Martin Katschinski

Gastric emptying and release of incretin hormones after glucose ingestion in humans.

This study investigated in eight healthy male volunteers (a) the gastric emptying pattern of 50 and 100 grams of glucose; (b) its relation to the phase of interdigestive motility (phase I or II) existing when glucose was ingested; and (c) the interplay between gastric emptying or duodenal perfusion of glucose (1.1 and 2.2 kcal/min; identical total glucose loads as orally given) and release of glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1(7-36)amide (GLP-1), C-peptide, insulin, and plasma glucose. The phase of interdigestive motility existing at the time of glucose ingestion did not affect gastric emptying or any metabolic parameter. Gastric emptying of glucose displayed a power exponential pattern with a short initial lag period. Duodenal delivery of glucose was not constant but exponentially declined over time. Increasing the glucose load reduced the rate of gastric emptying by 27.5% (P < 0.05) but increased the fractional duodenal delivery of glucose. Both glucose loads induced a fed motor pattern which was terminated by an antral phase III when approximately 95% of the meal had emptied. Plasma GLP-1 rose from basal levels of approximately 1 pmol/liter of peaks of 3.2 +/- 0.6 pmol/liter with 50 grams of glucose and of 7.2 +/- 1.6 pmol/liter with 100 grams of glucose. These peaks occurred 20 min after glucose intake irrespective of the load. A duodenal delivery of glucose exceeding 1.4 kcal/min was required to maintain GLP-1 release in contrast to ongoing GIP release with negligibly low emptying of glucose. Oral administration of glucose yielded higher GLP-1 and insulin releases but an equal GIP release compared with the isocaloric duodenal perfusion. We conclude that (a) gastric emptying of glucose displays a power exponential pattern with duodenal delivery exponentially declining over time and (b) a threshold rate of gastric emptying of glucose must be exceeded to release GLP-1, whereas GIP release is not controlled by gastric emptying.

Exendin(9-39)amide is an antagonist of glucagon-like peptide-1(7-36)amide in humans.

The gastrointestinal hormone, glucagon-like peptide-1(7-36)amide (GLP-1) is released after a meal. The potency of synthetic GLP-1 in stimulating insulin secretion and in inhibiting glucagon secretion indicates the putative physiological function of GLP-1. In vitro, the nonmammalian peptide, exendin(9-39)amide [ex(9-39)NH2], is a specific and competitive antagonist of GLP-1. This in vivo study examined the efficacy of ex(9-39)NH2 as an antagonist of exogenous GLP-1 and the physiological role of endogenous GLP-1. Six healthy volunteers underwent 10 experiments in random order. In each experiment, a 30-min period of euglycemia was followed by an intravenous infusion of glucose for 150 min that established a stable hyperglycemia of 8 mmol/liter. There was a concomitant intravenous infusion of one of the following: (1) saline, (2) GLP-1 (for 60 min at 0.3 pmol . kg-1 . min-1 that established physiological postprandial plasma levels, and for another 60 min at 0.9 pmol . kg-1 . min-1 to induce supraphysiological plasma levels), (3-5) ex(9-39)NH2 at 30, 60, or 300 pmol . kg-1 . min-1 + GLP-1, (6-8) ex(9-39)NH2 at 30, 60, or 300 pmol . kg-1 . min-1 + saline, (9 and 10) GIP (glucose-dependent insulinotropic peptide; for 60 min at 0.8 pmol . kg-1 . min-1, with saline or ex(9-39)NH2 at 300 pmol . kg-1 . min-1). Each volunteer received each of these concomitant infusions on separate days. ex(9-39)NH2 dose-dependently reduced the insulinotropic action of GLP-1 with the inhibitory effect declining with increasing doses of GLP-1. ex(9-39)NH2 at 300 pmol . kg-1 . min-1 blocked the insulinotropic effect of physiological doses of GLP-1 and completely antagonized the glucagonostatic effect at both doses of GLP-1. Given alone, this load of ex(9-39)NH2 increased plasma glucagon levels during euglycemia and hyperglycemia. It had no effect on plasma levels of insulin during euglycemia but decreased plasma insulin during hyperglycemia. ex(9-39)NH2 did not alter GIP-stimulated insulin secretion. These data indicate that in humans, ex(9-39)NH2 is a potent GLP-1 antagonist without any agonistic properties. The pancreatic A cell is under a tonic inhibitory control of GLP-1. At hyperglycemia, the B cell is under a tonic stimulatory control of GLP-1.

