Search

Glucagon-like peptide-1(7-36NH2) is a potent stimulator of insulin secretion, as well as of somatostatin-14 (SS-14) release from the pancreatic and gastric D-cells. To investigate the possible effects of this peptide on release of intestinal somatostatin (SS-28 and SS-14, rat intestinal cultures were treated with 10(-12)-10(-6) M GLP-1(7-36NH2), as well as with the structurally related peptides, GLP-1(1-36NH2) and GLP-2. Both forms of GLP-1 stimulated does-dependent increases in intestinal somatostatin; secretion reached 643 +/- 126% of controls (p < 0.001) after treatment with 10(-6) M GLP-1(7-36NH2), and 398 +/-76% of controls (p < 0.001) after 10(-6) M GLP-1(1-36NH2). Thus, GLP-1(7-36NH2) was more effective than GLP-1(1-36NH2) in stimulating secretion of intestinal somatostatin-like immunoreactivity (SLI) (p < 0.05). GLP-2 did not affect intestinal somatostatin release. Gel permeation analysis demonstrated that 10(-6) M GLP-1(7-36NH2) stimulated SS-28 by 2.9 +/- 0.4-fold and SS-14 by 9.1 +/- 3.7-fold, whereas GLP-1(1-36NH2) exerted equivalent effects (2.8 +/- 0.9-fold) on both forms of somatostatin. These findings define a novel biological role for GLP-1(7-36NH2) in the regulation of intestinal somatostatin secretion, and demonstrate that GLP-1(1-36NH2) exerts unique biological activities in this system.

Background: To compare the quality of life, nutritional status, and gastrointestinal profiles of post-Whipple patients and postcholecystectomy patients., Methods: A cross-sectional survey of post-Whipple procedure patients and age- and sex-matched postcholecystectomy patients was performed. Quality of life was assessed using six instruments: Time Trade-off Technique, Direct Questioning of Objectives, Gastrointestinal Quality of Life Index, Sickness Impact Profile, Physician Global Assessment, and Visick Scale. A gastrointestinal symptomatology questionnaire was completed. Nutritional status was assessed by weight, the Subjective Global Assessment instrument, and skin anthropometry. Fasting and postprandial serum gastrin, somatostatin, insulin, pancreatic glucagon, enteroglucagon, and pancreatic polypeptide were measured., Results: The quality of life and gastrointestinal function of the Whipple patients was excellent and was not significantly different from that of the control subjects. There were no significant differences in gastrointestinal symptomatology although 5 Whipple patients complained of greasy bowel movements, and 1 patient reported difficulty maintaining weight. Despite this, nutritional status was within normal limits in all subjects. Six patients in the Whipple group followed a diabetic diet, 1 required insulin, and 3 required an oral hypoglycemic agent, whereas none of the control subjects were diabetic. There were no significant differences in the mean basal, peak, or integrated postprandial responses of the gut hormones with the exception of pancreatic polypeptide and gastrin (in patients having a standard Whipple procedure only)., Conclusion: Quality of life and nutritional status are excellent in patients following a Whipple procedure.

Pancreatic polypeptide was infused intravenously in healthy fasting subjects at 1 pmol kg-1 (n = 7) and 4 pmol kg-1 min-1 (n = 10) producing plasma PP concentrations of 223 +/- 37 pmol/l (mean +/- SEM) and 891 +/- 64 pmol/l respectively. These levels are similar to and four-fold higher than those seen after a normal mixed breakfast in healthy young adults. In a separate study five healthy subjects ingested a small breakfast during infusion of PP on different days at 1 pmol kg-1 min-1 and 2 pmol kg-1 min-1 respectively. PP at 1 pmol kg-1 min-1 caused a marked reduction in fasting plasma motilin concentrations to 20% of the basal level (p less than 0.001). There were, however, no significant changes in plasma concentrations of insulin, glucagon, gastrin, secretin, enteroglucagon, gastric inhibitory peptide or neurotensin. Despite previous reports possibly implicating PP in metabolism, there were no significant effects on blood levels of glucose, alanine lactate, 3-hydroxybutyrate, glycerol or non-esterified fatty acids, either in the fasting state or after the ingestion of food. Although it seems unlikely that PP is a major hormonal regulator of intermediary metabolism in man, its ability to suppress motilin at physiological concentrations suggests the possibility of an indirect influence on digestive motor function.

