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Gastric inhibitory polypeptide (GIP) responses after oral glucose ingestion in hyperthyroidism.

Gastric inhibitory polypeptide (GIP) is a gastrointestinal hormone stimulated after oral nutrient ingestion, but not after intravenous nutrient administration. GIP stimulates insulin release in the presence of hyperglycemia and as such is considered a major enteroinsular hormone. Since elevated glucose and insulin levels are found in hyperthyroidism, we compared the GIP responses to oral glucose ingestion in 12 hyperthyroid patients and 10 age-matched controls. Seventy-five grams of oral glucose was ingested after overnight fasting and samples were obtained at 0, 30, 60, 90, 120, and 180 min for serum glucose and immunoreactive insulin (IRI) and GIP (IRGIP). The mean serum glucose levels in hyperthyroid subjects were significantly higher (P less than or equal to 0.05) at every time studied except at 180 min. At 60 min, peak mean glucose was 171 +/- 14 mg/dl versus 128 +/- 7 mg/dl in controls (P less than 0.02). Except for fasting, mean IRI levels were significantly higher (P less than 0.001) in hyperthyroid subjects than in controls at all times studied. At 60 min, IRI rose to a peak of 125 +/- 11 microU/ml in hyperthyroid subjects versus 50 +/- 9 microU/ml in controls (P less than 0.001). Mean fasting, stimulated, and incremental IRGIP levels were slightly higher but not statistically different in the hyperthyroid subjects versus controls. Glucose and IRI responses are exaggerated in hyperthyroidism after oral glucose ingestion. Even though GIP has insulinotropic action, its role in the hyperinsulinism found in hyperthyroid subjects appears to be minimal.

Adult↗

Development of an in vivo method to study bovine intestinal response to dietary manipulation at the molecular level.

Our objective was to develop an in vivo method for analysis of nutrient-gene interactions in dairy cows at the molecular level. A series of techniques was applied to study the molecular response of cells in bovine small intestine to dietary manipulation. Three Holstein cows fitted with ruminal and duodenal cannulae were used for the investigation. As part of the validation of the procedure, lipid flow to the small intestine was manipulated using an abomasal infusion technique to study the expression of the gene encoding for the gastrointestinal hormone cholecystokinin (CCK). Biopsies (10 to 25 mg) were collected from the duodenum approximately 40 to 50 cm distal from the pyloric sphincter using a fiberoptic endoscope and biopsy forceps. Total RNA was isolated from the intestinal biopsies with yields of 20 to 50 microg. Cholecystokinin gene expression was analyzed in intestinal mucosa obtained from Holstein cows after slaughter either at a local abattoir or at our research facilities and compared with CCK gene expression in the biopsy samples collected from the cannulated animals. Using the technique of northern hybridization, we found that 15 microg of total RNA was sufficient to detect a strong CCK mRNA signal in the biopsy tissue samples, whereas 30 microg of total RNA showed a slightly weaker CCK mRNA signal in the postmortem duodenal tissues collected at our research facility. In contrast, the CCK mRNA signal in postmortem duodenal tissues obtained from cows slaughtered at the local abattoir was only barely detectable with 40 microg of total RNA. We conclude that the biopsy procedure is relatively noninvasive and is useful for monitoring intestinal responses to dietary manipulation and to physiological changes, such as those that occur during lactation and with metabolic disorders. The application of the method will provide insight into nutrient-gene interactions that occur in bovine intestinal mucosa.

Abattoirs↗

Further purification of gastrozymin and spectrum of activities.

Gastrozymin differed from secretin in several chromatographic and solubility characteristics. However, it showed a spectrum of activities which resembled those of secretin, including stimulation of pepsin, hepatic bile secretion, and pancreatic bicarbonate secretion. This study revealed differences in the quantitative ratios of these activities when induced by secretin or gastrozymin. In particular, if the ratio of the stimulation of pepsin secretion to that of pancreatic juice bicarbonate was 1:1 for secretin, it was 4:1 for gastrozymin. Further purification will show whether all these effects are induced by one molecule or by several peptides. It will also determine whether there is a structural relationship between gastrozymin and secretin or its precursor(s).

Animals↗

Effect of Pentagastrin, secretin, and cholecystokinin on gastric secretion of pepsin in man.

