Although GLP-1 was originally identified as a β-cell secretagogue, a considerable body of experimental evidence in rodents, pigs and human studies demonstrates that GLP-1 is a potent regulator of gastrointestinal motility and gastric secretion. This action of GLP-1 accounts for the observation that glycemic excursion is often blunted and insulin secretion is frequently attenuated, following oral nutrient ingestion in the setting of co-administered exogenous GLP-1. These properties of GLP-1, taken together with the tight correlation between the levels of circulating GLP-1 and the rate of gastric emptying Relation between gastric emptying of glucose and plasma concentrations of glucagon-like peptide-1. Peptides. 1998;19(6):1049-53 have prompted some to opine that the gastric emptying actions of GLP-1 may be as or more important than the "incretin" actions of GLP-1, as outlined in Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol. 1997 Nov;273(5 Pt 1):E981-8. and reviewed in Is glucagon-like peptide 1 an incretin hormone? Diabetologia. 1999 Mar;42(3):373-9.
Indeed, the potent dose-dependent inhibition of gastric emptying observed following GLP-1 infusion in human subjects with Type 2 diabetes will produce significant lowering of meal-related glycemic excursion, even without any increase in levels of circulating insulin, as outlined in Normalization of Glucose Concentrations and Deceleration of Gastric Emptying after Solid Meals during Intravenous Glucagon-Like Peptide 1 in Patients with Type 2 Diabetes. J Clin Endocrinol Metab. 2003 Jun;88(6):2719-25. Even low dose GLP-1 infusion produces clear attenuation of gastric emptying and reduction of glycemic excursion, together with reduced, not enhanced insulin secretion following ingestion of a test meal in healthy human subjects. See EFFECTS OF INTRAVENOUS GLP-1 ON GASTRIC EMPTYING AND INTRAGASTRIC DISTRIBUTION IN HEALTHY SUBJECTS - RELATIONSHIPS WITH POSTPRANDIAL GLYCEMIC AND INSULINEMIC RESPONSES. J Clin Endocrinol Metab. 2006 Feb 21; [Epub ahead of print]
A direct role for GLP-1 in gastric physiology was shown by demonstrating stimulation of cAMP formation in rat gastric gland preparations and the human HGT-1 human cancer cell line. Effect of truncated glucagon-like peptide 1 on cAMP in rat gastric glands and HGT-1 human gastric cancer cells. FEBS Lett. 1988 Aug 15;236(1):119-22 which was followed by the demonstration that GLP-1 also inhibited pentagastrin-stimulated gastric acid secretion in human studies at physiologically relevant concentrations in some: GLP-1 (glucagon-like peptide 1) and truncated GLP-1, fragments of human proglucagon, inhibit gastric acid secretion in humans. Dig Dis Sci. 1989 May;34(5):703-8. and Glucagon-like peptide-1 (7-36)-NH2: a physiological inhibitor of gastric acid secretion in man.J Endocrinol. 1990 Jul;126(1): 169-73 but not all studies Lack of effect of synthetic human gastric inhibitory polypeptide and glucagon-like peptide 1 [7-36 amide] infused at near-physiological concentrations on pentagastrin-stimulated gastric acid secretion in normal human subjects. Digestion. 1992;52(3-4):214-21.
The effect of GLP-1 on inhibition of gastric acid secretion is lost in human subjects previously subjected to a vagotomy for control of ulcer disease, as demonstrated in The inhibitory effect of glucagon-like peptide-1 (GLP-1) 7-36 amide on gastric acid secretion in humans depends on an intact vagal innervation. Gut. 1997 May;40(5):597-601. Similarly, the vagal afferents play an important role in mediating both the central and peripheral effects of GLP-1 on gastric emptying in rats, as shown in Glucagon-like peptide-1 inhibits gastric emptying via vagal afferent-mediated central mechanisms. Am J Physiol. 1997 Oct;273(4 Pt 1):G920-7 and rat studies have also shown potent inhibition of small bowel motility Glucagon-like peptide-1 retards gastric emptying and small bowel transit in the rat: effect mediated through central or enteric nervous mechanisms. Dig Dis Sci. 1998 Oct;43(10):2284-90. Vagal innervation is also important for the inhibitory effects of GLP-1 on gut motility in pigs Glucagon-like peptide-1 inhibits gastropancreatic function by inhibiting central parasympathetic outflow. Am J Physiol. 1998 Nov;275(5 Pt 1):G984-92.
