GLP-1 regulates gastroduodenal motility involving cholinergic pathways.

The gut-born incretin hormone glucagon-like peptide-1 (GLP-1) delays gastric emptying. To elucidate the mechanisms by which GLP-1 affects gastroduodenal motility and glycaemia, we studied the effects of exendin(9-39), a potent GLP-1 receptor antagonist, on gastroduodenal motility and pancreatic hormones. In this randomized, double-blind, placebo-controlled, four-arm, cross-over trial, 10 healthy volunteers were studied during the interdigestive period followed by duodenal perfusion of a mixed liquid meal (250 kcal). On four separate days, exendin(9-39), atropine, exendin(9-39) + atropine or saline were infused intravenously. Antro-pyloro-duodenal and fundic motility were assessed. The compliance of the proximal stomach was determined by isobaric distensions. During fasting, exendin(9-39) did not influence proximal gastric volume, pyloric tone, and duodenal contractility. Exendin(9-39) significantly increased antral waves only in the absence of atropine. During duodenal meal perfusion, exendin(9-39) significantly reduced proximal gastric volume accommodation, abbreviated postprandial antral inhibition, reduced the postprandial increase in pyloric tone, and reduced gastric compliance. Atropine abolished the effects of exendin(9-39) on gastric volume accommodation but did not affect its effects on postprandial antroduodenal motility and on gastric compliance. Exendin(9-39) increased fasting and postprandial glycaemia and plasma glucagon but not insulin concentrations. Atropine did not affect GLP-1 secretion. Cholinergic mechanisms mediate the effects of GLP-1 on postprandial gastric accommodation but not on antro-pyloro-duodenal motility. GLP-1 reduces fasting and postprandial glycaemia, in part by reducing glucagon secretion.

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 alpha 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 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.

GLP-1-induced alterations in the glucose-stimulated insulin secretory dose-response curve.

The present study was undertaken to establish in normal volunteers the alterations in beta-cell responsiveness to glucose associated with a constant infusion of glucagon-like peptide-1 (GLP-1) or a pretreatment infusion for 60 min. A high-dose graded glucose infusion protocol was used to explore the dose-response relationship between glucose and insulin secretion. Studies were performed in 10 normal volunteers, and insulin secretion rates (ISR) were calculated by deconvolution of peripheral C-peptide levels by use of a two-compartmental model that utilized mean kinetic parameters. During the saline study, from 5 to 15 mM glucose, the relationship between glucose and ISR was linear. Constant GLP-1 infusion (0.4 pmol x kg(-1) x min(-1)) shifted the dose-response curve to the left, with an increase in the slope of this curve from 5 to 9 mM glucose from 71.0 +/- 12.4 pmol x min(-1) x mM(-1) during the saline study to 241.7 +/- 36.6 pmol x min(-1) x mM(-1) during the constant GLP-1 infusion (P < 0.0001). GLP-1 consistently stimulated a >200% increase in ISR at each 1 mM glucose interval, maintaining plasma glucose at <10 mM (P < 0.0007). Pretreatment with GLP-1 for 60 min resulted in no significant priming of the beta-cell response to glucose (P = 0.2). Insulin clearance rates were similar in all three studies at corresponding insulin levels. These studies demonstrate that physiological levels of GLP-1 stimulate glucose-induced insulin secretion in a linear manner, with a consistent increase in ISR at each 1 mM glucose interval, and that they have no independent effect on insulin clearance and no priming effect on subsequent insulin secretory response to glucose.

[Diagnosis and treatment of esophageal motility disorders]. / Diagnostik und Behandlung von Motilitätsstörungen der Speiseröhre.