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

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-pyloro-duodenal motility by utilising the GLP-1 receptor antagonist exendin(9-39)amide (ex(9-39)NH2). Methods: Nine healthy volunteers underwent four experiments each. In two experiments with and without intravenous infusion of ex(9-39)NH2 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-pyloro-duodenal 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)NH2 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)NH2 raised plasma glucagon during fasting and abolished the decrease in glucagon at the high duodenal glucose load. Ex(9-39)NH2 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 α 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.

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

BACKGROUND Glucagon-like peptide-1(7-36)amide (GLP-1) is a gut hormone released postprandially. Synthetic GLP-1 strongly inhibits gastric emptying in healthy subjects and in patients with diabetes mellitus. AIMS To investigate the effects of GLP-1 on antro-pyloro-duodenal motility in humans. METHODS Eleven healthy male volunteers were studied on two separate days. On the interdigestive study day, a basal period was followed by a 60 minute period of saline infusion and two further 60 minute periods of intravenous infusion of GLP-1 0.4 and 1.2 pmol/kg/min to achieve postprandial and supraphysiological plasma levels, respectively. On the postprandial study day, the same infusions were coadministered with intraduodenal lipid perfusion at 2.5 ml/min (2.5 kcal/min) followed by another 60 minutes of recording after cessation of GLP-1. Antro-pyloro-duodenal motility was measured by perfusion manometry. RESULTS GLP-1 significantly inhibited the number and amplitudes of antral and duodenal contractions in the interdigestive state and after administration of duodenal lipid. It abolished interdigestive antral wave propagation. In the interdigestive state, GLP-1 dose dependently increased pyloric tone and significantly stimulated isolated pyloric pressure waves (IPPW). Pyloric tone increased with duodenal lipid, and this was further enhanced by GLP-1. GLP-1 transiently restored the initial IPPW response to duodenal lipid which had declined with lipid perfusion. Plasma levels of pancreatic polypeptide were dose dependently diminished by GLP-1 with and without duodenal lipid. CONCLUSIONS GLP-1 inhibited antro-duodenal contractility and stimulated the tonic and phasic motility of the pylorus. These effects probably mediate delayed gastric emptying. Inhibition of efferent vagal activity may be an important mechanism. As postprandial plasma levels of GLP-1 are sufficient to appreciably affect motility, we believe that endogenous GLP-1 is a physiological regulator of motor activity in the antro-pyloro-duodenal region.

Effects of glucagon-like peptide-1(7–36)amide on motility and sensation of the proximal stomach in humans

Background: Glucagon-like peptide-1(7–36)amide (GLP-1) retards gastric emptying, reduces food intake, and inhibits antroduodenal and stimulates pyloric motility. Aims: To assess the effects of synthetic GLP-1 on fundus tone and volume waves, gastric compliance, and perception of gastric distension. Subjects: Eleven healthy male volunteers. Methods: Background infusions were saline, or GLP-1 at 0.3 or 0.9 pmol/ kg/min on separate days in random order. Interdigestive fundus motility was recorded by barostat (maximum capacity of intragastric bag 1200 ml) during basal and peptide periods of 60 minutes each. Thereafter stepwise isobaric distensions were performed with ongoing peptide infusion, and gastric sensation was scored. Results: Low and high loads of GLP-1 induced physiological and supraphysiological plasma immunoreactivities, respectively. GLP-1 dose dependently diminished fundus tone (162.9 (15.0) and 259.5 (17.2) v 121.1 (6.0) ml with saline; p<0.0001). It greatly reduced volume waves and total volume displaced by these events (p<0.0001). Gastric compliance derived from isobaric distension rose in a dose related manner (42.6 (5.5) and 63.6 (7.7) v 27.0 (3.5) ml/mm Hg; p=0.0004) with a concomitant reduction of the pressure at half maximum bag volume (6.4 (0.4) and 5.5 (0.4) v 7.2 (0.1) mm Hg; p<0.0001). GLP-1 did not change perception of isobaric distension but reduced the perception score related to corresponding bag volume (p<0.0001). Conclusions: GLP-1 is a candidate physiological inhibitory regulator of fundus motility. It allows the stomach to afford a larger volume without increase in sensation.

