Localization of regulatory peptides in the gut.
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Glucagon↗
Biomedical subjects
S R Bloom
Publications and source records attributed to S R Bloom.
The effect of adrenergic and cholinergic mechanisms on the secretion of pancreatic polypeptide and gastrin following hypoglycaemia in man.
The changes of plasma pancreatic polypeptide (PP) and plasma gastrin following acute insulin-induced hypoglycaemia (0 . 15 U/kg) were examined in six normal subjects, six tetraplegic subjects (preganglionic sympathectomy) and six tetraplegic subjects given atropine (combined adrenergic denervation and cholinergic blockade). Adequate hypoglycaemia was achieved in all three groups. The normal rise of plasma PP following hypoglycaemia was present in the tetraplegic group without atropine but was abolished in the tetraplegic subjects given atropine. There was no significant rise in plasma gastrin following hypoglycaemia except in the tetraplegic group given atropine. These results confirm that the secretion of PP in response to acute hypoglycaemia is mediated via cholinergic activity, while gastrin secretion appears to be inhibited in normal subjects by a vagal cholinergic mechanism.
Adult↗
The pharmacokinetics of porcine glucose-dependent insulinotropic polypeptide (GIP) in man.
The pharmacokinetics of porcine glucose-dependent insulinotropic polypeptide were investigated in six healthy volunteers. At the maximum infusion dose (0 . 5 pmol kg-1 min-1) a plateau concentration of 115 +/- 5 . 0 pmol/l plasma was obtained. On discontinuation of the infusion, the half-time of disappearance was calculated to be 20 . 3 +/- 1 . 2 min. The metabolic clearance rate was 2 . 6 +/- 0 . 1 ml kg-1 min-1 and the apparent space of distribution was 75 . 8 +/- 5 . 7 ml kg-1. Blood glucose, pancreatic and gastrointestinal hormones remained at basal concentrations throughout. No side effects were noted by any of the subjects studied.
Adult↗
Effects of intravenous somatostatin and motilin on the blood glucose and hormonal response to oral glucose.
Exogenous intravenous infusions of control saline, somatostatin, motilin and somatostatin and motilin together were compared in normal volunteers for their effects on the rise of blood glucose following 50 g oral glucose and for their effects on gastric emptying and plasma hormone concentrations. All regulatory peptide infusions increased the rate of gastric emptying by between 182% and 198% at 60 min post-ingestion. The glucose response during the oral glucose tolerance test was suppressed when somatostatin with or without motilin was infused but was increased during motilin. The somatostatin infusion reduced concentrations of motilin, insulin, gastric inhibitory polypeptide, gastrin and neurotensin whilst the motilin infusion was associated with an increased initial rise in insulin and gastric inhibitory polypeptide. The metabolic effects of the motilin infusion were overriden by the effects of somatostatin when both peptides were infused together; this suggests that somatostatin inhibits both the effects and secretion of motilin.
Adult↗
Gastric acid regulates the release of plasma secretin in man.
Fasting plasma secretin determined in nine healthy subjects, twelve patients with active duodenal ulcer and four with Zollinger-Ellison syndrome were 3.2 +/- 0.4, 5.1 +/- 1.2 and 20.3 +/- 1.3 pmol/l respectively (mean +/- SEM). Cimetidine significantly (P less than 0.05) reduced levels in those with duodenal ulcer, as did gastric aspiration in the Zollinger-Ellison group. A significant correlation (P less than 0.001) was found between basal acid output and mean fasting plasma secretin. After a solid meal and subsequent liquid soft drink, no sustained mean rise in plasma secretin was observed; changes in secretin appeared to coincide in time with rapid falls in duodenal pH, though little relationship could be established between the absolute level of pH and changes in plasma secretin. The mean peak post-prandial rise in plasma secretin observed after solids was significantly (P less than 0.05) greater in duodenal ulcer patients than controls (9.1 +/- 1.1 versus 6.7 +/- 0.5 pmol/l) as was the mean integrated post-prandial release (1002 +/- 110 versus 710 +/- 67 pmol min-1 1(-1)). Cimetidine reduced both rises (P less than 0.05) and was associated with significantly less duodenal pH readings below 4 (P less than 0.001). These results suggest that gastric acid is a major release mechanism for plasma secretin both fasting and after meals but it is likely the acid load rather than absolute pH in the duodenum which determines circulating levels.
Adult↗
Vasoactive intestinal peptide (VIP) in preterm and term neonates.