Apart from gastroesophageal reflux disease, achalasia, non-cardiac chest pain and functional dysphagia are the most important manifestations of disturbed esophageal motility. Achalasia is characterized by esophageal aperistalsis and impaired deglutitive relaxation of the lower esophageal sphincter. The morphological correlate is a degeneration of nitrergic neurons in the myenteric plexus. Diagnosis is based on barium esophagram or esophageal manometry with the latter setting the gold standard. Endoscopic exclusion of a tumor at the gastroesophageal junction is mandatory. Appropriate therapeutic interventions are pneumatic dilatation or (laparoscopic myotomy) of lower esophageal sphincter. In patients unfit for these procedures endoscopic injection of botulinum toxin into the lower esophageal sphincter is appropriate. Non-cardiac chest pain may be of esophageal origin. Gastroesophageal reflux, spastic motility disorders and visceral hypersensitivity are arguable underlying mechanisms. The most important diagnostic procedure is 24 h esophageal pH metry correlating symptoms and reflux episodes. Proton pump inhibitors and tricyclic antidepressants serving as visceral analgesics are appropriate therapeutic approaches. Functional dysphagia defines the sensation of impaired passage without mechanical obstruction or a neuromuscular disease with known pathology, e.g. scleroderma. Impaired transit is proven by esophageal scintigraphy or radiogram both using solid boluses. Manometry assesses the underlying mechanisms.

MR hydrometry to assess exocrine function of the pancreas: initial results of noninvasive quantification of secretion.

PURPOSE: To evaluate magnetic resonance (MR) hydrometry, a method of quantifying fluid amounts by using MR imaging, for assessing the exocrine function of the pancreas after stimulation with secretin. MATERIALS AND METHODS: Images were obtained with a single-shot turbo spin-echo sequence by using a 1.0-T magnet with a quadrature body coil. Image postprocessing and evaluation were performed at an external workstation by using a specially designed histogram algorithm that translates the MR signal intensity of duodenal filling into an actual amount of duodenal fluid. This algorithm was tested in vitro and in vivo. Finally, MR hydrometry results in five patients were correlated with those of the secretin-cerulein test. RESULTS: The phantom measurements showed a high correlation (r = 0.99) between the actual amount of fluid in the imaging volume and the calculated results. In vivo, the ability of MR hydrometry to enable exact quantification of fluid amounts was demonstrated. In correlating the signal intensity of duodenal filling with the exact amount of additional fluid in the duodenum in volunteers, a coefficient of 0.043 gray tones per pixel per milliliter was calculated. The correlation (r) between secretin-stimulated duodenal fluid output estimated by using tube aspiration and that estimated by using MR hydrometry was 0.946 (P <.05). CONCLUSION: MR hydrometry is a promising noninvasive method of assessing fluid output as a measure of exocrine pancreatic function.

Nutritional implications of cephalic phase gastrointestinal responses.

Palatable cephalic stimuli induce a simultaneous activation of gastrointestinal motility, gastric acid and pancreatic enzyme secretion, as well as, release of the gastrointestinal hormones gastrin and pancreatic polypeptide. Cholinergic neural input is the dominant mediator of these responses with cholecystokinin and gastrin acting as additional stimulatory modulators. Central cholinergic circuits, neuropeptide Y, and thyrotropin releasing hormone are candidate central stimulators of the cephalic phase. There are good arguments for glucagon-like peptide-1 and peptide YY to be physiological inhibitors of cephalic-phase responses with these peptides being released in the intestinal phase of digestion and putatively contributing to termination of the cephalically stimulated pattern. Cephalic-phase responses are used clinically as diagnostic tests to assess completeness of selective proximal vagotomy and to explore autonomic neuropathy. Pancreatic polypeptide secretion with sham feeding is an appropriate test of abdominal vagal function. Cephalically stimulated motor and secretory activity contribute greater than 50% of overall postprandial responses. Pharmacological inhibition of cephalic-vagal stimulation, resulting in reduced food intake, may be a novel approach to obesity management. Glucagon-like peptide-1 is a particular candidate because it inhibits the cephalic phase of digestion, diminishes food intake, and reduces the glycemic excursion after a meal by retarding gastric emptying, stimulating insulin and lowering glucagon release.

