Morten Wojdemann

Glucagon-Like Peptide-2 Inhibits Centrally Induced Antral Motility in Pigs

BACKGROUND Glucagon-like peptide-2 is formed from proglucagon in the intestinal L-cells and is secreted postprandially in parallel with the insulinotropic hormone GLP-1 (glucagon-like peptide-1), which in addition acts to inhibit gastric motility (enterogastrone effect) by inhibiting central parasympathetic outflow. GLP-2 has no effect on the endocrine pancreas. We here tested the hypothesis that GLP-2 acts as an enterogastrone. METHODS Fourteen anesthetized pigs with their splanchnic nerves cut were subjected to insulin hypoglycemia, and force transducers were sutured to the antrum to record motility. GLP-2 was infused intravenously in doses from 1 to 6 pmol/kg/min after the onset of antral motility in response to hypoglycemia. RESULTS Insulin hypoglycemia invariably and greatly increased the frequency and amplitude of antral phasic contractions. Infusions of GLP-2 dose dependently (1-6 pmol/kg/min) inhibited antral motility. At 2 pmol/kg/min, resulting in plasma GLP-2 concentrations of 102.5+/-19 pmol/l (normal postprandial range, 30-82 pmol/l), the motility index was inhibited by 91%+/-14%. CONCLUSIONS Both of the intestinal glucagon-like peptides may operate as hormonal transmitters of the ileal brake effect.

Glucagon-like peptide-1 inhibits gastropancreatic function by inhibiting central parasympathetic outflow

Glucagon-like peptide (GLP)-1 inhibits acid secretion and gastric emptying in humans, but the effect on acid secretion is lost after vagotomy. To elucidate the mechanism involved, we studied its effect on vagally stimulated gastropancreatic secretion and motility in urethan-anesthetized pigs with cut splanchnic nerves, in which insulin-induced hypoglycemia elicited a marked stimulation of gastropancreatic secretion and antral motility. In addition, we studied vagally stimulated motility and pancreatic secretion in isolated perfused preparations of the porcine antrum and pancreas. GLP-1 infusion (2 pmol ⋅ kg-1 ⋅ min-1) strongly and significantly inhibited hypoglycemia-induced antral motility, gastric acid secretion, pancreatic bicarbonate and protein secretion, and pancreatic polypeptide (PP) secretion. GLP-1 (at 10-10-10-8mol/l) did not inhibit vagally induced antral motility, pancreatic exocrine secretion, or gastrin and PP secretion in isolated perfused antrum and pancreas. We conclude that the inhibitory effect of peripheral GLP-1 on upper gastrointestinal secretion and motility is exerted via interaction with centers in the brain or afferent neural pathways relaying to the vagal motor nuclei.Glucagon-like peptide (GLP)-1 inhibits acid secretion and gastric emptying in humans, but the effect on acid secretion is lost after vagotomy. To elucidate the mechanism involved, we studied its effect on vagally stimulated gastropancreatic secretion and motility in urethan-anesthetized pigs with cut splanchnic nerves, in which insulin-induced hypoglycemia elicited a marked stimulation of gastropancreatic secretion and antral motility. In addition, we studied vagally stimulated motility and pancreatic secretion in isolated perfused preparations of the porcine antrum and pancreas. GLP-1 infusion (2 pmol. kg-1. min-1) strongly and significantly inhibited hypoglycemia-induced antral motility, gastric acid secretion, pancreatic bicarbonate and protein secretion, and pancreatic polypeptide (PP) secretion. GLP-1 (at 10(-10)-10(-8) mol/l) did not inhibit vagally induced antral motility, pancreatic exocrine secretion, or gastrin and PP secretion in isolated perfused antrum and pancreas. We conclude that the inhibitory effect of peripheral GLP-1 on upper gastrointestinal secretion and motility is exerted via interaction with centers in the brain or afferent neural pathways relaying to the vagal motor nuclei.

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.

BACKGROUND: Glucagon-like peptide-1 (GLP-1)(7-36) amide is an intestinal incretin hormone which also inhibits gastric acid secretion in humans. Its mechanism of action is unclear, but it strongly inhibits vagally induced secretion (sham feeding), suggesting that it could influence vagal activity. AIM/METHODS: The effect of intravenous GLP-1 (7-36 amide) (1 pmol/kg/min) was studied on pentagastrin induced acid secretion in otherwise healthy subjects, previously vagotomised for duodenal ulcer (n = 8) and in a group of young (n = 8) and old (n = 6) healthy volunteers. RESULTS: Pentagastrin increased acid secretion significantly in all three groups, but the plateau concentration in the vagotomised subjects was lower than in controls. Infusion of GLP-1 (7-36 amide) significantly inhibited acid secretion in the control groups (to 67 (SEM 6) and 74 (SEM 3)% of plateau concentrations in young and old controls, respectively) but had no effect in the vagotomised subjects. Differences in plasma concentrations of GLP-1 (7-36 amide), recovery of gastric marker, duodenal regurgitation, or Helicobacter pylori status could not explain the lack of effect. Blood glucose was lowered equally by GLP-1 (7-36 amide) in all subjects. CONCLUSION: The inhibitory effect of GLP-1 (7-36 amide) on acid secretion depends on intact vagal innervation of the stomach.

