. 2005 Dec;289(6):H2401-8.

Moreover, emerging evidence suggests that the cardiovascular biology of GLP-1receptor agonists and GLP-1-derived peptides is increasingly complex and likely involves multiple distinct receptors and mechanisms. Classical GLP-1R agonists exert cardioprotective actions dependent on the knownGLP-1 receptor. However, GLP-1(9-36)amide also appears to be cardioprotective in the ischemic mouse heart when infused post-ischemia, and these actions are independent of the known GLP-1R. Moreover GLP-1(9-36) also appears to exert vasodilatory actions directly on murine blood vessels, increasing coronoary flow and vasodilation in mesenteric vessels. Furthermore, unexpectedly, even exendin-4 exerts some cardioprotective activity in a GLP-1R-independent manner. Hence, it is important to evaluate the existing GLP-1 cardiovascular literature in the context of understanding that some of the actions attributed to GLP-1 may be due in part to actions of GLP-1(9-36)amide; See Cardioprotective and Vasodilatory Actions of Glucagon-Like Peptide 1 Receptor Are Mediated Through Both Glucagon-Like Peptide 1 Receptor–Dependent and –Independent Pathways  Circulation 2008 May 6;117(18):2340-50.

Ban and colleagues carried out studies using cell lines and mouse hearts with both exendin-4 and GLP-1(9-36) to demonstrate that these peptides exert both overlapping yet distinct actions in the cardiovascular system. Intact GLP-1 was rapidly cleaved to GLP-1(9-36) in the coronary circulation ex vivo. Both peptides activated similar cardioprotective signal transduction pathways in WT murine cardiomyocytes. GLP-1(9-36) amide, but not exendin-4 continued to exert actions in Glp1r-/- cardiomyocytes. Unexpectedly, the actions of both peptides were attenuated by the GLP-1R antagonist exendin(9-39). Moroever, GLP-1(9-36), but not exendin-4, activated cardioprotective signaling pathways in human endothelial cells. See GLP-1(9-36)amide-mediated cytoprotection is blocked by exendin(9-39) yet does not require the known GLP-1 receptor Endocrinology 2010 in press