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.

The efficacy of a 40-mg extended-release formulation of cisapride in the treatment of patients with gastro-oesophageal reflux.

BACKGROUND: This study was conducted to assess the efficacy of a novel 40-mg extended-release formulation of cisapride in reducing gastro-oesophageal reflux. METHODS: According to a double-blind, randomized, placebo-controlled design, 19 patients with pathological gastro-oesophageal reflux were treated with extended (40 mg o.d.) or immediate (10 mg q.d.s.) release formulations for two periods of 4 days each (pH-monitoring on day four). Patients received identical treatments in both periods to allow limits of agreement defining equivalent potency of both formulations to be derived from intra-individual variability of treatment effects. RESULTS: The extended-release formulation decreased total and upright reflux times by 5.5 +/- 1.3% and 8.1 +/- 2.1% (P < 0.001), respectively. It did not change the percentage supine reflux time but diminished the mean duration of reflux episodes by 1.0 +/- 0.4 min (P=0.005). The total number of reflux episodes remained unaltered with both formulations. Immediately-released cisapride decreased total, upright, and supine acid exposures by 5.8 +/- 1.3%, 6.8 +/- 1.6% (P < 0.002) and 3.6 +/- 1.8%, respectively, and mean duration of episodes by 0.9 +/- 0.2 min (P

A double-blind, randomized, multicentre, crossover study to prove equivalence of pancreatin minimicrospheres versus microspheres in exocrine pancreatic insufficiency.

BACKGROUND: Modern pancreatin preparations consist of enteric-coated microspheres to protect the enzymes from gastric acid. There are, however, no clinical trials comparing different sizes of pancreatin microspheres with regard to fat excretion and fat intake. AIM: To prove both equivalent efficacy and safety of conventional pancreatin microspheres and smaller pancreatin minimicrospheres in patients with exocrine insufficiency due to chronic pancreatitis. METHODS: In this prospective, randomized, double-blind, multicentre, crossover trial, patients with a stool fat excretion of > 7.5 g/day during a placebo period were randomly assigned either to the minimicrosphere/microsphere treatment sequence or vice versa. The primary end-point was the coefficient of fat absorption, which was calculated from fat excretion and fat intake during the course of a standardized diet. Stool weight, clinical symptoms and the safety of the preparations were also evaluated. RESULTS: Thirty-seven patients entered the study, of whom 23 fulfilled the criteria for the crossover period. In the per protocol analysis (n=18), the 90% confidence intervals for the coefficient of fat absorption of both crossover periods lay entirely within the equivalence range (P=0.02). The intention-to-treat analysis revealed similar results, but the equivalence range was slightly missed (P=0.07). Similar results were obtained for the secondary parameters and the reported adverse events. CONCLUSIONS: Pancreatin minimicrospheres have been shown to be equally effective as microspheres in improving the coefficient of fat absorption in patients with exocrine insufficiency due to chronic pancreatitis.

Glucagon-like peptide 1 improves the ability of the beta-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 beta-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 beta-cell to sense and respond to glucose. Glucose was infused with a mean rate of 4 mg x kg(-1) x 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 x kg(-1) x 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 beta-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 beta-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. Beta-cell dysfunction was improved by GLP-1 infusion, suggesting that early GLP-1 therapy may preserve beta-cell function in subjects with IGT or mild NIDDM.

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.

Inhibitory effects of hyperglycaemia on fed jejunal motility: potential role of hyperinsulinaemia.

