André Wettergren

Truncated GLP-1 (proglucagon 78–107-amide) inhibits gastric and pancreatic functions in man

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.

Tissue and Plasma Concentrations of Amidated and Glycine-Extended Glucagon-Like Peptide I in Humans

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. The higher meal response of amidated GLP-I compared with glycine-extended GLP-I probably reflects the larger amount of amidated GLP-I produced in the tissues compared with glycine-extended GLP-I.

Biological Effects and Metabolic Rates of Glucagonlike Peptide-1 7–36 Amide and Glucagonlike Peptide-1 7–37 in Healthy Subjects Are Indistinguishable

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 × L−1) and C-peptide secretion (integrated hormone response 9064 ± 1804 vs. 9954 ± 2031 pmol/h × L−1) and equipotently lowered plasma glucose (integrated decrease 48.3 ± 5.7 vs. 46.2 ± 8.4 mmol/h × L-1) and plasma glucagon (integrated decrease 80.4 ± 24.3 vs. 156.0 ± 34.6 pmol/h × 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 × min). In conclusion, COOH-terminal amidation is neither important for the metabolism of GLP-1 nor for its effects on the endocrine pancreas.

Secretion of the Incretin Hormones Glucagon-Like Peptide-1 and Gastric Inhibitory Polypeptide Correlates with Insulin Secretion in Normal Man Throughout the Day

BACKGROUND The insulinotropic hormones gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), secreted from the K-cells of the upper small intestine and from the L-cells of the lower small intestine, respectively, are thought to be responsible for intestinal stimulation of insulin secretion. If true, their plasma concentrations should parallel the meal-related diurnal changes in plasma insulin concentrations. METHODS Using COOH-terminal assays, thought to reflect accurately their rates of secretion, we measured circulating levels of GIP and GLP-1 in six normal subjects for 15 h of a day, during which they ate three mixed meals. RESULTS Both GIP and GLP-1 concentrations increased significantly and in parallel with insulin in response to all three meals. The plasma insulin concentrations correlated significantly with both GIP and GLP-1 values throughout the study period (correlation coefficients, 0.49 +/- 0.07 and 0.56 +/- 0.05; p < 0.001). CONCLUSIONS These results support the notion that GLP-1 and GIP are important incretin hormones.

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.

Glucagon-like peptide-1 7-36 amide and peptide YY from the L-cell of the ileal mucosa are potent inhibitors of vagally induced gastric acid secretion in man

BACKGROUND Glucagon-like peptide (GLP-1) 7-36 amide and peptide YY (PYY) from the L-cell of the ileal mucosa are potent inhibitors of gastric acid secretion in man. It is not clear, however, by which mechanism(s) they inhibit acid secretion. In dogs the inhibitory effect of PYY on acid secretion may be mediated mainly through neural pathways. The mechanism of action of GLP-1 might be similar. The aim of the present study was to examine the effects of GLP-1 might be similar. The aim of the present study was to examine the effects of GLP-1 and PYY on the vagally induced gastric acid secretion in man. METHODS A modified sham feeding technique, chew and spit, was used. Six healthy volunteers were randomly assigned to receive intravenous infusion of saline, GLP-1 (41 pmol/kg/h), or peptide YY (50 pmol/kg/h). RESULTS The infusion of GLP-1 and PYY resulted in plasma concentrations of 60 +/- 9 pmol/l and 84 +/- 11 pmol/l, respectively. GLP-1 and PYY both significantly inhibited the intergrated acid output by 67 +/- 6% and 68 +/- 9%, respectively, compared with the integrated outputs in a control experiment with saline infusion. Serum gastrin and plasma somatostatin concentrations remained unchanged during saline, GLP-1, and PYY infusions. CONCLUSIONS GLP-1 and PYY are both potent inhibitors of the cephalic phase of acid secretion, indicating that at least part of the inhibitory effect of GLP-1 and PYY in man is mediated through neural pathways. Furthermore, the inhibitory effect seems to be independent of circulating concentrations of gastrin and somatostatin.

Contrast-enhanced FDG-PET/CT vs. SPIO-enhanced MRI vs. FDG-PET vs. CT in patients with liver metastases from colorectal cancer: a prospective study with intraoperative confirmation.

