cholecystokinin and Atrophy

Topics: Adrenalectomy; Animals; Atrophy; Cell Division; Cholecystokinin; Digestive System; DNA Replication; Gastrins; Gastrointestinal Hormones; Hypophysectomy; Intestinal Mucosa; Pancreas; RNA, Ribosomal; Somatostatin

Spinocerebellar ataxias (SCAs) are a group of genetic diseases characterized by progressive ataxia and neurodegeneration, often in cerebellar Purkinje neurons. A SCA1 mouse model, Pcp2-ATXN1[30Q]D776, has severe ataxia in absence of progressive Purkinje neuron degeneration and death. Previous RNA-seq analyses identify cerebellar upregulation of the peptide hormone cholecystokinin (Cck) in Pcp2-ATXN1[30Q]D776 mice. Importantly, absence of Cck1 receptor (Cck1R) in Pcp2-ATXN1[30Q]D776 mice confers a progressive disease with Purkinje neuron death. Administration of a Cck1R agonist, A71623, to Pcp2-ATXN1[30Q]D776;Cck

Topics: Animals; Ataxin-1; Atrophy; Behavior, Animal; Calbindins; Chemokines, CC; Cholecystokinin; Disease Models, Animal; Female; Genetic Predisposition to Disease; Guanine Nucleotide Exchange Factors; Male; Mechanistic Target of Rapamycin Complex 1; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Nerve Degeneration; Neuropeptides; Purkinje Cells; Signal Transduction; Spinocerebellar Ataxias; Tetragastrin

Dietary protein deficiency results in diminished capacity of the pancreas to secrete enzymes needed for macronutrient digestion. Previous work has suggested that modulation of the mammalian target of rapamycin (mTOR) pathway by the hormone cholecystokinin (CCK) plays an important role in normal digestive enzyme synthesis after feeding. The purpose of this study was to elucidate the role of mTOR in protein deficiency-induced pancreatic dysfunction.. Wild-type and CCK-null mice were fed protein-deficient chow for 4 days and then allowed to recover on control chow in the presence or absence of the mTOR inhibitor rapamycin.. The size and secretory capacity of the pancreas rapidly decreased after feeding protein-deficient chow. Refeeding protein-replete chow reversed these changes in both wild-type and CCK-null mice. Changes in the size of the pancreas were paralleled by changes in the content and secretion of digestive enzymes, as well as the phosphorylation of downstream targets of mTOR. Administration of the mTOR inhibitor rapamycin decreased regrowth of the pancreas but did not affect digestive enzyme content or secretory capacity.. These studies demonstrate that dietary protein modulates pancreatic growth, but not digestive enzyme synthesis, via CCK-independent activation of the mTOR pathway.

Topics: Animals; Atrophy; Carrier Proteins; Cholecystokinin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Organ Size; Pancreas; Phosphotransferases (Alcohol Group Acceptor); Protein Deficiency; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

The aim of this study was to evaluate the concept that pancreatic dysfunction in patients having gluten sensitivity (celiac disease [CD]) or cow's milk protein enteropathy (CMPE) may result from the lack of pancreatic enzyme stimulation in the absence or decrease of cholecystokinin (CCK) secretion caused by villous atrophy.. The following parameters were measured: plasma CCK in response to a fatty meal and human pancreatic fecal elastase in 24 patients with CD while on gluten-free diet and after gluten provocation and in 12 patients with CMPE at diagnosis and after a 6-month period of cow's milk-free diet. Intestinal mucosa morphology was examined by small bowel biopsy. Sixty-three controls having no organic gastrointestinal problems were investigated once at the time of diagnostic evaluation.. Fasting CCK, obtained at a time when patients with CD or CMPE had normal intestinal mucosa, was significantly different from postprandial and comparable to that of the control group. Fasting CCK obtained from patients with villous atrophy was also statistically different, but not significantly, from the postprandial. Fasting and postprandial plasma CCK and fecal pancreatic elastase values from patients having normal intestinal mucosa were significantly higher than those obtained from patients with villous atrophy. Significant correlation of intestinal mucosa morphology and CCK with fecal elastase concentration was documented.. Exocrine pancreatic dysfunction in individuals having villous atrophy may be the consequence of decreased CCK secretion. Cholecystokinin and pancreatic secretion is restored to normal, with intestinal mucosa regeneration.