After colectomy, continent ileal reservoirs are an accepted alternative to conventional ileostomy for patients with ulcerative colitis. To assess the effect of these reservoirs on digestive function, circulating and morphologic gut endocrine responses were measured in patients with a continent ileostomy or with a pelvic pouch and compared to patients with conventional ileostomy, with active ulcerative colitis and healthy controls. Eight subjects were studied in each group. Basal and postprandial plasma gastrin, enteroglucagon, neurotensin, vasoactive intestinal polypeptide, insulin, pancreatic glucagon, and pancreatic polypeptide in both groups with ileal reservoirs were equivalent to controls. Basal plasma motilin and postprandial plasma gastric inhibitory polypeptide were raised in ileal reservoir patients, but similar changes also occurred in ulcerative colitis patients and those with conventional ileostomy. In one half of patients, cell populations of enteroglucagon, peptide YY, and neurotensin were decreased in pouch mucosa that corresponded with the presence of mucosal inflammation. On the other hand, with pouch inflammation vasoactive intestinal polypeptide immunoreactive nerves were increased and a proportion of the fibres were moderately coarsened. Mucosal concentrations of vasoactive intestinal polypeptide did not, however, exceed that of controls. After an ileal reservoir sufficient reserve remains for gut hormone release into the circulation, suggesting compensation for the presence of a reservoir and the absence of a colon; circulating hormone changes do occur but are consequent upon previous ulcerative colitis. Reservoirs may show neuromorphologic alterations that appear to be related to mucosal inflammation.

Regulation of pancreatic exocrine secretion is comprised of a complex interplay between hormonal and nervous mechanisms. Stimulatory gut hormones which act via the circulation include secretin, CCK, gastrin and bombesin, while VIP operates through peptidergic nervous release. Pancreatic polypeptide and glucagon are two examples of circulating inhibitory hormones while inhibition by somatostatin is through a paracrine release mechanism. Although the effects of vagal cholinergic nerves have been previously thought to be indirect through hormone release evidence is now accumulating for a direct role. Altered hormone release has been noted in chronic pancreatic insufficiency, cystic fibrosis and coeliac disease and may contribute in an important way to the pathophysiology of these malabsorptive disorders.

A potential role of pancreatic polypeptide (PP) in the regulation of phase III of the migrating motor complex (MMC) was investigated in conscious dogs before and during bilateral vagal blockade. After a control fasting period, cyclical increments in plasma PP occurred with peak levels of 45 +/- 8 pmol/l coinciding with late phase II MMC motility. By contrast, after food a substantially higher (approximately five times peak fasting concentrations) and more prolonged elevation of PP was observed, in association with a postprandial pattern of activity. To approximate fasting plasma PP concentrations, porcine PP was infused at 100 pmol X kg-1 X h-1, which produced levels of plasma PP of 99 +/- 8 pmol/l. At this dose PP had no effect on phase III activity. However, at a dose of 400 pmol X kg-1 X h-1, which achieved plasma PP concentrations (283 +/- 33 pmol/l) similar to postprandial levels, there was a specific inhibition of phase III in the lower esophageal sphincter, stomach, duodenum, and upper jejunum. The phase III-associated increment of plasma motilin was also inhibited by this dose of PP. These inhibitory effects at the 400 pmol X kg-1 X h-1 dose of PP were also observed after bilateral blockade of the vagus nerves. Our results suggest that PP has no significant role in the modulation of phase III of the fasting MMC nor does it induce a typical feeding motor pattern. The selective inhibition of both phase III and the associated rise in plasma motilin by PP plasma levels similar to postprandial concentrations does, however, point to a possible role for pancreatic polypeptide in the postprandial inhibition of phase III of the MMC.

Both the vagus nerve and motilin have been implicated in the initiation of phase III of the fasting migrating motor complex. To investigate the contribution of each, the effects of intravenous porcine motilin, vagosympathetic nerve blockade, and atropine were assessed. Intralumenal pressures of the lower esophageal sphincter, stomach, and upper small intestine, and plasma motilin levels were monitored. Porcine and canine motilin in plasma were distinguished by radioimmunoassay using two different antibodies. Injection of porcine motilin (75-370 pmol), initiated dose-dependent phase III-like motor activity in the lower esophageal sphincter, stomach, and small bowel if the vagi were intact; if the vagi were blocked, activity was initiated in the small bowel only. Moreover , a significant (p less than 0.001), dose-dependent peak in canine plasma motilin was observed after the onset of the induced motor activity when the vagi were intact or blocked, with plasma motilin peaks comparable to those occurring spontaneously. In both intact and vagally blocked dogs, atropine abolished both the spontaneous motor activity and associated rise in motilin level, and also abolished porcine motilin-induced activity. However, a diminished, but significant (p less than 0.01) peak in porcine motilin-induced canine motilin persisted in the presence of atropine. These results in dogs indicate that while spontaneous phase II motility in the upper gastrointestinal tract and phase III activity in the lower esophageal sphincter and stomach are dependent on vagally mediated excitatory pathways, spontaneous and induced phase III motor activity in the small intestine are dependent on nonvagal cholinergic innervation. Canine motilin release induced by porcine motilin is mediated primarily by a nonvagal cholinergic (muscarinic) pathway, with minor contributions from vagal noncholinergic, and nonvagal noncholinergic mechanisms. Because spontaneous or induced motilin release peaks well after the onset of phase III motor activity, it is unlikely that motilin is the primary factor responsible for initiation of the migrating motor complex in the dog. Motilin may, however, modulate motility produced by preexisting neural excitation.