BACKGROUND: Acute hyperglycaemia is known to inhibit jejunal interdigestive motility. This study was undertaken to establish the effects of hyperglycaemia on fed jejunal motility and small intestinal transit time, and to establish if the effects of hyperglycaemia are mediated in part by hyperinsulinaemia. METHODS: Nine healthy male volunteers were studied in random order using three experimental conditions: (a) euglycaemic clamp [glucose 5 mmol L(-1)]; (b) hyperglycaemic clamp [glucose 15 mmol L(-1)]; and (c) euglycaemic hyperinsulinaemic clamp [glucose 5 mmol L(-l)]. Fed jejunal motility was induced by an intrajejunal perfusion of lipid (Lipofundin medium-chained triglyceride 10%) at 1.5 mL min(-1) [1.5 kcal min(-1)] for 180 min through the most proximal port of a manometry catheter (eight ports spaced at 2-cm intervals) located just distal to the ligament of Treitz. One minute after starting the lipid perfusion, 15 g of lactulose dissolved in 20 mL of tap water was infused. Small intestinal transit time was measured by the hydrogen breath test. RESULTS: Acute hyperglycaemia reduced the total number of jejunal contractions and progradely propagated contractions, the motility index (P < 0.05) and the mean amplitude of contractions and delayed intestinal transit time. Hyperinsulinaemia reduced the total number of jejunal contractions, motility index (P < 0.05) and intestinal transit time. CONCLUSIONS: Thus, hyperinsulinaemia may contribute to the inhibitory effects of hyperglycaemia on jejunal motility. In addition, this study demonstrated that intrajejunal infusion of lipid stimulates sustained glucagon-like peptide-1 release. In contrast to fat-induced gastric inhibitory polypeptide release, this glucagon-like peptide-1 release is not inhibited by exogenous or endogenous hyperinsulinaemia (P = 0.59).

Mechanisms of the antidiabetic action of subcutaneous glucagon-like peptide-1(7-36)amide in non-insulin dependent diabetes mellitus.

Twelve patients with non-insulin dependent diabetes mellitus (NIDDM) under secondary failure to sulfonylureas were studied to evaluate the effects of subcutaneous glucagon-like peptide-1(7-36)amide (GLP-1) on (a) the gastric emptying pattern of a solid meal (250 kcal) and (b) the glycemic and endocrine responses to this solid meal and an oral glucose tolerance test (OGTT, 300 kcal). 0.5 nmol/kg of GLP-1 or placebo were subcutaneously injected 20 min after meal ingestion. GLP-1 modified the pattern of gastric emptying by prolonging the time to reach maximal emptying velocity (lag period) which was followed by an acceleration in the post-lag period. The maximal emptying velocity and the emptying half-time remained unaltered. With both meals, GLP-1 diminished the postprandial glucose peak, and reduced the glycemic response during the first two postprandial hours by 54.5% (solid meal) and 32.7% (OGTT) (P < 0.05). GLP-1 markedly stimulated insulin secretion with an effect lasting for 105 min (solid meal) or 150 min (OGTT). The postprandial increase of plasma glucagon was abolished by GLP-1. GLP-1 diminished the postprandial release of pancreatic polypeptide. The initial and transient delay of gastric emptying, the enhancement of postprandial insulin release, and the inhibition of postprandial glucagon release were independent determinants (P < 0.002) of the postprandial glucose response after subcutaneous GLP-1. An inhibition of efferent vagal activity may contribute to the inhibitory effect of GLP-1 on gastric emptying.

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 chymotrypsin, 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 chymotrypsin 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 chymotrypsin, 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 chymotrypsin 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.

Differential effects of subcutaneous GLP-1 on gastric emptying, antroduodenal motility, and pancreatic function in men.

