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Enteroglucagon and peptide Y-Y response after construction of a pelvic reservoir in humans.

The results of an investigation of plasma levels of gastrointestinal hormones in patients after the construction of a pelvic reservoir are reported. Enteroglucagon (EG) and peptide tyrosine-tyrosine (PYY), two hormones believed to play a relevant role in the adaptive response to bowel resection, were investigated using a specific radioimmunoassay in basal conditions and after a standard meal. Pouch patients showed a statistically significant increase in basal levels of both enteroglucagon and PYY compared with control subjects (P less than 0.02 and P less than 0.001, respectively). The response of enteroglucagon to food ingestion, evaluated by means of the total integrated response, was similar in patients and controls. Conversely, the response of PYY was significantly increased in pouch patients compared with control cases (P less than 0.02). Results of this investigation suggest that gut hormones may be involved in mediating the adaptive response of the intestine to pouch construction. Changes of gut peptides may explain, at least in part, the functional results observed after pouch construction.

Adult↗

Immunocytochemical study of endocrine cells in pelvic ileal reservoirs.

The distribution and morphology of intestinal endocrine cells was investigated in the mucosa of pelvic ileal reservoirs using immunocytochemical methods. Endoscopic biopsies were obtained from 15 patients after the construction of a modified J-pouch. The mucosa of the reservoir showed a variable degree of colonic metaplasia in all cases. No relevant quantitative variations of gut endocrine cells were detected, as revealed by immunostaining for the general marker, chromogranin, compared with normal ileal mucosa. Immunostaining for different peptide-containing cells resulted in normal number and morphology of serotonin, enteroglucagon, peptide tyrosine-tyrosine, and somatostatin-containing cells. Neurotensin cells were less numerous than in normal mucosa. The role played by gastrointestinal hormones in the adaptive response of the intestine to pouch construction is, presently, unclear. Further studies involving measurements of fasting and meal-stimulated levels of gut hormones in pouch patients might clarify this aspect.

Adult↗

Therapeutic effect of secretin in patients with jaundice; double-blind placebo-controlled multicentric trial.

Secretin, a gastrointestinal hormone, has been shown to have a potent choleretic effect. Having already obtained some beneficial effects with secretin in patients with intrahepatic cholestasis, we sought to confirm its effects in a double-blind placebo-controlled study in patients with mild jaundice after acute or during chronic hepatitis, where total bilirubin level was in excess of 4.0 mg/dl for 3 days or more. Patients with primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and familiar hyperbilirubinemia were excluded from the study. Ninety-three patients were included in this analysis, but the final evaluation covered 69 of them. No statistically significant differences were found in the reduction of serum bilirubin levels between secretin and placebo groups. As a number of patients with liver cirrhosis had been included, the subjects were subdivided into one group with cholestasis in hepatitis and one with liver cirrhosis. In the subgroup of cirrhotic patients who received secretin, serum levels of AST were significantly increased compared with the placebo group. However, since the choleretic effect of secretin is unique, further studies seem to be warranted.

Adolescent↗

The effects of diet on the residual small intestine following massive resection.

The midportions of rat small intestines were resected by 90 per cent, and the residual intestines studied for the effects of diet on mucosal morphology, nutrition and gastrointestinal hormones. Groups of rats were fed chow, an elemental diet (ED), or an ED + dietary fiber (EDF) for 1 or 3 weeks. Nonresected rats which were fed chow or ED for 3 weeks were used as controls. Nutritional parameters, such as concentrations of serum total protein, albumin and transferrin were favorable but gain in body weight was not. The parameters indicated that resected rats fed EDF fared better than resected rats fed ED. Mucosal villous height in the residual jejunum, similar in all the resected groups after 1 week, was significantly increased in the resected rats fed chow or EDF after 3 weeks, but did not differ between 1 and 3 weeks in the resected rats fed ED. Changes in the number of villous epithelial cells and villous width were also examined. The level of plasma enteroglucagon was high in the rats fed chow or EDF after both 1 and 3 weeks, and was positively correlated with the increases in villous height. Levels of serum gastrin were not affected by dietary change. Luminal nutrients were significantly associated with the adaptive changes in the mucosa of the residual intestine, and mucosal morphology was also considerably influenced by dietary change.