Plasma VIP, secretin and motilin were measured in 9 volunteers following intraduodenal instillation of 50 ml of 0.1 mol/1 HCl over 3 minutes. VIP rose from 1.7 +/- 0.7 pmol/1 to a peak at 6 minutes of 6.6 +/- 0.9 pmol/1 and was still significantly elevated at 30 minutes. By comparison the elevation of secretin was more transitory rising from a basal value of 2.5 +/- 0.4 pmol/1 to a peak of 10 +/- 1.5 pmol/1 at 3 minutes and returning to baseline by 10 minutes. The rise of motilin, from a higher baseline, was intermediate in pattern, from 23 +/- 7 pmol/1 basally to a 4 minute peak of 40 +/- 10 pmol/1. Thus the elevation of VIP was the most longlasting, and while probably not of sufficient magnitude to stimulate pancreatic bicarbonate secretion via the circulation, could reflect a significant local role in regulating the response of the intestinal mucosa to acid.

The role of the vagus nerve in the control of gastrin releasing peptide (GRP) stimulated gastroenteropancreatic hormone release and gastric acid secretion was investigated in four conscious gastric fistula dogs using a technique of bilateral cryogenic vagal blockade. A 90-min infusion of GRP at a dose of 400 pmol X kg-1. h-1 produced significant elevations in plasma levels of gastrin, motilin, GIP, enteroglucagon, insulin, pancreatic glucagon, pancreatic polypeptide and VIP. Vagal blockade reversibly inhibited the rise of plasma PP and significantly blunted the elevation of plasma VIP. However, the GRP stimulated response of the other hormones investigated was not modified by vagal blockade. Similarly, the substantial secretion of gastric acid observed with GRP was not influenced by vagal blockade. Thus GRP acts predominantly via mechanisms which are independent of vagal integrity, findings that are in support of a major role for the local neuromodulation of hormone release and gastric acid secretion.

Plasma gastrin and somatostatin responses to ingestion of a solid meal, to insulin hypoglycemia, and to intravenous infusion of gastrin-releasing peptide were measured in 4 conscious dogs with and without bilateral cryogenic blockade of the cervical vagus nerves. Vagal cooling to -2 degrees C abolished meal-stimulated rises in plasma gastrin and somatostatin. Atropine did not modify the gastrin response to cooling but bethanechol reduced the magnitude of inhibition to 37% +/- 9% without influencing plasma somatostatin. Gastrin-releasing peptide elevated postprandial plasma gastrin during vagal blockade to levels comparable to those with the vagus intact but did not alter the nadir plasma somatostatin response. The plasma gastrin and somatostatin rises associated with insulin hypoglycemia were similarly inhibited by cooling to -2 degrees C. Cooling to 12 degrees C, which selectively blocks vagal inhibitory pathways, had no effect on meal-stimulated gastrin release and partially decreased the plasma gastrin response to insulin hypoglycemia. Thus, gastrin release by food and by insulin hypoglycemia is mediated by a vagal nonmuscarinic excitatory pathway that is independent of changes in circulating plasma somatostatin but may include participation by the candidate neurotransmitter gastrin-releasing peptide.

The role of the vagus nerve in the control of fasting plasma pancreatic polypeptide (PP), gastrin, and motilin levels was investigated in conscious dogs. Lowest plasma levels of motilin (81 +/- 8 pmol/L), PP (19 +/- 1 pmol/L) and gastrin (5 +/- 1 pmol/L) were observed during phase I of the migrating motor complex (MMC). Significant peaks in plasma motilin (127 +/- 11 pmol/L, P less than 0.005), PP (26 +/- 2 pmol/L, P less than 0.005), and gastrin (14 +/- 2 pmol/L, P less than 0.005) were seen, coinciding with the appearance of phase II (PP and gastrin) or phase III (motilin) of the migrating motor complex in the upper gut. Whereas bilateral vagal blockade abolished the peaks in PP and gastrin, a significant (P less than 0.025) increment in plasma motilin remained, which correlated with the late phase III equivalent of the vagally independent complex (VIC) in the duodenum. This VIC-related motilin peak (170 +/- 20 pmol/L) was significantly higher (P less than 0.025) and the time course (9 +/- 2 min) significantly shorter (P less than 0.01) than the peak (127 +/- 11 pmol/L) and duration (31 +/- 9 min) observed without vagal blockade. Thus, in fasting, the cyclical increments of PP and gastrin are both dependent on excitatory vagal innervation, whereas excitatory pathways controlling phase III associated peak motilin release are nonvagal. In addition, the pattern of fasting motilin release and the amplitude of peak motilin secretion may be affected by vagal inhibition.