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.

In plasma, glucagon-like peptide-1 7-36 amide (GLP-1) is rapidly degraded from the N terminus, generating the endogenous metabolite GLP-1 9-36 amide. This cleavage of GLP-1 eliminates its incretin effect, and the metabolite even may act as an antagonist. We have shown previously that GLP-1 strongly inhibited cephalic-induced antral motility in pigs. We decided, therefore, to examine the effect of GLP-1 9-36 amide, with and without GLP-1, on cephalic-induced motility in pigs. In one series of experiments, we studied the effect of three different doses of GLP-1 9-36 amide (2, 4, and 10 pmol/kg/min) on insulin-induced (hypoglycemia) antral motility in anaesthetized pigs (n = 9). In another series, we studied the effect of infusion of GLP-1 9-36 amide in two different doses (1 and 5 pmol/kg/min) in six pigs in which the antral motility was inhibited by GLP-1 7-36 amide in a dose of 2 pmol/kg/min. Plasma levels of intact GLP-1 7-36 amide and GLP-1 9-36 amide were determined using specific radioimmunoassays. Insulin-induced hypoglycemia increased the antral motility index from 0.4 +/- 0.1 to 8.3 +/- 3.5 (cm/min). The motility was constant throughout the experimental period and was absolutely unaffected by the infusion of GLP-1 9-36 amide at 10 pmol/kg/min, which resulted in a plasma concentration of 351 +/- 60 pmol/l. The inhibitory effect of GLP-1 7-36 amide on antral motility was reduced from 93 +/- 3% to 33 +/- 9% (p < 0.05) by concomitant infusion of GLP-1 9-36 amide in a dose of 5 pmol/kg/min. The metabolite GLP-1 9-36 amide has no effect on antral motility in pigs but is able to antagonize the inhibitory effect of GLP-1. Thus, an intact N terminus is essential for the gastrointestinal actions of GLP-1. Its primary metabolite may act as an endogenous antagonist.

Endoscopic Palliation of Inoperable Cancer of the Oesophagus or Cardia by Argon Electrocoagulation

BACKGROUND Cancer of the oesophagus and the cardia tends to present late. Palliation of dysphagia is the prospect of most of the patients. This paper reports the use of argon electrocoagulation in 83 patients with inoperable cancer strictures in the oesophagus and cardia. METHODS The argon electrocoagulation was done by a fibre conducting electricity and argon air to the site of coagulation. After treatment the patients were allowed to take fluids and normal food the same evening or the next morning. After recanalization the patients were treated regularly every 3-4 weeks. RESULTS Recanalization enabling passage for normal food was achieved with 1 treatment in 48 patients (58%), whereas 22 (26%) needed more than 1 treatment. In 13 patients (16%) the ability to eat normal food was not achieved. In these patients dysphagia improved at least one grade. Perforation was seen in seven patients (8%) and in 1% of treatments. Perforations were successfully treated conservatively in six of the seven patients. Sixty-three patients (76%) died during the investigation period, on average 146 days (range, 43-397 days) after diagnosis. CONCLUSION Argon electrocoagulation offers an easy, cheap, and safe alternative to treatment with laser photocoagulation and expandable metal stents.

Amidated and non-amidated glucagon-like peptide-1 (GLP-1): non-pancreatic effects (cephalic phase acid secretion) and stability in plasma in humans

The incretin and enterogastrone hormone, GLP-1, occurs in an amidated (GLP-1 (7-36) amide; 75%) and a glycine-extended (GLP-1 (7-37); 25%) form. Their effects on the endocrine pancreas are similar and their overall (mainly renal) elimination rates appear to equal. Assuming that they might differentially affect non-pancreatic targets we investigated the effect of GLP-1 (7-37) infused at 0.7 pmol/kg/min on sham-feeding induced acid secretion in six healthy volunteers. The infusion increased the plasma concentrations from 16+/-2 pmol/l to 45+/-2 pmol/l. This was associated with a 61+/-14% decrease in acid output compared to saline and was not significantly different from that previously observed with GLP-1 (7-36) amide infused at the same rate. We then compared the degradation of the two forms in human plasma at 37 degrees C in vitro. T1/2 values were 32+/-3 (7-37) and 42+/-2 min (7-36) amide (P=0.007). The difference in metabolism persisted after addition of diprotin A, an inhibitor of dipeptidyl peptidase IV, the enzyme responsible for the initial degradation of GLP-1 in plasma, and broader enzyme inhibitors. Thus, the only effect of the amidation of GLP-1 seems to be to enhance its survival in plasma.