Adaptation, Physiological↗

Selection of a chemically defined medium for culturing fetal mouse small intestine.

We evaluated six commercially available tissue culture media in their capacity to support villi morphogenesis and enterocyte differentiation during duodenal development of the fetal mouse in vitro: McCoy's 5A, Medium 199, Swim's S77, Trowell T8, Leibovitz L-15, and RPMI-1640. The duodenal segments were resected at 15 d gestation, before the formation of intestinal villi. In the segments cultured with the first four media, no villi differentiated even at 72 h culture. The number of epithelial cells per transverse section of the explants did not increase at 24 h and thereafter the number of epithelial cells decreased, except with McCoy's 5A. With the Leibovitz and RPMI media, rudimentary villi differentiated at 24 h of culture and they attained their longest length at 48 h. With the RPMI medium, the number of epithelial cells doubled at 24 h of culture and with Leibovitz medium it doubled at 48 h. At the fine structural level absorptive cells remained poorly differentiated with all the media studied. Goblet cells were easily identified after 24 h culture; they had a well developed rough endoplasmic reticulum and numerous mucous granules. Endocrine cells differentiated in culture and they were loaded with secretion granules. It was concluded that the small intestine of the fetal mouse can be kept in organ culture for at least 72 h. Full maturation of absorptive cells seemed to require some additional factor(s) as they remained poorly differentiated with all the media studied. Because well differentiated endocrine cells were present in all the explants, it appeared that gastrointestinal hormones do not affect villi morphogenesis and absorptive cells differentiation.

Animals↗

Study of A- and B-cell function in beta-thalassemia major.

Hepatic and pancreatic damage owing to iron overload is often present in patients with beta-thalassemia major. In order to investigate B-cell function and hepatic insulin clearance in these patients, under a high transfusion program and regular chelation therapy, we studied the glucose (BG), insulin (IRI) and C-peptide (CPR) response and the CPR/IRI ratio after OGTT in 27 patients with Cooley's anemia and in 10 sex- age- and weight-matched healthy subjects; we also studied BG and IRI levels after IVGTT in 9 beta-thalassemic patients and in 9 control subjects. Furthermore, BG, CPR, IRI and glucagon (IRG) response to arginine infusion were evaluated in 5 thalassemic patients with normal OGTT and in 5 age-, sex- and weight-matched normal children, in order to assess pancreatic A-cell function, too. OGTT and IVGTT were normal in the patients with beta-thalassemia major. Plasma IRI level 30 min after an oral glucose load and the insulinogenic index for cumulative intervals were significantly lower in thalassemics after OGTT, whereas the insulin response and insulinogenic index were normal following i.v. glucose. No significant difference was observed for the CPR/IRI ratio during OGTT between thalassemics and normal subjects. Finally, BG, CPR, IRI and IRG levels were similar in the thalassemic patients and in healthy children both fasting and following arginine infusion. Our data suggest that patients with beta-thalassemia major, under a high transfusion program and regular chelation therapy, may have normal glucose tolerance and normal hepatic insulin clearance in spite of iron overload in pancreas and liver. Insulin response to oral glucose was lower than the one to IVGTT, probably because of diminished secretion of the gastrointestinal hormones which stimulate insulin release.

Adolescent↗

The effect of motilin on the gastrointestinal propulsion in rats.

We studied the gastrointestinal propulsion in unanaesthetized rats by 51Cr method that permits the simultaneous determination of two functions of the gastric emptying and the intestinal propulsion. The results obtained are as follows: 1) The semi-logarithmic presentation of the gastric emptying showed a linear relationship with the time. 2) When synthetic motilin was subcutaneously injected at the dose of 1 microgram/kg, the gastric emptying was promoted to a statistically significant extent.