Background: The choice of imaging before liver surgery is debated regarding the use of magnetic resonance (MR) imaging, computed tomography (CT), and positron emission tomography (PET). No studies have compared contrast-enhanced PET/CT with superparamagnetic iron oxide (SPIO)-enhanced MR imaging. Purpose: To compare PET/CT with superparamagnetic iron oxide (SPIO)-enhanced MR imaging, PET, and CT in the detection of liver metastases (LM) and extrahepatic tumor from colorectal cancer (CRC). Material and Methods: Thirty-five patients with suspected LM underwent PET/CT with a contrast-enhanced CT protocol and SPIO-enhanced MR imaging. Readers independently analyzed images from MR imaging, PET/CT, and the CT part and PET part of the PET/CT study. Imaging findings were compared with surgical and histological findings. Results: Lesion-by-lesion sensitivity and accuracy for liver lesions was 54% and 77% for PET alone, 66% and 83% for PET/CT, 82% and 82% for SPIO-enhanced MR imaging, and 89% and 77% for CT alone, respectively. CT and SPIO-enhanced MR imaging were less specific but significantly more sensitive than PET (P<0.0001). For extrahepatic tumor, sensitivity and specificity was 83% and 96% for PET/CT and 58% and 87% for CT, respectively. Conclusion: 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 place of liver transplantation in the treatment of hepatic epitheloid hemangioendothelioma: report of the European liver transplant registry.

Background:Hepatic epitheloid hemangioendothelioma (HEHE) is a rare low-grade vascular tumor. Its treatment algorithm is still unclear mainly due to a lack of larger clinical experiences with detailed long-term follow-up. Material and Methods:Fifty-nine patients, reported to the European Liver Transplant Registry, were analyzed to define the role of liver transplantation (LT) in the treatment of this disease. Eleven (19%) patients were asymptomatic. Eighteen (30.5%) patients had pre-LT surgical [hepatic (7 patients) and extrahepatic (3 patients)] and/or systemic or locoregional (10 patients) medical therapy. Ten (16.9%) patients had extrahepatic disease localization before or at the time of LT. Follow-up was complete for all patients with a median of 92.5 (range, 7–369) from moment of diagnosis and a median of 78.5 (range, 1–245) from the moment of LT. Results:HEHE was bilobar in 96% of patients; 86% of patients had more than 15 nodules in the liver specimen. Early (<3 months) and late (>3 months) post-LT mortality was 1.7% (1 patient) and 22% (14 patients). Fourteen (23.7%) patients developed disease recurrence after a median time of 49 months (range, 6–98). Nine (15.3%) patients died of recurrent disease and 5 are surviving with recurrent disease. One-, 5-, and 10- year patient survival rates from moment of transplantation for the whole series are 93%, 83%, 72%. Pre-LT tumor treatment (n = 18) (89%, 89%, and 68% 1-, 5-, and 10-year survival rates from moment of LT vs. 95%, 80%, and 73% in case of absence of pre-LT treatment), lymph node (LN) invasion (n = 18) (96%, 81%, and 71% 1-, 5-, and 10-year survival rates vs. 83%, 78%, and 67% in node negative patients) and extrahepatic disease localization (n = 10) (90%, 80%, and 80% 1-, 5-, and 10-year survival rates vs. 94%, 83%, and 70% in case of absence of extrahepatic disease) did not significantly influence patient survival whereas microvascular (n = 24) (96%, 75%, 52% 1-, 5-, and 10-year survival vs. 96%, 92%, 85% in case of absence of microvascular invasion) and combined micro- and macrovascular invasion (n = 28) (90%, 72%, and 54% 1-,5-, and 10-year survival vs. 96%, 92%, and 85% in case of absence of vascular invasion, P = 0.03) did. Disease-free survival rates at 1, 5, and 10 years post-LT are 90%, 82%, and 64%. Disease-free survival is not significantly influenced by pre-LT treatment, LN status, extrahepatic disease localization, and vascular invasion. Conclusions:The results of the largest reported transplant series in the treatment of HEHE are excellent. Preexisting extrahepatic disease localization as well as LN involvement are not contraindications to LT. Microvascular or combined macro-microvascular invasion significantly influence survival after LT. LT therefore should be offered as a valid therapy earlier in the disease course of these, frequently young, patients. Recurrent (allograft) disease should be treated aggressively as good long-term survivals can be obtained. Long-term prospective follow-up multicenter studies as well as the evaluation of antiangiogenic drugs are necessary to further optimize the treatment of this rare vascular hepatic disorder.