There is a little information on vasoactive intestinal peptide (VIP) in the neonatal period. We have measured plasma concentrations of this biologically important peptide in 159 preterm infants and 98 term neonates. Preterm neonates during the first four days of life had plasma VIP concentrations which were five times greater than the levels in 12 healthy adult controls (9.6+/-0.7 pmol/l, mean +/-S.E.M., compared with 1.9+/-0.5 pmol/l, p less than 0.001), and these elevated concentrations persisted throughout the neonatal period. In contrast term infants on the sixth day of life, had plasma VIP concentrations only half those seen in preterm infants on the same post natal age (p less than 0.001). Bottle-fed term infants had higher VIP levels than those who were breast fed (5.6+/-0.4 vs. 4.3+/-0,4, p less than 0.05). Plasma VIP concentrations did not change following a feed in any of the groups of neonates studied. The high plasma levels of VIP described may indicate a reduced neuropeptide clearance mechanism in neonates or alternatively, suggest a hitherto unrecognised role for this peptide hormone in the neonatal period.
Adult↗
Feeding and the development of enteroinsular hormone secretion in the preterm infant: effects of continuous gastric infusions of human milk compared with intermittent boluses.
Preterm infants receive gastric milk feeds as continuous infusions or intermittent boluses. It is not known whether these feeding methods have different effects on the development of digestive metabolism. We have measured plasma levels of insulin, pancreatic polypeptide (PP), gastric inhibitory polypeptide (GIP), gastrin, motilin, enteroglucagon (EG) and neurotensin (NT) in 19 preterm infants (28-34 weeks gestation) tolerating full enteral feeding from birth. 7 infants received human milk by continuous infusion, 12 infants were bolus fed. Hormones were measured in cord blood and at 6 and 13 days of age; samples were drawn preprandially in bolus fed infants. Both groups showed similar significant increases in plasma motilin, PP, NT and EG levels. At 13 days infusion fed infants had higher insulin. GIP and gastrin levels. No difference in rate of weight gain was seen in the two groups of infants. We conclude that both methods of feeding induce progressive changes in circulating enteroinsular hormone levels. However, the endocrine milieu is different in the two groups, particularly since bolus-fed infants experience marked cyclical surges in hormones after boluses of milk by 13 days of age. These differences in hormone release may affect metabolic homeostasis.
Enteral Nutrition↗
The central and peripheral distribution of neurotensin.
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Adrenal Medulla↗
Aspects of neurotensin physiology and pathology.
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Adult↗
Changes in circulating gut hormones in the horse during long distance exercise.
Venous blood samples were collected before and immediately after an 80 km ride and a 42 km race. They were analysed for blood glucose and lactate, and for plasma non-esterified fatty acids, insulin, pancreatic glucagon, pancreatic polypeptide, gastrin, gastric inhibitory peptide, somatostatin and vasoactive intestinal polypeptide concentrations. The 80 km ride was associated with marked hypoglycaemia and a slight lactic acidaemia together with an increase in plasma glucagon, somatostatin, pancreatic polypeptide and vasoactive intestinal polypeptide values. The 42 km race produced hyperglycaemia and marked lactic acidaemia together with an increase in plasma glucagon, somatostatin and vasoactive intestinal polypeptide. The increase in these peptides is not related to alterations in blood glucose or the relative contributions of aerobic and anaerobic muscle metabolism. It is suggested that the changes in circulating gut peptides are part of the endocrine response to exercise and the possible physiological role of these changes is discussed.
Animals↗
Effects of stimulation of the chorda tympani in bursts on submaxillary responses in the cat.