In eight volunteers the effect of pentagastrin (0.15, 1.0 and 6.0 microgram/kg body weight/h), secretin (0.5 and 1.0 clinical units/kg b.w./h), and cholecystokinin (CCK) (0.5 and 1.0 Ivy dog units/kg b.w./h) on the gastric secretion of pepsin was investigated to ascertain whether interaction occurred. A high intraindividual variation was found, and also a significant washout of pepsin in the initial period after stimulation. Pepsin secretion was stimulated after pentagastrin (50% above basal level) and even more after secretin (75%-200% above basal level), whereas no stimulation but a tendency for depression was seen after CCK. With the doses of gastrointestinal hormones used in this investigation, no interaction between secretin and CCK on gastric secretion of pepsin in man was demonstrated.

Adult↗

The effect of insulin-induced hypoglycemia with and without atropine on plasma vasoactive intestinal polypeptide in man.

Plasma vasoactive intestinal polypeptide (VIP) was measured in six healthy male students on 2 separate days after insulin-induced hypoglycemia with and without atropine and on a 3rd day in five of the students after atropine alone. A significant increase in peripheral plasma VIP was observed when atropine was given together with insulin, whereas insulin or atropine alone had no effect on plasma VIP. It is suggested that cholinergic nicotinic receptors may be involved in the increase of VIP after insulin-induced hypoglycemia and that the lack of VIP increase seen after insulin alone may be caused by an inhibitory effect of other gastrointestinal hormones.

Adult↗

Cephalic phase of gastroduodenal alkaline secretion.

This study was designed to determine gastric alkaline secretion (GAS) and duodenal alkaline secretion (DAS) and their relation to the duodenal motility pattern in conscious dogs under basal conditions and after vagal stimulation by sham-feeding and insulin hypoglycaemia. GAS was measured in the gastric perfusate and DAS was determined in the perfusate of the upper duodenum (7 cm in length between occluding balloons). Resting GAS and DAS showed typical periodicity in phase with myoelectric and motor activity, reaching peaks during phases II and III, respectively, and nadir during phase I of the migrating motor cycle (MMC). Vagal excitation by sham-feeding or insulin hypoglycaemia resulted in an immediate rise in GAS and DAS, accompanied by a suppression of MMC. Atropine (25 micrograms/kg) reduced basal GAS and DAS by about 50% and abolished GAS but not DAS in response to vagal stimulation, being accompanied by complete suppression of MMC for several hours. Following injection of indomethacin (2.5 mg/kg) to suppress the generation of endogenous prostaglandins, a prolonged reduction in basal GAS and DAS and an increase in the myoelectric activity and the disruption of the MMC occurred. Neither GAS nor DAS responses to vagal stimulation were affected by indomethacin. We conclude that resting GAS and DAS fluctuate cyclically in phase with gastroduodenal motor activity, and that vagal excitation results in a potent stimulation of alkaline secretion and myoelectric activity which are, in part, cholinergic and do not depend upon the generation of endogenous prostaglandins.

Animals↗

Identification of the neurotransmitter/neuromodulator functions of the neuropeptide gastrin-releasing peptide in the porcine antrum, using the antagonist (Leu13-psi-CH2 NH-Leu14)-bombesin.

We studied the effects of a new bombesin/gastrin-releasing peptide (GRP) receptor antagonist, Leu13-psi-(CH2NH)-Leu14-bombesin, on the secretion of gastrin and somatostatin and on the motor activity of isolated perfused porcine antrum in response to infusions of GRP at 10(-10) or 10(-9) mol/l and in response to electric stimulation of the vagus nerves. GRP significantly increased the secretion of gastrin and somatostatin and increased the frequency of antral contractions threefold. At 0.5 x 10(-6) mol/l the antagonist completely abolished the effects on motality and gastrin secretion and strongly inhibited the effect on somatostatin secretion. Vagus stimulation significantly increased gastrin and somatostatin secretion and increased the contraction frequency threefold. The antagonist strongly inhibited the somatostatin response, abolished the motility effects and reversed the stimulatory effect on gastrin secretion to a significant inhibition. Assuming that the antagonist interacts specifically with GRP receptors, we conclude that our data strongly support the concept that GRP-producing nerves are essential for vagally induced secretion of gastrin and somatostatin from the antrum. The GRP nerves may also play a role in the control of gastric motor activity.

