Potential regulators of feeding behavior in anorexia nervosa.

We recruited 10 patients with anorexia nervosa and 6 age- and height-matched control subjects. Basal and postprandial concentrations of glucose, insulin, cholesterol, amino acids, gastrin, and pancreatic polypeptide (PP) were measured in response to a standard mixed meal. The only satiety signal that was significantly different between the anorectic group and the control group was PP (P less than 0.001). Tryptophan-LNAA and tyrosine-LNAA ratios were not significantly different in the two groups; however, there was a trend toward a lower tryptophan-LNAA ratio in the anorectic group. Gastrin concentrations were significantly decreased in the anorectic group (P less than 0.001) as were basal insulin concentrations (P less than 0.05). Decreased gastrin concentrations may play a role in the gastric symptoms associated with anorexia nervosa. Previous findings that PP release is diminished in obesity, together with the present findings of PP increase in anorexia nervosa, suggest that this peptide may play a role in appetite control mechanisms.

Evidence that the cholinergic enteropancreatic reflex may be independent of cholecystokinin release.

Studies were performed in four dogs with chronic gastric and pancreatic fistulas following intraduodenal perfusion with 10 mmole hr-1 of sodium oleate for 30 minutes. Radioimmunoassay (RIA) of plasma CCK LI was undertaken by an RIA method using labeled, desulfated CCK 8 I125 and an antiserum raised to CCK 8. The detection limit for the assay was 0.25 to 0.5 fmole and the lowest detectable plasma level was 5 to 10 fmoles ml-1. Since there was equal cross-reactivity to gastrin, a gastrin-specific assay also was employed to evaluate any changes in gastrin levels. After oleate infusion the plasma CCK increment above basal was 50 +/- 11 fmoles ml-1, with return to basal levels after 60 minutes. Administration of atropine significantly (P less than 0.01) inhibited the release of CCK in the first 20 minutes. Thereafter CCK release was not reduced. Plasma gastrin values did not change before and after oleate perfusion. Pancreatic protein output increased from 72 +/- 12 to 420 +/- 55 mg/10 min-1 after oleate administration. However, after atropinization the rise in pancreatic protein output was significantly lower (152 +/- 36 mg/10 min-1) (P less than 0.01). We have shown that, using our RIA method, there is a measurable rise in plasma CCK LI after intraduodenal oleate. After atropinization the CCK response was decreased significantly during the first 30 minutes, but was virtually unchanged during the second 30 minutes, when the fall in pancreatic protein output was most marked. We conclude that the cholinergic mechanism which plays a role in the endogenous stimulation of pancreatic protein secretion by intraduodenal oleate cannot be explained simply be decreased CCK release. This mechanism may be hormonal, distinct from secretin, or neural possibly, via activation of an enteropancreatic reflex.

The role of some central catecholamine systems in cholecystokinin-induced satiety.

Cholecystokinin (CCK), bombesin and gastrin were stereotaxically injected into catecholamine (CA) innervated areas of the lateral hypothalamus (LH), the nucleus caudatus putamen (NP) and the olfactory tubercle (OT) in male Sprague Dawley rats. Bilateral injections of 100 ng of CCK in 2 microliters of vehicle into the LH produced a slight but significant decrease in food intake during the first hour of a 4 hour eating test. The other peptides when injected into any of the brain areas did not significantly alter food intake. Water intake was affected by the injection of all three hormones although differentially in all 3 sites. The observed changes in drinking were not related to the prandial characteristics of drinking typically seen in rodents. Denervation of the CA innervation of the OT, LH or NP with 6-hydroxydopamine did not change the satiety response to peripherally administered CCK displayed by intact animals. These results suggest that the satiety which occurs after the central and peripheral administration of CCK may be mediated by different mechanisms and that central CA systems may not be necessary for CCK-induced satiety to occur during natural feeding.

Bombesin-like immunoreactivity in rat brain and gastrointestinal tract: influence of diet and starvation.

A radioimmunoassay has been developed for the measurement of bombesin-like immunoreactivity (BLI) in mammalian tissues. BLI has been demonstrated in large amounts in the rat stomach and colon and in smaller amounts in the rat central nervous system. A 7-day high-carbohydrate diet leads to an increase in gastric and colonic BLI, a high protein diet to a decrease in fundic BLI. High fat and protein diets led to a decrease in midbrain BLI but other nervous tissues were not influenced by variation in diet. A 6-day fast increased antral, jejunal and ileal BLI; these increased levels fell on refeeding. These studies suggest a role for endogenous BLI in some aspects of gastric physiology, perhaps gastrin release.

Distribution of bombesin- and cholecystokinin-like immunoreactivity in rat and dog brain and gastrointestinal tract.

