Endogenous glucagon-like peptide 1 controls endocrine pancreatic secretion and antro-pyloro-duodenal motility in humans

Abstract

Background: Exogenous use of the intestinal hormone glucagon-like peptide 1 (GLP-1) lowers glycaemia by stimulation of insulin, inhibition of glucagon, and delay of gastric emptying. Aims: To assess the effects of endogenous GLP-1 on endocrine pancreatic secretion and antro-pyloroduodenal motility by utilising the GLP-1 receptor antagonist exendin(9-39)amide (ex(9-39)NH 2 ). Methods: Nine healthy volunteers underwent four experiments each. In two experiments with and without intravenous infusion of ex(9-39)NH 2 300 pmol/kg/min, a fasting period was followed by intraduodenal glucose perfusion at 1 and 2.5 kcal/min, with the higher dose stimulating GLP-1 release. Antro-pyloroduodenal motility was measured by perfusion manometry. To calculate the incretin effect (that is, the proportion of plasma insulin stimulated by intestinal hormones) the glycaemia observed during the luminal glucose experiments was mimicked using intravenous glucose in two further experiments. Results: Ex(9-39)NH 2 significantly increased glycaemia during fasting and duodenal glucose. It diminished plasma insulin during duodenal glucose and significantly reduced the incretin effect by approximately 50%. Ex(9-39)NH 2 raised plasma glucagon during fasting and abolished the decrease in glucagon at the high duodenal glucose load. Ex(9-39)NH 2 markedly stimulated antroduodenal contractility. At low duodenal glucose it reduced the stimulation of tonic and phasic pyloric motility. At the high duodenal glucose load it abolished pyloric stimulation. Conclusions: Endogenous GLP-1 stimulates postprandial insulin release. The pancreatic a cell is under the tonic inhibitory control of GLP-1 thereby suppressing postprandial glucagon. GLP-1 tonically inhibits antroduodenal motility and mediates the postprandial inhibition of antral and stimulation of pyloric motility. We therefore suggest GLP-1 as a true incretin hormone and enterogastrone in humans.

Diabetic Neuropathy: A Position Statement by the American Diabetes Association

“…Symptoms such as anorexia, nausea, vomiting, and dyspepsia are nonspecific and resemble many other conditions (186) and may just be associated with the presence of diabetes (181). Importantly, hyperglycemia, hypoglycemia, and acute changes in blood glucose are well documented to alter gastric emptying (182,187,188), as are some medications, especially opioids, other pain management agents, and glucagon-like peptide 1 receptor agonists (189,190). Therefore, all these factors known to affect gastric emptying should always be considered before a firm diagnosis is established.…”

Genetic variation inGlp1rexpression influences the rate of gastric emptying in mice

“…The physiological effects of GLP-1 have been examined using GLP-1 receptor antagonists to block endogenous GLP-1 action, e.g., administration of exendin-(9-39) to rats or human subjects increases gastric emptying (40). Because Glp1r mRNA and protein expression in stomach is lower in the CAST parental and B6.CAST-17 congenic strains (26), we tested the hypothesis that decreased GLP-1 receptor function is responsible for the strain difference in gastric emptying.…”

Effects of Sitagliptin on Glycemia, Incretin Hormones, and Antropyloroduodenal Motility in Response to Intraduodenal Glucose Infusion in Healthy Lean and Obese Humans and Patients With Type 2 Diabetes Treated With or Without Metformin

“…In type 2 diabetes, the insulinotropic effects of GIP and GLP-1 are diminished, although the effect of GLP-1 is better preserved (2,3). GLP-1 also suppresses glucagon secretion (4), appetite, and energy intake (5) and slows gastric emptying (6,7). Therefore, the glucoselowering effect of DPP-4 inhibitors in this disorder is likely to depend primarily on the actions of GLP-1 rather than of GIP.…”

“…Although endogenous GLP-1 slows gastric emptying through suppression of antral motility and stimulation of pyloric contractions (6,7), the effect of DPP-4 inhibitors on these motor mechanisms has not been assessed. DPP-4 inhibitors appear to be weight neutral (23), but reports on their effect on appetite are limited.…”