Animals↗

Pathophysiology and treatment of functional dyspepsia.

Functional dyspepsia (or 'non-ulcer') is usually defined as chronic or intermittent upper abdominal symptoms for which no organic cause can be found. Division of functional dyspepsia into subgroups such as reflux-like, ulcer-like, dysmotility-like and non-specific dyspepsia has been proposed, but lacks a scientific basis. Gastric acid hypersecretion, Helicobacter pylori-associated gastritis, gastric and small intestinal motor disorders, psychological and neurohormonal factors all might play a role in the pathogenesis. The heterogeneity of the underlying abnormalities makes it unlikely that one single treatment modality will ever be beneficial to all patients. In general practice, a therapeutic trial, with either a prokinetic or an acid secretion inhibiting drug, is usually carried out before diagnostic procedures are performed to exclude organic abnormalities. In the choice of the initial therapy, some guidance can be derived from the prominent symptoms. In a study in 30 H. pylori-negative patients with functional dyspepsia ranitidine (150 mg bid) significantly reduced the severity of heartburn. The effect was most pronounced in patients of the reflux-like subgroup.

Adult↗

A human gastric cancer cell line possesses a functional receptor for gastrin-releasing peptide.

Bombesin (BBS) exhibits diverse biological functions including those of neurotransmitter, regulator of gastrointestinal hormone release, and mitogen. Gastrin-releasing peptide (GRP, the mammalian equivalent of BBS) is found in mucosal cells of the gastric fundus and antrum. We determined whether a human gastric cancer cell line (SIIA) expresses a functional GRP-receptor (GRP-R). BBS increased intracellular calcium ([Ca2+]i), and a specific GRP-R antagonist, ([D-Phe6, Des-Met14]-BBS (6-14)-ethylamide), blocked BBS-induced increase in [Ca2+]i. SIIA cells possess GRP-R mRNA by reverse transcriptase-PCR. Furthermore, these cells possess an 80-kDa cell surface protein that specifically binds BBS with two high-binding affinities (Kd1 = 0.6 nM, Kd2 = 6.7 nM). These findings indicate that SIIA cells possess a GRP-R that is capable of physiological signal transduction, though the cellular response remains unknown.

Adenocarcinoma↗

Total parenteral nutrition and its effects on bone metabolism.

Total parenteral nutrition (TPN) may affect bone metabolism in a variety of ways. These may include potential indirect effects such as on gastrointestinal hormone secretion, liver function, especially cytochrome P450 isoenzymes, metabolic biorhythms where established, and the continuous compared with the intermittent supply of nutrients. More substantial evidence exists for the reduction of bone formation, parathyroid hormone secretion, and calcitriol production in TPN patients along with high urinary calcium excretion. This review considers both aluminum loading and vitamin D sensitivity as etiologic factors and suggests that aluminum may have played a primary role in the pathogenesis of these abnormalities in bone and mineral metabolism, but that vitamin D may have potentiated the deleterious actions of aluminum. While the sources of aluminum contamination of TPN solutions have been identified and efforts are under way to reduce its contamination of TPN solutions, the persistence of low bone mass measurement in TPN patients is a problem that has been identified repeatedly, does not have a current explanation, and requires further study.

Aluminum↗

Gastrointestinal transit in an animal model of human diabetes type 2: relationship to gut neuroendocrine peptide contents.

Gastrointestinal transit (GIT) was determined in obese diabetic mice (ob/ob, Umeå/Bom). Blood glucose level, and insulin concentration in the serum and pancreas extracts as well as neuroendocrine peptide contents were measured in several segments of the gut. GIT was significantly slower in the obese diabetic mice, but was not correlated with the blood glucose level, serum insulin, or pancreatic insulin content. GIT was correlated with duodenal secretin content and colonic vasoactive intestinal peptide (VIP) content, but not with the content of other neuroendocrine peptides in different segments investigated. The antral gastrin content in obese diabetic mice was significantly higher than in controls. The concentration of secretin in obese diabetic mice was higher than in controls. Whereas the contents of peptide YY (PYY) and somatostatin were higher in obese diabetic mice, the contents of substance P and VIP were lower. The increased content of duodenal secretin and decreased content of colonic VIP may be among the factors that cause slow GIT in obese diabetic mice. The changes in the colonic contents of PYY, VIP and somatostatin may cause low intestinal secretion and, together with slow GIT, give rise to constipation, which is a common symptom in diabetes.