Animals↗

Inhibitory effect of pentagastrin and feeding natural and motilin-induced interdigestive contractions in the stomach of conscious dogs.

The interaction between motilin, pentagastrin and feeding was investigated during the interdigestive gastric motor state in 4 healthy conscious dogs. We confirmed previous reports that an i.v. infusion of synthetic motilin always induced a pattern precisely like that of the naturally-occurring interdigestive contractions of the stomach. Pentagastrin inhibited the occurrence of the interdigestive contractions at dose between 0.2-1.6 microgram/kg-hr; this inhibition had a dose-related relationship to the occurrence of the motilin-induced contractions. The ingestion of food strongly inhibited the occurrence of not only the natually-occurring contractions but also the motilin-induced contractions in the stomach and changed the motor pattern to the digestive one. These findings strongly support our hypothesis that the interdigestive contractions in the dog are, at least in part, under the control of motilin. Furthermore, it should be emphasized that pentagastrin not always stimulates gastric motor activity but conversely, in the interdigestive state it inhibits movements characteristic of that condition and replaces them with the digestive pattern.

Animals↗

Human pancreatic polypeptide, neuropeptide Y and peptide YY reduce the contractile motility by depressing the release of acetylcholine from the myenteric plexus of the guinea pig ileum.

Transmural stimulation (TS; 15 V, 0.5 msec, 1-5 Hz, for 30 sec) caused a contraction in a frequency-dependent manner of the longitudinal muscle with myenteric plexus of the guinea pig ileum. Two-min premedication with human pancreatic polypeptide (HPP, 10(-8) M-10(-6) M), neuropeptide Y (NPY, 10(-8) M-10(-6) M), and peptide YY (PYY, 10(-8) M-10(-6) M) partially, by less than 35%, reduced TS (15 V, 0.5 msec, 10 Hz)-evoked contraction in a dose-dependent manner without affecting the resting tensions. Hexamethonium, phentolamine, prazocine, yohimbine, propranolol, naloxone and theophylline had no effects on the inhibitory actions of these peptides on TS-evoked contractions. TS (15 V, 0.5 msec, 10 Hz)-evoked 3H-ACh release was significantly reduced by 2-min premedication of HPP (10(-6) M), NPY (10(-6) M) and PYY (10(-6) M). The order of potency of these depressant effects on TS-evoked contraction and 3H-ACh release was PYY greater than NPY greater than HPP. It is suggested that the members of PP family have inhibitory effects on the contractile motility by depressing ACh release from myenteric plexus of the guinea pig ileum.

Acetylcholine↗

Effect of a somatostatin analogue (SMS 201-995) on hemodynamics and glucagon secretion in cirrhotic rats.

The effects of somatostatin analogue, SMS 201-995, on systemic and splanchnic hemodynamics and glucagon secretion were investigated in control and cirrhotic rats induced by thioacetamide administration. Hemodynamics were measured using the radioactive microsphere method. Immunoreactive glucagon (IRG) was determined in the portal vein and femoral artery and the splanchnic output (OP) of IRG was calculated. In control rats, SMS 201-995 induced a decrease of 5.6% in portal venous inflow and a 25.8% decrease in OP of IRG. In cirrhotic rats, SMS 201-995 produced a 14% decrease in portal pressure, a 13.6% decrease in portal venous inflow, and a 57.8% decrease in OP of IRG. In systemic hemodynamics no significant changes were noted following SMS 201-995 administration in the control or cirrhotic rats. The ratio of cirrhotic rats to the controls in the rate of decrease in portal venous inflow was similar to that in the percentage of decrease in OP of IRG. We conclude that SMS 201-995 is useful for the treatment of portal hypertension because of its effect of reducing portal pressure with mild changes in systemic hemodynamics. We suspect that the decrease in portal venous inflow by SMS 201-995 is mainly due to a reduction in the release of glucagon, a vasodilatory gastrointestinal hormone.

Animals↗

Effects of antioxidants on calcium signal induced by cholecystokinin in mouse pancreatic acinar cells.

