Using specific radioimmunoassays, we studied the occurrence of amidated and glycine-extended glucagon-like peptide I (GLP-I) molecules in the human small intestine and pancreas and in the circulation system in response to a breakfast meal. Through gel permeation chromatography of extracts of the human pancreas (n = 5), we found that 71% of the GLP-I immunoreactivity eluted as a large molecule corresponding to the major proglucagon fragment, 24% corresponded to GLP-I 1-36 amide, and 5% to GLP-I 1-37. By gel permeation chromatography of extracts of human small intestine (n = 6), we found that all immunoreactivity eluted in one peak at the common elution position of the two insulin-releasing peptides, GLP-I 7-36 amide and GLP-I 7-37. Of the GLP-I immunoreactivity, 80% corresponded to GLP-I 7-36 amide and 20% to GLP-I 7-37. The mean concentrations of amidated GLP-I and glycine-extended GLP-I in fasting plasma were 7 +/- 1 and 6 +/- 1 pM, respectively (n = 6). In response to a breakfast meal, the concentration of amidated GLP-I rose significantly amounting to 41 +/- 5 pM 90 min after the meal ingestion, whereas the concentration of glycine-extended GLP-I only rose slightly to a maximum of 10 +/- 1 pM. Thus, both amidated and glycine-extended GLP-I molecules are produced in the small intestine and in the pancreas in humans. Both amidated and glycine-extended GLP-I are measurable in fasting plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied the effect of intravenous infusion of synthetic truncated GLP-1 (proglucagon 78-107-amide) on fasting and postprandial gastric acid secretion, gastric emptying, and pancreatic secretion of trypsin and lipase in eight normal volunteers using marker dilution and aspiration technique. The infusion resulted in a plasma concentration of 110 +/- 14 pmol/liter (mean +/- SEM). Truncated GLP-1 significantly inhibited postprandial acid secretion by 43 +/- 11% in spite of unchanged plasma gastrin concentration. Gastric emptying rate decreased significantly; 50% emptying time increased from 16 +/- 2 min to 30 +/- 5 min. Postprandial trypsin and lipase outputs were significantly inhibited by 47 +/- 17% and 40 +/- 9% during truncated GLP-1 infusion. Pancreatic enzyme output was linearly correlated to gastric emptying, and truncated GLP-1 did not affect this relationship, suggesting that the effect on pancreatic secretion was secondary to the effect on gastric emptying. Postprandial insulin and glucagon concentrations were similar with and without truncated GLP-1 infusion in spite of significantly lower blood glucose levels (5.2 +/- 0.2 versus 3.7 +/- 0.3), indicating that GLP-1 stimulated insulin secretion and inhibited glucagon secretion. In conclusion, our results suggest that truncated GLP-1 act as a physiological inhibitor of gastric and pancreatic functions in man.

These results support the notion that GLP-1 and GIP are important incretin hormones.

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.

Rapid degradation of glucagon-like peptide-1 (GLP-1) by dipeptidyl peptidase-4 suggests that endogenous GLP-1 may act locally before being degraded. Signaling via the vagus nerve was investigated in 20 truncally vagotomized subjects with pyloroplasty and 10 matched healthy controls. Subjects received GLP-1 (7-36 amide) or saline infusions during and after a standardized liquid mixed meal and a subsequent ad libitum meal. Despite no effect on appetite sensations, GLP-1 significantly reduced ad libitum food intake in the control group but had no effect in the vagotomized group. Gastric emptying was accelerated in vagotomized subjects and was decreased by GLP-1 in controls but not in vagotomized subjects. Postprandial glucose levels were reduced by the same percentage by GLP-1 in both groups. Peak postprandial GLP-1 levels were approximately fivefold higher in the vagotomized subjects. Insulin secretion was unaffected by exogenous GLP-1 in vagotomized subjects but was suppressed in controls. GLP-1 significantly reduced glucagon secretion in both groups, but levels were approximately twofold higher and were nonsuppressible in the early phase of the meal in vagotomized subjects. Our results demonstrate that vagotomy with pyloroplasty impairs the effects of exogenous GLP-1 on food intake, gastric emptying, and insulin and glucagon secretion, suggesting that intact vagal innervation may be important for GLP-1's actions.

CT and SPIO-enhanced MR imaging are more sensitive but less specific than PET in the detection of LM. PET/CT can detect more patients with extrahepatic tumor than CT alone.

The biological effects and the metabolism of the intestinal hormone glucagonlike peptide-1 7-36 amide and glucagonlike peptide-1 7-37 were studied in normal healthy subjects. GLP-1 7-36 amide and GLP-1 7-37 equipotently stimulated insulin secretion (integrated hormone response 0-60 min, 631 +/- 211 vs. 483 +/- 177 pmol/h x L-1) and C-peptide secretion (integrated hormone response 9064 +/- 1804 vs. 9954 +/- 2031 pmol/h x L-1) and equipotently lowered plasma glucose (integrated decrease 48.3 +/- 5.7 vs. 46.2 +/- 8.4 mmol/h x L-1) and plasma glucagon (integrated decrease 80.4 +/- 24.3 vs. 156.0 +/- 34.6 pmol/h x L-1). Both GLP-1 7-36 amide and GLP-1 7-37 lowered the plasma concentration of free fatty acids significantly. The plasma half-lives of GLP-1 7-36 amide and GLP-1 7-37 were 5.3 +/- 0.4 vs. 6.1 +/- 0.8 min, and the metabolic clearance rates of the two peptides also were similar (14.6 +/- 2.4 vs. 12.2 +/- 1.0 pmol/kg x min). In conclusion, COOH-terminal amidation is neither important for the metabolism of GLP-1 nor for its effects on the endocrine pancreas.

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 vagaily induced secretion (sham feeding), suggesting that it could influence vagal activity. Aim/Methods-The effect of intravenous GLP-1 (7-36 amide) (1 pmollkg/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 pylorn 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. (Gut 1997; 40: 597-601) Keywords: ileal brake, enterogastrone, vagotomy, pentagastrin, proglucagon.Glucagon-like peptide-1 (GLP-1) (7-36 amide) is a peptide processed from proglucagon in open type endocrine cells (L cells) in the small intestine and colon,'-5 from which it is released into the circulation in response to feeding.3 9It has attracted considerable interest because of its potent insulinotropic and glucagonostatic effects, whereby it lowers blood glucose. Because of this it has been proposed as a therapeutic agent in the treatment of type 2 diabetes mellitus.1l-5 In addition to its glucoregulatory effects GLP-1 (7-36 amide) strongly inhibits gastrointestinal motility and secretion including meal and pentagastrin stimulated acid secretion.'1'8 It has, therefore, been suggested to act as an important enterogastrone in humans.""'5It is not clear by what mechanism(s) GLP-1 (7-36 amide) inhibits acid secretion in humans. Conceivably, it might act locally by inhibiting parietal cell secretion directly or indirectly via a paracrine action of an increased release of somatostatin. It might also act by inhibiting vagal transmission to the parietal cells at the gastric level or by inhibiting vagal efferent activity via a central mechanism. Recent experiments in our laboratory have shown that GLP-1 (7-36 amide) in physiological concentrations almost abolished acid secretion induced by sham feeding, indicating that GLP-1 (7-36 amide) effectively also inhibits neurally induced acid secretion.19To determine whether the inhibitory effect of GLP-1 (7-36 amide) on acid secretion is exerted at the gastric level or whether it involves mainly neural mechanisms we have investigated its effec...