Animals↗

Bioactive milk peptides: a prospectus.

Bioactive peptides have been identified within the amino acid sequences of native milk proteins. Hydrolytic reactions, such as those catalyzed by digestive enzymes, result in their release. These peptides directly influence numerous biological processes evoking behavioral, gastrointestinal, hormonal, immunological, neurological, and nutritional responses. The specific bioreactions associated with each physiological class have been well characterized. Herein, we review the scientific literature and attempt to stimulate consideration of the continued use of bioactive peptides and their expanded development as a commercial product. Several applications have already evolved. For example, phosphopeptides derived from casein fractions are currently used as both dietary and pharmaceutical supplements. Potentially, the addition of bioactive peptides to food products could improve consumer safety as a result of their antimicrobial properties. Lastly, bioactive peptides may function as health care products, providing therapeutic value for either treatment of infection or prevention of disease.

Angiotensin-Converting Enzyme Inhibitors↗

Influence of avian pancreatic polypeptide on pancreatic and biliary secretion in laying hens.

White Leghorn hens, 14 to 29 wk of age, were surgically prepared with cannulae for collecting secretions from the cystic duct and the duct draining the ventral pancreatic lobe and for infusing the jugular vein with avian pancreatic polypeptide (aPP) or saline. A plasma infusion rate that produced a plasma level of 15 ng of aPP/mL was used. A comparison of values obtained during saline infusion with those obtained during aPP infusion indicated that pancreatic and biliary secretory volumes and pancreatic total protein concentration were significantly depressed by aPP. The pH of pancreatic and biliary secretions were not significantly affected by aPP. Because aPP also depresses gastric secretion and motility in hens, it is proposed that its physiological role may be to oppose or modulate the actions of other, stimulatory gastrointestinal hormones.

Animals↗

Localization of cholecystokinin and vasoactive intestinal peptide in lower biliary tract in cats following electroacupuncture on right Qimen (LR14) and Riyue (GB 24): an immunohistochemistry study.

Accumulating evidence has shown that control of the motility of the sphincter of Oddi (SO) involves a complex interaction between nerves, neurotransmitters and gastrointestinal hormones such as vasoactive intestinal peptide (VIP) and cholecystokinin (CCK). Our previous studies demonstrated that electroacupuncture (EA) modulated the SO motility in cats and rabbits through activation of nonadrenergic non-cholinergic (NANC) pathway. This study was designed to investigate the changes of neurotransmitters such as CCK and VIP in lower biliary tract in cats receiving EA stimulation. After cats were anesthetized with intramuscular injection of ketamine hydrochloride, they were prepared to conduct EA stimulation on right Qimen (LR14) and Riyue (GB 24). The parameters of EA were 6 pulses/ 3 sec and 45 pulses/ 3 sec alternatively in frequency, 1-2 mA in intensity and 20 min in stimulation duration. After the completeness of EA stimulation, visceral organs such as gallbladder, duodenum and the sphincter of Oddi were removed and frozen for immunohistochemistry localization of CCK and VIP. The results showed that the distribution of CCK-labeled cells in duodenum, gallbladder and SO were more and distinct after EA than before EA stimulation. Whereas, the VIP-labeled cells were significantly more and distinct in duodenum and SO, but not in gall bladder. We conclude that EA regulates the biliary motility though increasing the distribution of CCK- and VIP-containing cells in duodenum and the sphincter of Oddi.

Animals↗

Correlation between the expressions of gastrin, somatostatin and cyclin and cyclin-depend kinase in colorectal cancer.