Gastric lipase secretion after sham feeding and cholinergic blockade

Our purpose was to examine gastric lipasesecretion after cephalic stimulation (sham feeding) andto examine the effect of cholinergic blockade. Eighthealthy volunteers, four women and four men, age 21-58 years, were studied twice on separate days.They were sham fed with and without infusion ofatropine. Gastric content was measured and the amount aswell as the activity of gastric lipase output weredetermined. Plasma concentrations of gastrin, secretin, andcholecystokinin (CCK) were measured simultaneously byradioimmunoassays. Cephalic stimuli can evoke humangastric lipase secretion, and this effect was almost ablated by atropine blockade of cholinergicreceptors. The concentrations of CCK and secretin inplasma were unaffected by sham feeding with or withoutatropine blockade, whereas gastrin was stimulated by sham feeding after atropine blockade.Gastric lipase secretion in man is apparently controlledby interacting vagal and hormonal mechanisms.

Inhibition of Human Gastric Lipase Secretion by Glucagon-like Peptide-1

Glucagon-like peptide-1 (GLP-1) may be one ofthe enterogastrone hormones of the ileal brakemechanism. We therefore studied its effects on gastriclipase secretion in healthy volunteers and vagotomized patients during infusion of pentagastrin. Theintestinal incretin hormone GLP-1 (glucagon-likepeptide-1, 7-36 amide) was investigated because of itsinhibitory effects on gastric acid secretion andmotility. GLP-1 infused intravenously in amountscorresponding to the postprandial release significantlyinhibited pentagastrinstimulated gastric lipasesecretion and lipolytic activity. The inhibitory effectof GLP-1 persisted in vagotomized patients,suggesting that fundic chief cells, from which gastriclipase is released, or neighboring inhibitory cellscould be equipped with GLP-1 receptors. Vagotomizedpatients had significantly higher plasma concentrationsof gastrin and secretin. No significant changes ofgastrin, secretin, and CCK secretion were seen duringGLP-1 infusion in the vagotomized patients, whereas secretin decreased significantly in the healthyvolunteers. GLP-1 seems to be a naturally occurringinhibitor of gastric lipase secretion acting via anonvagal mechanism. Our results indicate that gastric lipase secretion is subject to hormonalstimulatory as well as inhibitory mechanisms.

Low Doses of Pentagastrin Stimulate Gastric Lipase Secretion in Man

BACKGROUND Gastric lipase is an important enzyme for dietary triglyceride digestion in normal subjects. Its regulation is unknown, as is the relation between the quantity and activity of the enzyme. METHODS In a dose-response study we investigated the effect of low doses of pentagastrin (less than 1000 ng/kg/h) on the output of gastric lipase measured by a kinetic assay and an enzyme-linked immunosorbent assay (ELISA). RESULTS In five healthy volunteers stepwise intravenous pentagastrin infusions of 0, 50, 100, 500, and 1000 ng/kg/h resulted in a stepwise increase in the lipase output, as measured with ELISA. However, the lipolytic activity, measured with a kinetic assay, decreased as the pH of the gastric contents decreased. CONCLUSION We conclude that secretion of the gastric lipase is stimulated by pentagastrin, but the simultaneous secretion of acid counteracts the lipolytic activity of the enzyme when food is not present.

Secretin and Gastric Lipase Secretion

Background: Gastric lipase secretion is stimulated by gastrin in plasma, but its regulation by secretin is unknown. Methods: In 7 normal persons we investigated the effect of exogenous secretin on the output of gastric lipase stimulated by intravenous gastrin-17. The gastric content was measured using a nasogastric tube for aspiration. The quantitative lipase secretion was measured by an enzyme-linked immunosorbant assay (ELISA) and the lipolytic activity by a kinetic assay. Plasma concentrations of secretin and gastrin were measured by radioimmunoassay. Results: Gastric lipase secretion (the quantity as well as the lipolytic activity) was significantly stimulated by gastrin. In response to secretin infusion, the lipolytic activity increased as acid secretion decreased. Conclusion: Secretin in postprandial concentrations does not influence the quantitative gastric lipase secretion stimulated by gastrin, but it increases lipolytic activity due to inhibition of acid secretion.