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PubMed2006

[New approaches in obesity treatment: the gastrointestinal tract as an endocrine organ].

The gastrointestinal tract, besides digesting and processing nutrients, is now regarded as an endocrine organ able to modulate appetite, satiety, and carbohydrate metabolism. Several enteroendocrine cells produce numerous peptides codifying either orexigenic (ghrelin, orexins) or anorexigenic signals (pancreatic polypeptide, peptide YY, cholecystokinin, amylin, bombesin homologs, apolipoprotein A-IV, glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, oxyntomodulin), which interact in a complex network with other peripheral signals of energy balance and with different neuropeptides involved in the central control of appetite and energy homeostasis. The growing knowledge of the actions of these gastrointestinal peptides on appetite regulation and carbohydrate metabolism, and subsequent synthesis of analogs, particularly those derived from amylin and incretins, herald a new era in the therapy of 2 closely related diseases, obesity and type 2 diabetes mellitus.

Anti-Obesity Agents↗
PubMed1986

Peptide YY immunoreactive cells in gastrointestinal carcinoids: immunohistochemical and ultrastructural studies of 60 tumors.

The distribution and frequency of peptide YY (PYY) cells in 60 gastrointestinal carcinoids and in the nonneoplastic mucosa around the carcinoids were studied by an indirect immunoperoxidase method with anti-PYY serum. Additionally, the endocrine cell type of the PYY cells in appendiceal and rectal carcinoids was assessed by transmission electron microscopy. A few PYY cells were present in specimens of nonneoplastic mucosa from stomach, duodenum, jejunum, ileum, and appendix, with an abundance of these cells in rectal mucosa. Peptide YY cells were found in one of 13 gastric, one of 13 duodenal, one of one jejunal, zero of two ileal, three of 11 appendiceal, and 16 of 20 rectal carcinoids. All but one of the PYY-positive carcinoids were argyrophil carcinoids. Peptide YY cells in the gastric, duodenal, and jujunal carcinoids were present in small numbers. The three PYY-positive carcinoids of the appendix were composed almost totally of PYY cells, whereas those of the rectum generally contained only sporadic PYY cells. The peptide YY cells observed ultrastructurally contained almost round secretory granules (about 160 nm in average diameter), which were most consistent with D1(H) cell type granules with respect to shape and average diameter. This is the first systematic immunohistochemical and ultrastructural study of PYY cells in gastrointestinal carcinoids.

Carcinoid Tumor↗
PubMed1976

Release of motilin after duodenal acidification.

The physiological stimulus leading to motilin release in man has not yet been determined. Six healthy volunteers had 3-minute intraduodenal infusions of acid, alkali, or saline solutions. After infusing acid, plasma-motilin rose by 90% at 4 min and was still significantly raised at 45 min, whereas there was an insignificant fall in plasma-motilin after alkali and no change after saline solution. Release of motilin after duodenal acidification may be an important factor in inhibiting gastric emptying.

Adolescent↗
PubMed1984

Fetal abnormalities in cystic fibrosis suggest a deficiency in proteolysis of cholecystokinin.

Ultrastructural and microvillous enzyme (MVE) histochemical studies of fetuses with cystic fibrosis (CF) and trisomies 13 and 18 identified features in CF which differed from the abnormalities in trisomies 13 and 18. The principal abnormalities in CF were in the tight (occluding) junctions and intracellular organelles, particularly the golgi and mitochondria, of the epithelial cells of the pancreas, respiratory system, intestine, and gallbladder. Abnormalities of amniotic fluid MVE levels in CF and trisomy 13 occur because of disruption of the pathways by which the MVE reach the amniotic fluid. Trisomy 18 shows hypoplasia and deficiency of epithelial cell microvilli. It is postulated that the basic defect in CF is due to the deficiency of an enzyme that cleaves the Arg-Asp peptide bond in cholecystokinin to produce the active octapeptide CCK-8, which normally stimulates exocrine secretion, especially in pancreas, gallbladder, and intestine, and potentiates the action of other gastrointestinal hormones.

Amniotic Fluid↗
PubMed2003

GIP or not GIP? That is the question.

Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone that is released during a meal and facilitates the disposal of both glucose and fat. Because of the insulinotropic action of GIP, this hormone has been considered as a potential therapy of type 2 diabetes, where insulin secretion is inadequate. However, a recent study using GIP receptor knockout mice suggests that inhibition of GIP signalling might be a new target for anti-obesity drugs.

Animals↗
PubMed1998

Xenin--a review.