1. The effects of continuous preganglionic stimulation of the chorda tympani at 2 Hz for 10 min were compared with those of stimulation at 20 Hz in 1 sec bursts at 10 sec intervals for the same period in cats treated with atropine (0.5 mg/kg). Both the fall in mean submaxillary vascular resistance (s.v.r.) and the rise in mean vasoactive intestinal peptide (VIP) output from the gland were increased significantly (P < 0.01; P < 0.02) when the same total number of impulses were delivered in the form of bursts at the higher frequency.2. Both responses were also consistently increased by stimulating the post-ganglionic innervation in bursts in atropinized cats, or by stimulating the preganglionic innervation in bursts in the absence of atropine.3. The effects of stimulation of the chorda tympani in 1 sec bursts at 10 sec intervals for 2-3 min were investigated over the frequency range 2-160 Hz. The change in mean s.v.r. under these conditions was significantly reduced by administration of atropine at frequencies between 2 and 20 Hz, but not at higher frequencies. In atropinized cats, the fall in mean s.v.r. was linearly related to stimulus frequency (r = 0.993) over the range 2-60 Hz and a maximal response was obtained during stimulation at 80 Hz. In the same experiments the fall in mean s.v.r. was linearly related to log mean VIP output over the frequency range 20-160 Hz (r = 0.998).4. Closely similar changes in mean s.v.r occurred in response to both pre- and post-ganglionic stimulation at all frequencies tested between 2 and 160 Hz in atropinized cats when the stimuli were delivered in bursts. The changes in mean s.v.r. were not significantly affected by varying the duration of individual stimuli over the range 0.1-25.0 msec.5. The flow of submaxillary saliva was also linearly related to stimulus frequency over the range 2-40 Hz (r = 0.997) when the stimuli were delivered in bursts in the absence of atropine and secretion of saliva was maximal at 60 Hz.6. It is concluded that release of VIP from the submaxillary gland of the cat is optimal in response to stimulation of the chorda tympani at relatively high frequencies, when the impulses are delivered in bursts. Flow of saliva which is mediated by acetyl choline, may also be potentiated under the same conditions.
Animals↗
Effects of the autonomic system on insulin release in response to exogenous glucose in weaned lambs.
1. The role of the autonomic innervation to the pancreas in mediating the release of insulin in response to exogenous glucose has been investigated in conscious weaned lambs 4-5 months after birth. 2. The incremental rise in mean plasma insulin concentration was consistently lower in lambs with cut splanchnic nerves, which had been pre-treated with atropine (0.2 mg kg-1), than in normal control lambs, although the differences did not achieve statistical significance. 3. Pre-treatment with propranolol (0.25 mg kg-1) effectively suppressed release of insulin in response to exogenous glucose in atropinized lambs with intact splanchnic nerves, but not in atropinized lambs with cut splanchnic nerves. 4. The rise in mean plasma insulin concentration was significantly greater in lambs pre-treated with atropine (0.2 mg kg-1) and phentolamine (0.1 mg kg-1 initially, followed by 0.02 mg kg-1 min-1) than in atropinized lambs with cut splanchnic nerves. 5. It is concluded that release of insulin in response to exogenous glucose is normally modified by both sympathetic alpha-adrenergic inhibition and beta-adrenergic excitation in this species.
Animals↗
Parotid responses to stimulation of the parasympathetic innervation in bursts in weaned lambs.
1. The effects of stimulation of the peripheral end of the parotid nerve in 1 sec bursts at 10 sec intervals has been investigated in weaned Suffolk lambs 3-4 months after birth.2. Stimulation in bursts at either 10 or 20 Hz for 10 min produced a significantly greater flow of parotid saliva, output of Na(+) and K(+) and fall in parotid vascular resistance (p.v.r) than continuous stimulation at the corresponding constant frequency (1 or 2 Hz) for the same period.3. Stimulation at 40 Hz in bursts for the same period produced a significantly greater output of K(+) and fall in p.v.r. than continuous stimulation at 4 Hz, whereas the salivary flow rates and Na(+) outputs were closely similar.4. Comparison of the effects of stimulation of the parotid nerve in bursts over a wide range of frequencies showed that each of these parotid responses was maximal at about 80 Hz.5. Parotid salivary responses to continuous stimulation of the parotid nerve at 20 Hz for 10 min were effectively abolished by prior administration of atropine (> 1.0 mg/kg), whereas the percentage fall in p.v.r. was merely reduced from 80.2+/-3.6 to 33.1+/-8.3% under the same conditions. There was no significant change in the mean arterior-venous difference in the plasma concentration of vasoactive intestinal peptide, substance P or somatostatin, in either the presence or absence of atropine in these experiments.6. The results are discussed in relation to the proposition that the enhancement of parotid responses which is observed during intermittent stimulation of the parasympathetic innervation at relatively high frequencies under experimental conditions also occurs normally in conscious sheep.
Animals↗
Gut hormone release after intestinal resection.