Topics: Adolescent; Atrophy; Biopsy; Celiac Disease; Child; Child, Preschool; Cholecystokinin; Dietary Fats; Feces; Female; Humans; Infant; Intestinal Mucosa; Intestines; Male; Milk Hypersensitivity; Milk Proteins; Pancreas; Pancreatic Elastase; Sincalide

Celiac disease is associated with impaired cholecystokinin (CCK) release. The mechanism by which CCK release is impaired is poorly understood and seems to be related to the mucosal atrophy or to decreased stimulation due to reduced intraduodenal nutrient hydrolysis. The aims of our study were to evaluate basal and postprandial CCK in celiac patients presenting with distinctive types of mucosal lesions (normal, infiltrative and atrophic), and to study the role of protein hydrolysis on CCK release. Plasma CCK was measured in 20 celiac patients (normal mucosa: n=6; infiltrative type: n=6; atrophic type=8) and 9 controls, before and after ingestion of a polymeric or a semi-elemental meal. Significant decreases in basal CCK plasma (B 0.6 [95% CI, 0.3-1.3] pmol/l; p<0.003) and postprandial CCK area under curve (AUC 34 [19-61] pmol/l x 120 min, p<0.0001) were observed in patients with an atrophic mucosa compared with treated patients (B 1.6 [1.0-2.4] pmol/l, AUC 267 [172-414] pmol/l x 120 min) or healthy volunteers (B 1.0 [0.7-1.4] pmol/l, AUC 186 [131-264] pmol/l x 120 min). A significant defective CCK release was also observed in patients with an infiltrative type: B 0.4 [0.2-0.7] pmol/l and AUC 56 [31-101] pmol/l x 120 min; p<0.0001. Administration of a semi-elemental diet did not correct the defective CCK release. In conclusion, the decreased CCK levels observed in celiac patients are not strictly related to the mucosal atrophy but rather to the lymphocytic infiltrate. Administration of a predigested meal did not correct the impaired CCK release. Some inhibitory mechanism could be involved in the CCK cell dysfunction observed in celiac patients presenting with lesser degrees of disease activity.

Topics: Adult; Area Under Curve; Atrophy; Celiac Disease; Cholecystokinin; Dietary Proteins; Female; Food, Formulated; Gallbladder; Glutens; Humans; Hydrolysis; Intestinal Mucosa; Lymphocytes; Male; Postprandial Period; Radioimmunoassay

According to recent reports, the powerful and selective cholecystokinin (CCK)-A receptor antagonist devazepide (also referred to as L-364,718 or MK-329) is without effect on the weight of the pancreas. This has been interpreted to mean that basal and meal-stimulated endogenous CCK does not play a major role in the normal maintenance of the pancreas. In the present study we show that continuous subcutaneous infusion of devazepide effectively and dose-dependently reduced the weight of the pancreas both in normal rats and in hyperCCKemic rats (because of pancreaticobiliary diversion). The maximum reduction of the pancreatic weight was 40%. Maximum or near-maximum effects were seen with a dose of 200 micrograms/kg/h. The DNA content of the pancreas was also reduced. The reduction in weight and DNA content of the pancreas was maximal after 10 days. Provided that devazepide acts solely by inhibiting CCK-A receptors, we can conclude that endogenous CCK plays an important role in both normal and stimulated growth of the rat pancreas.

Topics: Animals; Atrophy; Benzodiazepinones; Cholecystokinin; Devazepide; Dose-Response Relationship, Drug; Male; Organ Size; Pancreas; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin

As compared to healthy persons and patients with non-atrophic duodenitis, patients with atrophic duodenitis manifest a decrease of gallbladder contractility as shown by the ultrasonography data. In chronic pancreatitis with concomitant atrophic duodenitis, the degree of a decrease in pancreatic enzymic secretion is more considerable than in patients suffering from chronic pancreatitis without duodenitis or from non-atrophic duodenitis. Comparison of the tests for enhancement of the incretion of endogenous cholecystokinin-pancreozymin and with intravenous injection of the hormone formed the basis for regarding incretory duodenal insufficiency as a cause of hypomotor dyskinesia of the gallbladder and deepening of pancreatic enzymic secretion inhibition in cases with atrophic duodenitis. The data obtained may be of importance for estimating the mechanisms of the impairment of gallbladder contractility and pancreatic enzymic secretion in alimentary diseases as well as for prognosis determination and choice of therapeutic modalities.