Pharmacological levels of GLP-1 appear to inhibit both gastric emptying and gastric acid secretion in normal human subjects Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci. 1993 Apr;38(4):665-73 and in obese subjects Glucagon-like peptide 1 increases the period of postprandial satiety and slows gastric emptying in obese men. Am J Clin Nutr. 1998 Sep;68(3):525-30
Although there are few studies examining the effect of GLP-1 receptor antagonism on physiological control of gastric emptying in humans, administration of exendin (9-39) to gastric fistula rats reverses the glucose meal-induced inhibition of gastric emptying if the antagonist is given peripherally, but not following icv injection. See Glucagon-like peptide-1 inhibits gastric emptying via vagal afferent-mediated central mechanisms. Am J Physiol. 1997 Oct;273(4 Pt 1):G920-7
In studies using rat parietal cell preparations, both exendin-4 and GLP-1 display similar properties with respect to H+ and cAMP production and the actions of these peptides are blocked by the GLP-1 receptor antagonist exendin(9-39). Exendin-4 and exendin-(9-39)NH2: agonist and antagonist, respectively, at the rat parietal cell receptor for glucagon-like peptide-1-(7-36)NH2. Eur J Pharmacol. 1994 Oct 14;269(2):183-91
The inhibitory effect of GLP-1 on gastric emptying likely accounts for at least part of the glucose-lowering effects observed in Type 1 diabetic patients Glucagon-like peptide I reduces postprandial glycemic excursions in IDDM. Diabetes. 1995 Jun;44(6):626-30. GLP-1 also inhibits gastric emptying in subjects with type 2 diabetes following a liquid test meal; Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7-36) amide in type 2 (noninsulin-dependent) diabetic patients. J Clin Endocrinol Metab. 1996 Jan;81(1):327-32. and Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7-36 amide]) in patients with NIDDM. Diabetologia. 1996 Dec;39(12):1546-53, following ingestion of only water GLP-1 inhibits gastric emptying of water but does not influence plasma. Scand J Gastroenterol. 2001 Feb;36(2):156-62 or following ingestion of a solid meal: GLP-1 slows solid gastric emptying and inhibits insulin, glucagon, and PYY release in humans. Am J Physiol. 1999 Sep;277(3 Pt 2):R910-6. and Effect of GLP-1 on gastric volume, emptying, maximum volume ingested, and postprandial symptoms in humans. Am J Physiol Gastrointest Liver Physiol. 2002 Mar;282(3):G424-31. The inhibitory effects of GLP-1 on GI motility are also detected in human studies in the inter-digestive state: Effects of glucagon-like peptide-1(7-36)amide on antro-pyloro- duodenal motility in the interdigestive state and with duodenal lipid perfusion in humans. Gut. 2000 May;46(5): 622-31 and Effects of glucagon-like peptide-1(7-36)amide on motility and sensation of the proximal stomach in humans. Gut. 2002 Mar;50(3):341-8.
The glucose-lowering effect of the drug acarbose may be attributed in part to the inhibition of gastric emptying perhaps due to the increase in levels of circulating GLP-1 that are detected following acarbose administration: Delayed gastric emptying occurs following acarbose administration and is a further mechanism for its anti-hyperglycaemic effect. Diabet Med. 1998 Feb;15(2):120-4. and Inhibition of gastric emptying by acarbose is correlated with GLP-1 response and accompanied by CCK release. Am J Physiol Gastrointest Liver Physiol. 2001 Sep;281(3):G752-63. Co-administration of acarbose and sucrose leads to a delay and sustained release of GLP-1 in human subjects Prolonged and enhanced secretion of glucagon-like peptide 1 (7-36 amide) after oral sucrose due to alpha-glucosidase inhibition (acarbose) in Type 2 diabetic patients.Diabet Med. 1998 Jun;15(6):485-91