AIM: To explore the correlation between the expressions of gastrin (GAS), somatostatin (SS) and cyclin, cyclin-dependent kinase (CDK) in colorectal cancer, and to detect the specific regulatory sites where gastrointestinal hormone regulates cell proliferation. METHODS: Seventy-nine resected large intestine carcinomatous specimens were randomly selected. Immunohistochemical staining for GAS, SS, cyclin D1, cyclin E, cyclin A, cyclin B1, CDK2 and CDK4 was performed according to the standard streptavidin-biotin-peroxidase (S-P) method. According to the semi-quantitative integral evaluation, SS and GAS were divided into high, middle and low groups. Cyclin D1, cyclin E, cyclin A, cyclin B1, CDK2, CDK4 expressions in the three GAS and SS groups were assessed. RESULTS: The positive expression rate of cyclin D1 was significantly higher in high (78.6%, 11/14) and middle GAS groups (73.9%, 17/23) than in low GAS group (45.2%, 19/42) (P<0.05, c2(high vs low) = 4.691; P<0.05, c2(middle vs low) = 4.945). The positive expression rate of cyclin A was significantly higher in high (100%, 14/14) and middle GAS groups (82.6%, 19/23) than in low GAS group (54.8%, 23/42) (P<0.01, c2(high vs low) = 9.586; P<0.05, c2(middle vs low) = 5.040). The positive expression rate of CDK2 was significantly higher in high (92.9%, 13/14) and middle GAS groups (87.0%, 20/23) than in low GAS group (50.0%, 21/42) (P<0.01, c2(high vs low) = 8.086; P<0.01, c2(middle vs low) = 8.715). The positive expression rate of CDK4 was significantly higher in high (78.6%, 11/14) and middle GAS groups (78.3%, 18/23) than in low GAS group (42.9%, 18/42) (P<0.05, c2(high vs low) = 5.364; P<0.01, c2(middle vs low) = 7.539). The positive expression rate of cyclin E was prominently higher in low SS group (53.3%, 24/45) than in high (9.1%, 1/11) and middle (21.7%, 5/23) SS groups (P<0.05, c2(high vs low) = 5.325; P<0.05, c2(middle vs low) = 6.212). The positive expression rate of CDK2 was significantly higher in low SS group (77.8%, 35/45) than in high SS group (27.3%, 3/11) (P<0.01, c2(high vs low) = 8.151). There was a significant positive correlation between the integral ratio of GAS to SS and the semi-quantitative integral of cyclin D1, cyclin E, cyclin A, CDK2, CDK4 (P<0.05, (D1)r(s) = 0.252; P<0.01, (E)r(s) = 0.387; P<0.01, (A)r(s) = 0.466; P<0.01, (K2)r(s) = 0.519; P<0.01, (K4)r(s) = 0.434). CONCLUSION: The regulation and control of gastrin, SS in colorectal cancer cell growth may be directly related to the abnormal expressions of cyclins D1, A, E, and CDK2, CDK4. The regulatory site of GAS in the cell cycle of colorectal carcinoma may be at the G(1), S and G(2) phases. The regulatory site of SS may be at the entrance of S phase.

Adult↗

Heterogeneity of the intrahepatic biliary epithelium.

The objectives of this review are to outline the recent findings related to the morphological heterogeneity of the biliary epithelium and the heterogeneous pathophysiological responses of different sized bile ducts to liver gastrointestinal hormones and peptides and liver injury/toxins with changes in apoptotic, proliferative and secretory activities. The knowledge of biliary function is rapidly increasing because of the recognition that biliary epithelial cells (cholangiocytes) are the targets of human cholangiopathies, which are characterized by proliferation/damage of bile ducts within a small range of sizes. The unique anatomy, morphology, innervation and vascularization of the biliary epithelium are consistent with function of cholangiocytes within different regions of the biliary tree. The in vivo models [e.g., bile duct ligation (BDL), partial hepatectomy, feeding of bile acids, carbon tetrachloride (CCl4) or alpha-naphthylisothiocyanate (ANIT)] and the in vivo experimental tools [e.g., freshly isolated small and large cholangiocytes or intrahepatic bile duct units (IBDU) and primary cultures of small and large murine cholangiocytes] have allowed us to demonstrate the morphological and functional heterogeneity of the intrahepatic biliary epithelium. These models demonstrated the differential secretory activities and the heterogeneous apoptotic and proliferative responses of different sized ducts. Similar to animal models of cholangiocyte proliferation/injury restricted to specific sized ducts, in human liver diseases bile duct damage predominates specific sized bile ducts. Future studies related to the functional heterogeneity of the intrahepatic biliary epithelium may disclose new pathophysiological treatments for patients with cholangiopathies.

1-Naphthylisothiocyanate↗