Topics: Atrophy; Cholecystokinin; Digestive System Diseases; Duodenitis; Duodenum; Gallbladder; Humans; Pancreatitis; Ultrasonography

Topics: Alcoholism; Amylases; Animals; Atrophy; Cholecystokinin; Dietary Fats; Male; Pancreas; Pancreatitis; Rats; Rats, Inbred Strains; Receptors, Cholecystokinin; Trypsinogen

Intestinal adaptation has been studied in rats with pancreatic atrophy induced by feeding a copper-deficient diet and penicillamine and in rats with carbohydrate maldigestion induced by feeding of an alpha-glucosidase inhibitor (acarbose). Pancreatic atrophy led to a significant increase of weight, protein, and DNA content as well as specific activities and total amounts of the enzymes sucrase and maltase in the distal but not in the proximal part of the small intestine. Plasma levels of CCK and GIP were significantly higher in rats with pancreatic atrophy, whereas plasma levels of gastrin and insulin were lower. Tissue concentrations of gastrin in the antrum and GIP in duodenum and jejunum were unchanged. Duodenal CCK and jejunal substance P, somatostatin, and VIP and ileal substance P and somatostatin were significantly decreased in rats with acinar atrophy. Glucosidase inhibition by acarbose feeding led to weight increase of the small intestine and cecum. This was more marked when acarbose was fed together with a fiber-free diet. Under these conditions the protein and DNA content also increased significantly in both gut segments and maltase and sucrase content predominantly in the distal part. Insulin plasma concentration decreased significantly in the acarbose-fed groups, whereas GIP, gastrin, and CCK plasma concentrations remained unchanged. After fiber-rich diet tissue concentrations of gastrin in the antrum and insulin in the pancreas were significantly higher and GIP concentrations in the duodenum and jejunum significantly lower than after fiber-free diet. Acarbose increased the pancreatic insulin concentration only in the fiber-free group and did not influence gastrin and GIP concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acarbose; Adaptation, Physiological; alpha-Glucosidases; Animals; Atrophy; Cholecystokinin; Copper; Diet; Digestive System Diseases; DNA; Gastric Inhibitory Polypeptide; Gastrins; Glucosidases; Glycoside Hydrolase Inhibitors; Insulin; Intestinal Absorption; Intestine, Small; Male; Oligosaccharides; Pancreatic Diseases; Penicillamine; Proteins; Rats; Rats, Inbred Strains; Sucrase; Trisaccharides

Rats were fed with a copper-deficient diet combined with penicillamine to produce an atrophy of the exocrine pancreas by selective destruction of the acinar cells, which are replaced by fat cells. Plasma cholecystokinin (CCK) concentrations in animals with exocrine pancreatic atrophy were 250% higher compared to control animals (21.7 +/- 7.8 vs. 6.1 +/- 1.07 pmol/l; p less than 0.001). Plasma concentrations of gastrin were significantly decreased by 44% and of gastric inhibitory polypeptide (GIP) significantly increased by 24%, while the decrease of the plasma insulin did not reach the level of significance. In the proximal duodenum a significant decrease of the CCK concentration could be observed, whereas tissue concentrations of GIP in duodenum and jejunum and gastrin in the gastric antrum remained unaltered. These data suggest that the negative feedback control of pancreatic enzyme secretion is mediated by the release of CCK.