Digital imaging fluorescence microscopy was used to study the effect of two antioxidants, N-acetyl-cysteine (NAC) and glutathione, on the cytosolic free calcium concentration ([Ca2+]i) induced by cholecystokinin-octapeptide (CCK-8) of mouse pancreatic acinar cells. When acinar cells were preincubated with either NAC or glutathione, subsequent stimulation with CCK-8 in the presence of each antioxidant had no significant effect on the typical pattern of [Ca2+]i transient evoked by the gastrointestinal hormone. However, application of NAC to acinar cells pretreated for 60 min with the same antioxidant, strongly blocked the oscillatory pattern initiated by CCK-8, inhibiting both amplitude and frequency of calcium oscillations. By contrast, glutathione had no effect on the oscillatory pattern evoked by CCK-8. The present results allow us to speculate that during [Ca2+]i oscillation there is a production of oxidants that facilitate oscillations by enhancing release of calcium from internal stores.

Acetylcysteine↗

Glucagon-like peptide 1 (GLP-1) and metabolic diseases.

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone, mainly secreted after meals, which enhances glucose-induced insulin secretion and induces satiety. It has been reported that GLP-1 levels after a mixed meal and after an oral glucose load are reduced in patients with Type 2 diabetes. The reduction of oral glucose-stimulated active GLP-1 levels in patients with Type 2 diabetes has also been observed during euglycemic iperinsulinemic clamp. The reduction of post-prandial circulating active GLP-1 in Type 2 diabetic subjects, as a consequence of chronic hyperglycemia, could contribute to the reduction of early post-prandial insulin secretion; in fact, the administration of GLP-1 receptor antagonists to healthy volunteers elicits both an impairment of meal-induced insulin secretion and an increase of post-prandial glycemia similar to that observed in Type 2 diabetes. GLP-1 is rapidly inactivated by dipeptidyl peptidase IV (DPP-IV), an enzyme produced by endothelial cells in different districts and that circulates in plasma. It is still not clear whether the reduction of mealor oral-glucose stimulated GLP-1 levels in Type 2 diabetic patients is due to impairment of secretion, increase of degradation, or both. The major limitation of using GLP-1 to treat diabetic patients is the short half-life of the native compound. There are now several compounds in various stages of pre-clinical or clinical development for the treatment of Type 2 diabetes that utilize the GLP-1 signaling pathway; these include GLP-1 receptor agonists with extended half-lives, and inhibitors of DPP-IV that increase circulating levels of endogenous, intact and bioactive GLP-1.

Diabetes Mellitus, Type 2↗

Accelerated gastric emptying of glucose in Zucker type 2 diabetic rats: role in postprandial hyperglycaemia.

Patients with early non-insulin-dependent diabetes mellitus (NIDDM) empty glucose solutions from their stomachs more rapidly than non-diabetic control subjects, and this exacerbates postprandial hyperglycaemia. To determine if accelerated gastric emptying occurred in a rat model of NIDDM and influenced postprandial hyperglycaemia, gastric emptying of glucose was measured, and the effect of slowing the gastric emptying rate on postprandial hyperglycaemia was observed. We tested eight male obese Zucker diabetic rats and eight age-matched lean Zucker controls at 10-13 weeks of age to measure gastric emptying of glucose (by gamma scintigraphy). Rats fasted overnight were gavaged with 30% glucose at 1 ml/100 g body weight. Separately, six Zucker diabetic rats and six lean controls were tested for sensitivity to the inhibitory effects of cholecystokinin and secretin on gastric emptying. The diabetic rats emptied glucose significantly faster than controls (t1/2 = 37.3 +/- 1.5 vs 58.8 +/- 2.3 min in controls), and aging exaggerated this differential. Camostat, a stimulant of cholecystokinin and secretin release, added to the glucose meal significantly slowed gastric emptying (t1/2 = 123 +/- 23 and 166 +/- 19 min, diabetic vs lean, respectively), and significantly reduced postprandial hyperglycaemia in diabetic rats. Compared to Zucker lean controls, Zucker diabetic rats were as sensitive (cholecystokinin) or more sensitive (secretin) to gastrointestinal hormones that inhibit gastric emptying. The results demonstrate accelerated gastric emptying in a rat model of NIDDM, consistant with similar observations in humans with early NIDDM. These results also support the proposal that interventions to slow gastric emptying improve glucose control in this disease.