Cephalic stimulation of gastrointestinal secretory and motor responses in humans

The present study was designed (a) to investigate the cephalic phase of gastropancreatic secretion, antroduodenal motility, and regulatory peptide release in six healthy young men and (b) to assess its regulation by the cholinergic system and endogenous cholecystokinin. Sham feeding performed for 15 minutes induced a concurrent stimulation of gastropancreatic secretion, antroduodenal motility, and pancreatic polypeptide release that lasted for 30 minutes. Reappearance of interdigestive phases III was retarded in the post-sham-fed state. Atropine abolished secretory, motor, and pancreatic polypeptide responses to sham feeding and enhanced gastrin release. The cholecystokinin receptor antagonist loxiglumide did not attenuate pancreatic enzyme response but diminished antral motor response by 72% (P less than 0.05) and release of pancreatic polypeptide by 91% (P less than 0.05); it enhanced gastrin release and abolished retardation of reappearance of phase III with sham feeding. It is concluded that (a) there is a distinct cephalic phase of gastropancreatic secretion, antroduodenal motility, and pancreatic polypeptide release in humans that is primarily under cholinergic control and that (b) endogenous cholecystokinin is involved in antral motor, gastrin, and pancreatic polypeptide responses to sham feeding.

Glucagon-Like Peptide 1 Improves the Ability of the β-Cell to Sense and Respond to Glucose in Subjects With Impaired Glucose Tolerance

Impaired glucose tolerance (IGT) and NIDDM are both associated with an impaired ability of the β-Cell to sense and respond to small changes in plasma glucose concentrations. The aim of this study was to establish if glucagon-like peptide 1 (GLP-1), a natural enteric peptide and potent insulin secretagogue, improves this defect. Two weight-matched groups, one with eight subjects having IGT (2-h glucose, 10.1 ± 0.3 mmol/l) and another with seven subjects with diet-treated NIDDM (2-h glucose, 14.5 ± 0.9 mmol/l), were studied on two occasions during a 12-h oscillatory glucose infusion, a sensitive test of the ability of the β-Cell to sense and respond to glucose. Glucose was infused with a mean rate of 4 mg · kg−1 · min−1, amplitude 33% above and below the mean rate, and periodicity of 144 min, with infusion of saline or GLP-1 at 0.4 pmol · kg−1 · min−1 for 12 h. Mean glucose levels were significantly lower in both groups during the GLP-1 infusion compared with during saline infusion: 9.2 ± 0.4 vs. 6.4 ±0.1 mmol/l in the IGT subjects (P < 0.0004) and 14.6 ± 1.0 vs. 9.3 ± 0.7 mmol/L in NIDDM subjects (P < 0.0002). Despite this significant reduction in plasma glucose concentration, insulin secretion rates (ISRs) increased significantly in IGT subjects (513.3 ± 77.6 vs. 583.1 ± 100.7 pmol/min; P < 0.03), with a trend toward increasing in NIDDM subjects (561.7 ± 122.16 vs. 642.8 ± 128 pmol/min; P = 0.1). These results were compatible with enhanced insulin secretion in the presence of GLP-1. Spectral power was used as a measure of the ability of the β-Cell to secrete insulin in response to small changes in the plasma glucose concentration during the oscillatory infusion. Spectral power for ISR increased from 2.1 ± 0.9 during saline infusion to 7.4 ±1.3 during GLP-1 infusion in IGT subjects (P < 0.004), but was unchanged in NIDDM subjects (1.0 ± 0.4 to 1.5 ± 0.6; P = 0.3). We concluded that low dosage GLP-1 improves the ability of the β-Cell to secrete insulin in both IGT and NIDDM subjects, but that the ability to sense and respond to subtle changes in plasma glucose is improved in IGT subjects, with only a variable response in NIDDM subjects. β-Cell dysfunction was improved by GLP-1 infusion, suggesting that early GLP-1 therapy may preserve β-Cell function in subjects with IGT or mild NIDDM

Duodenal Secretion and Fecal Excretion of Pancreatic Elastase-1 in Healthy Humans and Patients with Chronic Pancreatitis

Fecal elastase-1 is a candidate for a sensitive noninvasive test detecting chronic pancreatitis. This prospective study enrolled 10 healthy male controls and 23 patients referred for tube testing of pancreatic function. It was designed (a) to correlate duodenal outputs and fecal concentrations of elastase-1 with duodenal outputs of amylase, lipase, trypsin, and chymotrypsin in the fed state (duodenal perfusion of a mixed liquid meal at 2.5 kcal/min for 150 min), (b) to compare the diagnostic accuracy of fecal elastase-1 and fecal chyrnotrypsin, and (c) to characterize the cyclical pattern of postprandial pancreatic secretion in healthy subjects and patients with chronic pancreatitis. Based on their enzyme responses to duodenal meal perfusion and imaging procedures, 12 patients were classified as having normal pancreatic function and 11 patients as having chronic pancreatitis. Duodenal enzyme outputs of elastase-1 were markedly lowered in chronic pancreatitis (p <0.0001) and correlated well with the outputs of the other four enzymes (r >0.71, p <0.00001). Fecal concentrations of elastase-1 were also clearly reduced in chronic pancreatitis (p <0.0001). Fecal chyrnotrypsin was less strongly associated with duodenal enzyme outputs (r = 0.33 to r = 0.587), whereas fecal elastase-1 correlated more precisely with the duodenal outputs of all five enzymes (r = 0.637 to r = 0.830, p <0.00001). Sensitivity and specificity in the detection of chronic pancreatitis amounted to 0.64 and 0.95 for fecal elastase-1 and 0.27 and 0.95 for fecal chyrnotrypsin, respectively. In the postprandial state, peaks of enzyme secretion occurred at a frequency of about 1 peak/150 min. The amplitude but not the frequency of secretory peaks was markedly reduced in chronic pancreatitis (p <0.01). We conclude that fecal elastase-1 clearly exceeds the sensitivity of fecal chyrnotrypsin in the diagnosis of chronic pancreatitis but does not reliably detect all cases with mild to moderate disease. The pattern of postprandial pancreatic secretion is cyclical, even with minimal secretory outputs in chronic pancreatitis.