Topics: Animals; Atrophy; Cholecystokinin; Feedback; Gastric Inhibitory Polypeptide; Gastrins; Insulin; Intestine, Small; Male; Pancreas; Plasma; Pyloric Antrum; Rats; Rats, Inbred Strains

1. This study examines the influence of starvation on intestinal CCK content and pancreatic growth. Intestinal CCK content was determined by measuring the CCK-like activity using an in vitro gall-bladder bio-assay. Starvation for up to 72 hr causes a parallel fall in intestinal CCK content and pancreatic DNA synthesis. Since there was no significant decrease in liver DNA synthesis, the effect of starvation was probably not simply a consequence of malnutrition. Furthermore there was little effect of starvation on pancreatic protein and DNA content, suggesting that pancreatic cell turnover is particularly sensitive to changes in dietary stimulation.2. With refeeding after starvation CCK-like activity in intestinal extracts gradually increased, approaching non-fasting levels 72 hr after refeeding. Pancreatic DNA synthesis also returned to non-fasting levels after feeding but this rose faster than the intestinal CCK content.3. Pentagastrin treatment prevented the atrophy of both the pancreas and the gastrointestinal tract with starvation without influencing the fall in intestinal CCK-like activity. This suggests that the control of CCK-containing cells is different from that of the surrounding intestinal parenchyma.4. The effect of starvation was also studied in antrectomized rats. Antrectomy alone did not reduce pancreatic DNA synthesis although DNA synthesis of the small intestine was significantly reduced. When antrectomized rats were starved pancreatic DNA synthesis fell to the same degree as was found in unoperated animals. The pancreatic atrophy was also accompanied by a drop in intestinal CCK content. Starvation of antrectomized rats, however, did not further depress the already greatly reduced plasma gastrin concentration.

Topics: Animals; Atrophy; Biological Assay; Cholecystokinin; DNA; Intestine, Small; Liver; Male; Pancreas; Pentagastrin; Rats; Starvation

A secretin-pancreozymin test was conducted with 43 gastroenterologically healthy children and 12 patients with subtotal atrophy of intestinal mucosa. While the pancreas enzymes were normal, the patients with coeliac disease reacted to the injection of the peptide hormones by producing a larger volume of secretion than did the control group. Despite the increased secretion there was at the same time a significantly higher concentration of bile acids in the duodenal juice. Analysis of the bile acid distribution indicated no deviation from the norm. There was, however, a striking discrepancy between the bile acid and the bilirubin excretion in the children with subtotal atrophy, whose bilirubin secretion, compared to that of the control group, was greatly reduced.

Topics: Adolescent; Atrophy; Bile Acids and Salts; Celiac Disease; Child; Child, Preschool; Cholecystokinin; Giardiasis; Humans; Ichthyosis; Infant; Intestinal Diseases; Intestinal Mucosa; Intestine, Small; Psoriasis; Secretin

Eleven patients with celiac sprue were studied. Biliary function in the basal state and gallbladder response to perfusion of the small intestinal mucosa with magnesium sulfate was assessed. It was shown that bilirubin output in basal conditions is decreased in these patients and that magnesium sulfate does not stimulate gallbladder contraction. In addition it was shown that in 4 of the 11 cases studied there was a complete lack of bile reaching the duodenum in the basal state as well as in 7 of 11 cases in the digestive period. That gallbladder function was intact was shown by the normal response to intravenous CCK-PZ administration, and the patency of the common bile duct was demonstrated by intravenous cholangiography. Thus the already impaired fat absorption in celiac sprue is magnified by the lack of bile delivery, and this is probably due to an alteration in the synthesis or release of endogenous CCK-PZ.

Topics: Adult; Atrophy; Bile; Bile Ducts; Bilirubin; Celiac Disease; Cholecystokinin; Female; Gallbladder; Humans; Intestine, Small; Magnesium Sulfate; Male; Middle Aged; Stimulation, Chemical

Topics: Alanine Transaminase; Amylases; Animals; Atrophy; Bicarbonates; Blood Glucose; Cholecystokinin; Chronic Disease; Dogs; Fatty Acids, Unsaturated; Female; Glycerides; Intestinal Absorption; Linseed Oil; Male; Pancreas; Pancreatic Diseases; Pancreatic Juice; Secretin; Secretory Rate; Stimulation, Chemical

Topics: Animals; Atrophy; Body Weight; Castration; Cholecystokinin; Chymotrypsin; Female; Fishes; Fresh Water; Intestines; Male; Microscopy; Organ Size; Ovary; Staining and Labeling; Testis; Time Factors; Trypsin

Topics: Atrophy; Bile Acids and Salts; Cholecystokinin; Duodenum; Endopeptidases; Humans; Intestinal Secretions; Pancreatic Diseases; Secretin; Stimulation, Chemical; Trypsin