In this study of eight healthy male volunteers, we investigated the effects of graded doses of subcutaneous glucagon like peptide-1(7-36)amide (GLP-1) on: 1) the gastric emptying pattern of a mixed liquid meal (300 kcal); 2) pancreatic enzyme secretion; 3) antroduodenal motility; and 4) the glycemic response as well as releases of insulin, C-peptide, and glucagon. GLP-1, 0.125 nmol/kg, or 0.25 nmol/kg, or placebo was injected subcutaneously 5 min before meal ingestion. Subcutaneous GLP-1 dose-dependently prolonged the lag period (i.e., the time to reach maximal velocity of gastric emptying) by 46.2% (low dose) and 93.7% (high dose) (p < .05) but left unaltered maximal emptying velocity, total emptying time, and exponential emptying rate. With and without GLP-1, a fed motor pattern was induced by the meal and was terminated by an antral phase III when 98% of the meal had emptied. In parallel to the prolonged lag period, GLP-1 dose-dependently inhibited antral and duodenal motility and coordinated antroduodenal contractions by > 50% (low dose) and > 70% (high dose) (p < .05). GLP-1 initially reduced and thereafter transiently stimulated pancreatic enzyme secretion. This pattern correlated with the prolonged lag period and mirrored the delayed gastric emptying. GLP-1 retarded and diminished the postprandial glucose peak and reduced the total plasma glucose response by 46.6% (low dose) and by 59.4% (high dose) (p < .05). Both doses of GLP-1 delayed the postprandial insulin peak, enhanced total insulin release, and diminished postprandial responses of glucagon and pancreatic polypeptide. The duration of the lag period strongly correlated with the timing of postprandial glucose and insulin peaks (p < .001). The initial delay of gastric emptying, the enhancement of postprandial insulin release, and the inhibition of postprandial glucagon release were independent determinants (p < .01-.05) of the postprandial glucose response after subcutaneous administration of GLP-1.

Intestinal phase of human antro-pyloro-duodenal motility: cholinergic and CCK-mediated regulation.

In this study the muscarinic receptor antagonist atropine and the cholecystokinin (CCK)-A receptor antagonist loxiglumide were used to investigate the relative importance of cholinergic and CCK-mediated regulation of intestinal phase antro-pyloro-duodenal motility. Plasma levels of gastrointestinal hormones [pancreatic polypeptide (PP), gastrin, CCK] were concomitantly determined to estimate biological potency of the doses of the receptor antagonists. In eight healthy male volunteers, a 30-min basal interdigestive period was followed by duodenal perfusion of a mixed liquid meal for 150 min at 1.6 kcal min-1 against a background of saline or atropine (5 micrograms kg-1 h-1) or loxiglumide (10 mg kg-1 h-1). Antropyloro-duodenal motility was continuously monitored with a sleeve straddling the pylorus. Against a background of saline, duodenal nutrients persistently stimulated isolated pyloric pressure waves. After 60 min, the initially low antral and duodenal contraction rates increased. In the fed state, atropine reduced total number of antral contractions and integrated motility index by 73% (P < 0.01) and 76% (P < 0.005), total number of pyloric contractions and integrated motility index by 43% and 50% (P < 0.05) with inhibition increasing over time. It did not alter duodenal contraction frequency but diminished duodenal motility index by 39% (P < 0.05) owing to a reduction in amplitude and duration of contractions. Loxiglumide decreased total numbers of antral, pyloric and duodenal contractions by 44% (P < 0.05), 74% (P < 0.005) and 41% (P < 0.005) respectively. It reduced cumulative antral, pyloric and duodenal motility indexes by 60% (P < 0.01), 80% (P < 0.01) and 61% (P < 0.05) respectively. Atropine fully abolished PP release to duodenal nutrients whereas loxiglumide reduced it by 60% (P < 0.05). Both atropine and loxiglumide enhanced gastrin release whereas only loxiglumide markedly stimulated CCK release. We conclude that both cholinergic input and endogenous CCK are major stimulatory regulators of antro-pyloroduodenal motility in the intestinal phase. There appears to be a regional heterogeneity of cholinergic and CCK control. Cholinergic input predominates in the antrum. Both systems are equipotent at the pylorus. CCK predominates in the duodenum. We suggest that CCK primarily interacts with receptors on cholinergic neurons in the antropyloric region and primarily affects smooth muscle receptors in the duodenum.