Effect of cholecystokinin-A-receptor blockade on oesophageal motility

Objective: The cholecystokinin (CCK)-A-receptor antagonist loxiglumide, was used to evaluate the effects of exogenously infused and endogenously released CCK on oesophageal motility in 22 healthy male volunteers. Design and Methods: In the first set of experiments, step-wise doses of CCK-8 (3.3, 10 and 30 mg/kg/h) were infused with and without a background of loxiglumide (10 mg/kg/h). In the second and third sets of experiments, saline and loxiglumide were infused in the interdigestive state with concomitant duodenal perfusion of a mixed liquid meal. Oesophageal motility was recorded during each experiment with a sleeve sensor straddling the lower oesophageal sphincter. Results: Lower oesophageal sphincter pressure decreased from 20.5 ±2.4 to 13.4 ±2.5 mmHg(P< 0.01) and amplitude, area and contractility of distal oesophageal peristaltic contractions were slightly reduced following 30mg/kg/h CCK-8 (P<0.05). A background of loxiglumide eradicated these effects. Loxiglumide did not change interdigestive lower oesophageal sphincter pressure. Duodenal meal perfusion decreased lower oesophageal sphincter pressure from 25.8 ± 2.9 to 17.0±2.4mmHg (P<0.01). Loxiglumide eliminated this postprandial decrease of lower oesophageal sphincter pressure [24.3±2.8 (basal) compared with 23.2±2.6mmHg (loxiglumide); P<0.001 compared with duodenal perfusion without loxiglumide]. Loxiglumide did not have a significant effect on oesophageal peristaltic contractions. Conclusion: (1 ) Loxiglumide is a specific CCK-receptor antagonist at the oesophageal level. (2) CCK is not a major regulator of interdigestive oesophageal motility, and (3) CCK is a major regulator of postprandial lower oesophageal sphincter tone. This raises the question of whether CCK-A-receptor antagonists could be valuable in gastro-oesophageal reflux disease.

Comparison of cisapride and metoclopramide as oesophageal prokinetics in healthy humans

Objective To compare the prokinetic potencies of equal intravenous doses (10 mg) of cisapride and metoclopramide on oesophageal motility in healthy humans. Design Nine male volunteers were enrolled according to a double-blind, placebo-controlled, crossover design. Methods In each experiment, oesophageal motility was continuously recorded for 60 min in the fasting state. Analysis of motor events was computer-assisted. It referred to lower oesophageal sphincter pressure and relaxation, amplitude, duration, area, contractility and progression velocity of oesophageal peristalsis (wet swallows). Results Metoclopramide hastened progression velocity of proximal oesophageal peristalsis by 30% (P < 0.01) compared with placebo. In the distal oesophagus, metoclopramide raised the contraction amplitude by 9%, prolonged duration of contraction by 11% and increased the area under the contraction by 19% (P < 0.05). Cisapride increased the amplitude by 12%, prolonged duration by 14% (P < 0.05) and raised the area by 27% (P < 0.01). Lower oesophageal sphincter pressure increased with metoclopramide (P < 0.05) and, more distinctly, with cisapride (P < 0.0005) compared with the basal state. Lower oesophageal sphincter pressure was not changed by metoclopramide but rose by 28% with cisapride (P < 0.01) compared with placebo. Conclusions Cisapride and metoclopramide stimulate amplitude, duration and the area of distal, but not proximal, oesophageal peristalis to a similar extent. Cisapride is superior to metoclopramide in raising lower oesophageal sphincter pressure. These data support the use of cisapride as an oesophageal prokinetic.