Using a specific bombesin radioimmunoassay and an immunoassay for cholecystokinin which sees all C-terminal fractions, the distribution of bombesin-like (BLI) and cholecystokinin-like (CCK-LI) immunoreactivity in the brain and gastrointestinal tract of the rat and dog has been studied. Both peptides are found in the brain and gut but the rat contains more CCK and BLI than the dog; this is particularly noted in the stomach, colon and cerebral cortex whereas the small intestine of both species contains equivalent amounts of peptides. This contrasts with other comparative studies, mainly on nervous system CCK, which find no major distribution differences in man, monkey, pig and rat. This finding suggests that CCK-LI and BLI peptides may have a more predominant role in the rat than in the dog.

Central and peripheral proglumide administration and cholecystokinin-induced satiety.

Peripheral (50 mg/ml) or central (50 micrograms/microliter) injections of proglumide were made into Sprague-Dawley rats which displayed satiety-like responses after the peripheral (100 micrograms/kg) or central (50 ng in 1 microliter) administration of cholecystokinin (CCK). The satiety produced by CCK injection into the lateral hypothalamus, area postraema and ventromedial hypothalamus was significantly reversed by proglumide injections into these areas during a 4 h food intake test. Peripheral injection of proglumide after central or peripheral CCK injection did not modify this type of CCK-induced satiety. Central proglumide injection produced a reliable decrease in water intake and this is compatible with previous findings which describe the stimulation of water intake after central gastrin administration. These results suggest that various central and peripheral mechanisms which are involved in the regulation of appetite may function independently as a 'failsafe' system.

The effect of atropine and vagal stimulation on the release of neurotensin-like immunoreactivity in man.

This study investigated the food stimulated release of neurotensin-like immunoreactivity (NTLI) in man with and without the administration of atropine, and the influence of vagal stimulation by modified sham feeding and insulin hypoglycaemia. NTLI was measured, after ethanol extraction, by specific C- and N-terminally directed antisera. With both a liquid fat meal and a mixed meal an early peak of NTLI occurred. The mixed meal also produced a second sustained rise in plasma NTLI. An intramuscular injection of 0.6 mg atropine sulphate abolished the early peak, but had no effect on the late peak. Modified sham feeding and insulin hypoglycaemia did not release NTLI. We conclude that it is possible that a cholinergic non-vagal mechanism is responsible for the early phase of food stimulated release of NTLI in man, and that the second sustained rise may be cholinergically independent.

Ventricular, paraventricular and circumventricular structures involved in peptide-induced satiety.

Cholecystokinin, bombesin or gastrin (2 microliter of 50 ng/microliter) was injected stereotaxically into the paraventricular nucleus of the hypothalamus, the arcuate/ventromedial area, the subfornical organ, the area postrema and the cerebral aqueduct of Sprague-Dawley rats and the effects of these injections on food and water intake were studied. While the injection of cholecystokinin reduced food intake when it was injected into both hypothalamic loci, food and water intake were most severely affected by the injection of this peptide into the cerebral aqueduct. Bombesin reduced food intake after its injection into all areas except the subfornical organ and reliable reductions in water intake were seen after injection of this peptide into all areas except the paraventricular nucleus. Minor reductions in food intake were seen following gastrin injection into the paraventricular nucleus while increased water consumption was observed after this peptide was injected into the paraventricular nucleus and cerebral aqueduct. In a second study 6-hydroxydopamine injections (2 microliter of 8 micrograms/microliter were made into the five areas studied 10 days before animals were injected with 100 micrograms/kg of cholecystokinin (i.p.). All 6-hydroxydopamine-injected animals reduced their food and water intake in response to the cholecystokinin challenge as did intact controls. These results indicate that while the changes in food and water intake produced by the central injection of cholecystokinin, bombesin or gastrin may involve central catecholamine systems, those occurring after its systemic administration do not. Therefore, if the release of gastrointestinal peptides during natural feeding is part of a homeostatic mechanism regulating hunger and satiety, this mechanism may operate without directly involving central catecholamine systems.

Serum gastrin in newborn, sucking and weaned pigs.

Serum gastrin concentrations during the first six weeks of life in pigs reared on sow's milk alone were compared with those in pigs given access to solid food at two weeks and weaned at three weeks of age. Gastrin levels were higher in both parturient sows and newborn unsuckled pigs than in dry sows. It appears that the newborn pig is capable of secreting its own gastrin. High levels of gastrin persisted throughout the experimental period, being particularly high in the first two weeks of life. In weaned pigs, feeding after a period of fasting evoked a greater postprandial gastrin response than that which occurred in unweaned pigs after sucking from the sow. The results suggest a possible role for gastrin in early gastric development.

Immunoreactive gastrin concentrations in gastrointestinal tissues of sheep.