To investigate the possible role of gut and pancreatic hormones in the adaptive responses to gut resection, plasma concentrations of the circulating hormones were measured, in response to a test breakfast, in patients with either small or large intestinal resection and in healthy control subjects. In 18 patients with partial ileal resection a significant threefold rise was found in basal and postprandial levels of pancreatic polypeptide, a fourfold increase in motilin, and more than a twofold increase in gastrin and enteroglucagon levels compared with healthy controls. In contrast, nine patients with colonic resection had a threefold rise in levels of pancreatic polypeptide only. One or more of these peptides may have a role in stimulating the adaptive changes found after gut resection.
Adult↗
Interdigestive biliary output in man: relationship to fluctuations in plasma motilin and effect of atropine.
The fasting output of bile into the bowel was investigated in nine healthy volunteers by hepatobiliary scanning. Subjects were studied twice, on each occasion for 2.5 hours. A significant flow of radioactivity from the gall bladder to the duodenum was observed on one or two occasions during each experiment. A 32 +/- 4% mean decrease in counts over the gall bladder was recorded, indicating partial emptying of this organ in the interdigestive state. The output of bile into the bowel was found to be related to fluctuations in fasting plasma motilin levels in that a significant motilin increment (18 +/- 4 pmol/l, p less than 0.005) paralleled the appearance of radioactivity in the duodenum. The onset of gall-bladder emptying regularly preceded the peak in plasma motilin (mean: 25 +/- 2 minutes). Atropine, intravenously, 0.6 mg followed by 0.3 mg, nearly abolished both fasting biliary output and plasma motilin fluctuations. Thus, bile output appears to occur frequently in fasting humans, but our data do not allow any conclusions as to the possible causal relationship between fasting gall-bladder emptying and release of motilin. Cholinergic influences appear to be of importance in the regulation of interdigestive biliary output in man.
Adult↗
Effect of pancreatic polypeptide on gallbladder pressure and hepatic bile secretion.
Intraluminal gallbladder pressure, measured by radiotelemetry, and bile output were monitored during infusion of porcine pancreatic polypeptide (PP) at doses of 6, 25, 100, and 400 pmol . kg-1 . h-1 in healthy conscious pigs. Plasma PP concentrations during infusion of the three lower doses, measured by radioimmunoassay, were within the range seen postprandially in these animals. Gallbladder pressure fell in a dose-related manner during PP infusion by 2.2 +/- 0.9, 8.2 +/- 0.4, 11.6 +/- 0.7, and 14.8 +/- 0.8 mmHg, respectively. In addition, a significant reduction in the bile output was observed during infusion of the two higher doses of PP. In a separate series of experiments, using cholecystectomized pigs, PP had no effect on bile output. These findings suggest that the amount of PP released postprandially may be sufficient to influence gallbladder function but not hepatic secretion of bile in the pig.
Animals↗
Gut hormone responses in subjects with a permanent ileostomy.
The fasting and postprandial levels of insulin, gastric inhibitory polypeptide, gastrin, motilin, human pancreatic polypeptide, enteroglucagon and neurotensin have been measured in 10 subjects with a permanent ileostomy and in 10 healthy control subjects matched for age and sex. Most of the levels were similar in the two groups but the group that had undergone ileostomies had significantly raised basal motilin and postprandial neurotensin levels while the basal enteroglucagon levels were significantly low. The possible implications of these findings are discussed.
Adult↗
Mucosal enzyme activities, peptide hormone concentrations and hormone secretory granule properties in functioning proximal jejunum after shunt operation for obesity.
Crosby capsule biopsies were obtained from functioning jejunum in 6 patients between 7 and 15 months after jejuno-ileal for morbid obesity and compared with 6 normal control biopsies. Brush border and other mucosal enzyme activities and seven regulatory peptide concentrations were measured in each biopsy. Analytical subcellular fractionation by sucrose density gradient centrifugation was used to investigate brush border and peptide secretory granule properties. Specific activities of all the brush border enzymes assayed in the bypass patients were similar to the normal controls and subcellular fractionation studies showed no change in brush border properties. Similarly, properties of other mucosal organelles and their associated enzyme activities were unchanged in the bypass patients. The mucosal regulatory peptide concentrations in the bypass patients showed no significant difference from the normal controls and no changes were detected in peptide storage granule properties. These studies therefore support the concept that the adaptive changes occurring after jejuno-ileal bypass are due to changes in cell numbers or other parameters of function rather than changes in the specific activities of the brush border enzymes themselves. They also show that the marked abnormalities of plasma hormone release after bypass surgery are not in themselves due to alterations in mucosal hormone concentrations, or of the secretory granule properties.
Adult↗