Animals↗

Serum ghrelin concentrations in patients receiving olanzapine or risperidone.

RATIONALE: Although enhanced appetite and weight gain are potential side effects of treatment with antipsychotic agents, particularly olanzapine and clozapine, the mechanism is poorly understood. OBJECTIVES: To test the hypothesis that ghrelin, a gastrointestinal hormone that enhances appetite, is involved in increased food intake and weight gain during treatment with antipsychotics. METHODS: Serum ghrelin concentrations were investigated in schizophrenic patients receiving olanzapine or risperidone, and in healthy volunteers. RESULTS: Serum ghrelin concentrations did not increase, but rather decreased, in patients treated with olanzapine or risperidone in comparison with healthy volunteers. No significant difference was found in serum ghrelin concentration between patients treated with olanzapine and risperidone. CONCLUSIONS: Our results indicate that ghrelin is not a direct cause of increased food intake and weight gain during treatment with olanzapine or risperidone, whereas ghrelin is associated with metabolic change in patients receiving these agents.

Adult↗

Major biological actions of CCK--a critical evaluation of research findings.

Cholecystokinin (CCK) is one of the first discovered gastrointestinal hormones and one of the most abundant neuropeptides in the brain. Two types of CCK receptors have been identified: (1) CCK-A receptors are mainly located in the periphery, but are also found in some areas of the CNS; and (2) CCK-B receptors are widely distributed in the brain. Major biological actions of CCK are the reduction of food intake and the induction of anxiety-related behavior. Inhibition of feeding is mainly mediated by the A-type receptors, whereas anxiety-like behavior is induced by stimulating B-type receptors. This paper presents new findings on the effects of the biologically active CCK agonists, CCK-8S, CCK-4, and A71378. The results reviewed suggest that the hypophagic effects of CCK are strongly dependent on the experimental design, sex, and age of the rats. For example, food intake measured during the night or after food deprivation is reduced by CCK-8S in young adult and aged rats, whereas, under fixed feeding conditions, CCK-8S does not inhibit food intake in young adult rats. The sensitivity to the hypophagic CCK effect increases with age in male and female rats; however, female rats are less sensitive to the CCK action. Further, using a nongenetic and non-stressful model of obesity due to unspecific postnatal overfeeding, the satiating effect of moderate CCK-8S doses is weaker in obese than in normal rats. Again, the hypophagic effect is more pronounced in male than in female obese and normal rats. Considering that aversive reactions in rats are markedly influenced by strain and breeding-line variations, research results in this area are critically reviewed. It is shown that anxiety-like symptoms can only be induced by a selectively acting CCK-B agonist, whereas mixed CCK-A and -B agonists and selective CCK-A agonists fail to change behavior in anxiety tests. CCK-4 induces stable and reproducible anxiogenic-like behavior only in certain rat strains. Moreover, CCK-4 effects can be demonstrated in the conflict test, in the ultrasonic vocalization test in rat pups, on the elevated plus maze, and in the black and white box, but not in the social interaction test. CCK has also been reported to modulate memory processes. On the one hand, CCK-8S and CCK-4 enhanced habituation to the novelty of a hole board. On the other hand, repeated administration of CCK-8S did not improve maze performance in aged rats. The literature on the behavioral pharmacology of CCK is rife with inconsistency and contradiction. The major biological actions of CCK depend on the receptor selectivity of the CCK fragments used and on organismic and procedural variables. All these variables potentially influence behavioral responses in rats. Therefore, in CCK research more attention should be paid to the importance of these methodological factors.

Animals↗