Bovine pancreatic polypeptide (PP) was infused intravenously in 5 healthy subjects on two separate occasions with mean doses of 1 and 2 pmol kg-1 min-1, respectively, which achieved plasma levels equal to and twice those observed after a normal mixed breakfast. The gastric emptying rate of a carbohydrate-rich breakfast 20 min after the start of each PP infusion was not significantly different from a control infusion of 0.15 M saline. PP is unlikely to be an important physiological modulator of gastric emptying rate in man.

Vagal control of food- and hormone-stimulated release of pancreatic polypeptide (PP) and motilin was investigated in four conscious dogs by examining the effect of cryogenic vagosympathetic blockade. The postprandial PP response of 189 +/- 7 pM was totally, although reversibly, inhibited to 58 +/- 11 pM with the vagi blocked. Similarly, bombesin-, CCK-OP-, or neurotensin-stimulated PP release was abolished. Although the PP response to intraduodenal perfusion of an elemental diet was also reduced by blockade, the 52 +/- 15% inhibition was less than observed with the meal. In contrast to PP, plasma motilin fell after the meal from a fasting level of 128 +/- 16 pM to a nadir of 52 +/- 7 pM. Vagal blockade reversed this decline as plasma motilin rose to a peak of 121 +/- 18 pM with a pattern resembling the motilin response in the interdigestive state. This motilin increment during blockade was inhibited by atropine and by infusion of porcine PP. Plasma motilin also fell with the elemental diet, but this response was not affected by blockade. During infusion of bombesin, plasma motilin rose by 60 +/- 9 pM; vagal blockade augmented this increment twofold. Thus, the PP response to a meal and to hormonal stimulation is controlled by a vagal cholinergic excitatory pathway. However, intestinal release of PP is mediated in part by the vagus and in part by a vagally independent mechanism which may be neural or hormonal. Alternatively, vagal noncholinergic inhibition is a major mechanism modulating the motilin response after oral food but motilin release exclusively from intestinal nutriments is mediated by nonvagal, noncholinergic mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Intravenous infusion of galanin into conscious dogs during ingestion of oral glucose or a mixed meal or during iv infusion of arginine resulted in significant blunting of plasma insulin responses and significant increases in plasma glucose levels compared to those in control experiments. Galanin infusions did not significantly alter plasma gastric inhibitory peptide responses to oral glucose or a mixed meal, or plasma gastrin, pancreatic polypeptide, or pancreatic glucagon responses to a mixed meal. Similarly, galanin infusions did not significantly alter pancreatic glucagon responses to iv arginine. In all experimental situations, on cessation of the galanin infusions, prompt elevation of plasma insulin levels occurred. These results suggest that in the conscious dog, galanin administration produces a relatively selective, but readily reversible, inhibition of insulin secretion stimulated by oral nutrients or iv arginine.

The injection of trimebutine induces in the dog an increase of plasma motilin during the fasting period as well as after a meal. We studied the effect of trimebutine on several gastrointestinal hormones released into the circulation by the ingestion of a meal. The intravenous administration of trimebutine (10 mg/kg/h) in 4 dogs abolished the postprandial increase in plasma gastrin, pancreatic polypeptide, insulin, glucagon and GIP. Trimebutine could therefore, by its effects on various regulatory peptides, influence several digestive functions. Its mode of action could probably involves complex mechanisms, including paradoxical effects. The possibility that motilin is a mediator of the trimebutine effect on small bowel smooth muscle is discussed.

Gallbladder storage and emptying patterns were studied in fasting normal subjects by a duodenal perfusion technique using indocyanine green as a biliary marker. Fasting gallbladder storage patterns were very variable but a more uniform biliary output with net storage of about 40% of the biliary marker was observed during a simulated interprandial state (2--4 h after meals) produced by a low dose intravenous infusion of secretin and caerulein. With this background hormonal stimulation, infusion of bovine pancreatic polypeptide to achieve physiological interprandial levels promoted further gallbladder storage of bile. Bovine pancreatic polypeptide produced storage by a major effect on the gallbladder rather than on the liver, common bile duct or sphincter of Oddi since a reduction of biliary output was not observed during bovine pancreatic polypeptide infusion in cholecystectomized subjects. Bovine pancreatic polypeptide had a separate effect on the pancreas, reducing trypsin output in both normal and cholecystectomized subjects.