Radioimmunoassay of gastrin in gastrointestinal tissues of lambs and adult sheep showed highest concentrations (796 to 11,156 pmol g-1 mucosa) in the antral region of the abomasum. The next highest concentrations of gastrin were in the proximal duodenal mucosa (16 to 518 pmol g-1). Gastrin was undetectable or present in lower concentrations in caudal regions of the duodenum (less than 11 X 5 pmol g-1), the pancreas and in the body of the stomach. It is concluded that the distribution of gastrin secreting cells in sheep is similar to that in other animals.

Observations on plasma gastrin and plasma pepsinogen in relation to weaning and gastric (pars oesophagea) ulceration in pigs.

Plasma gastrin and pepsinogen were measured at weekly intervals in 38 pigs from weaning at about four weeks of age until slaughter at 24 weeks. Plasma gastrin was 104 +/- 6.2, 85 +/- 11.2, 126 +/- 11.67 mol per litre in the pigs aged four, five and six weeks and 43 +/- 2.57, 31 +/- 2.29, 17 +/- 0.87 mol per litre when they were 21, 22 and 23 weeks old. Sixteen of the pigs had apparently normal stomachs, the remainder had some degree of epithelial hyperplasia and, or, ulceration of the pars oesophagea of the stomach. No differences were detected between plasma gastrin and plasma pepsinogen in pigs with normal stomachs and those showing evidence of epithelial hyperplasia or ulceration of the pars oesophagea. If ulcers of this region arise from hypersecretion of gastric acid some factor(s) other than gastrin appear to be involved. The possibility is discussed that the progressive decline in plasma gastrin is part of the maturation process.

Changes in plasma pancreatic polypeptide and gastrin in sows after eating and atropine.

Changes in plasma gastrin, pancreatic polypeptide and pulse rate were examined in three adult female pigs in which venous cannulae had been placed and in two of which arterial cannulae allowed sampling of arterial blood or recording of pulse rate. Gastrin, pancreatic polypeptide and pulse rate increased when the pigs ate after fasting overnight. Pancreatic polypeptide was reduced to or below resting levels following administration of atropine (25, 50 or 100 micrograms/kg intravenously) after which gastrin remained at about its previous levels or rose and pulse rates rose. It is concluded that in the pig, as in other species, there is a cholinergic muscarinic (atropine sensitive) mechanism contributing both to postprandial increases of pancreatic polypeptide and of gastrin.

Reflux disease: the view of the internist.

Pathogenesis of GERD is mainly concerned with a defective antireflux barrier to gastric and duodenal contents. Transient lower oesophageal sphincter relaxation is thought to be the main mechanism by which reflux is permitted, but the mucosal exposure time to the refluxate, the nature of the refluxed material and oesophageal clearance are important mechanisms. The Internist only sees the 'tip of the iceberg' as far as GERD is concerned, and generally these are severe resistant cases of GERD. In this group, endoscopy is mandatory to assessing degree of inflammation and treatment is generally with proton-pump inhibitors, which have made the therapy of GERD relatively easy. Although treatment is effective, problems relating to safety of long-term profound gastric acid suppression, cost and effect on quality of life remain to be resolved.

Campylobacter pylori--a role in non-ulcer dyspepsia?

Non-ulcer dyspepsia (NUD) is a common complaint in which no systematic illness or organic proximal alimentary tract disease can be identified. The pathophysiology of NUD is probably heterogeneous. Eighty-two subjects with NUD were studied in a prospective randomized placebo-controlled study to assess the efficacy of colloidal bismuth subcitrate (CBS) chewable tablets at a dose of four tablets daily for 1 month. The role of Campylobacter pylori and associated histological gastritis was evaluated. Sixty-one percent of NUD patients had C. pylori in the gastric antrum compared with 25% of age-matched controls. C. pylori was associated with acute and chronic inflammation (P less than 0.001) in the antrum. C. pylori was cleared in 59% of CBS-treated subjects compared with only 4% placebo (P less than 0.05). Both acute and chronic inflammation improved in subjects cleared of bacteria. Clearance of C. pylori and histological improvement was associated with a significant decrease in symptoms. In C. pylori negative subjects improvement in symptoms occurred in both the placebo and active treatment groups. This study would suggest that C. pylori and associated histological gastritis may play a role in non-ulcer dyspepsia.

Current concepts in gastrointestinal peptides: a physician's guide.

Gastrointestinal hormones were the subject of a review at The Royal Australasian College of Physicians meeting in 1973. Over the past nine years there has been such an explosion of knowledge about these peptides that even the experts in the field cannot keep up with the almost monthly discovery of either new peptides or new actions for old peptides. This paper will consider only four aspects of gastrointestinal hormones encompassing areas that are relatively new and reviewing the clinical usefulness of gastrointestinal hormones in practice. The areas which require consideration are: (i) How do we define a gastrointestinal hormone. (ii) Concept of brain-gut peptides and relationship of amphibian peptides to mammalian hormones. (iii) Of the plethora of peptides discovered, which have a defined role in normal physiology. (iv) When should a clinician ask for a gastrointestinal hormone estimate in clinical practice.