Xenin, a 25 amino acid peptide, has been identified in human gastric mucosa in the search for a counterpart to the amphibian octapeptide xenopsin. Xenin is structurally related also to the hypothalamic and ileal peptide neurotensin and is, therefore, a member of the xenopsin/neurotensin/xenin peptide family. The biological activities of these peptides are similar: Xenin has been shown to inhibit pentagastrin-stimulated secretion of acid, to induce exocrine pancreatic secretion and to affect small and large intestinal motility. In the gut, xenin interacts with the neurotensin receptor. Radioimmunoassay and chromatography of postprandial plasma in humans indicate the release of xenin into the circulation. The identification of a 35-amino acid precursor peptide of xenin - proxenin, and a review of the Gen-bank revealed that xenin represents the N terminus of a cytosolic coat protein (alpha-COP) from which xenin can be cleaved by aspartic proteinases such as pepsin and cathepsin E. The physiological role of the peptide xenin is not known.

Amino Acid Sequence↗
PubMed1998

The inhibitory effect of glucagon-like peptide-1 (7-36)amide on antral motility is antagonized by its N-terminally truncated primary metabolite GLP-1 (9-36)amide.

In plasma, glucagon-like peptide-1 7-36 amide (GLP-1) is rapidly degraded from the N terminus, generating the endogenous metabolite GLP-1 9-36 amide. This cleavage of GLP-1 eliminates its incretin effect, and the metabolite even may act as an antagonist. We have shown previously that GLP-1 strongly inhibited cephalic-induced antral motility in pigs. We decided, therefore, to examine the effect of GLP-1 9-36 amide, with and without GLP-1, on cephalic-induced motility in pigs. In one series of experiments, we studied the effect of three different doses of GLP-1 9-36 amide (2, 4, and 10 pmol/kg/min) on insulin-induced (hypoglycemia) antral motility in anaesthetized pigs (n = 9). In another series, we studied the effect of infusion of GLP-1 9-36 amide in two different doses (1 and 5 pmol/kg/min) in six pigs in which the antral motility was inhibited by GLP-1 7-36 amide in a dose of 2 pmol/kg/min. Plasma levels of intact GLP-1 7-36 amide and GLP-1 9-36 amide were determined using specific radioimmunoassays. Insulin-induced hypoglycemia increased the antral motility index from 0.4 +/- 0.1 to 8.3 +/- 3.5 (cm/min). The motility was constant throughout the experimental period and was absolutely unaffected by the infusion of GLP-1 9-36 amide at 10 pmol/kg/min, which resulted in a plasma concentration of 351 +/- 60 pmol/l. The inhibitory effect of GLP-1 7-36 amide on antral motility was reduced from 93 +/- 3% to 33 +/- 9% (p < 0.05) by concomitant infusion of GLP-1 9-36 amide in a dose of 5 pmol/kg/min. The metabolite GLP-1 9-36 amide has no effect on antral motility in pigs but is able to antagonize the inhibitory effect of GLP-1. Thus, an intact N terminus is essential for the gastrointestinal actions of GLP-1. Its primary metabolite may act as an endogenous antagonist.

Animals↗
PubMedDate not supplied

Inhibition of gastrin-stimulated cell proliferation by the CCK-B/gastrin receptor ligand CI-988.

The gastrointestinal hormone gastrin functions as a trophic factor for oxyntic mucosa as well as a secretagogue for gastric acid. In preclinical toxicology studies CI-988, a peptoid cholecystokinin (CCK) ligand with nanomolar affinity for the CCK-B/gastrin receptor, caused gastric gland degeneration and mucosal atrophy in cynomolgus monkeys, perhaps consistent with an expected pharmacological outcome of inhibition of the trophic effect of gastrin on stomach mucosa. Because of the expense and difficulty associated with experimental use of non-human primates, we investigated the effects of CI-988 on signal transduction pathways associated with gastrin-stimulated cell proliferation using the AR42J rat pancreatic tumour cell line as a model. The AR42J cell line was selected because it is known to express the CCK-B/gastrin receptor and because it is responsive to the growth promoting effects of gastrin in vitro. Gastrin-17 at 1 nM stimulated proliferation of AR42J cells 26% and 104% above control after 24 and 96 hours, respectively. CI-988 at 1 nM had no apparent effect on basal cell proliferation rates, but decreased gastrin-17 stimulated cell proliferation 13% and 47%, respectively, after 24 and 96 hours of treatment, consistent with competitive antagonism at the gastrin receptor. Because the trophic effect of gastrin towards AR42J cells has been linked to intracellular calcium ([Ca2+]i) mobilization and/or cyclic AMP, the effect of CI-988 on these second messengers were also investigated. Gastrin-17 at 10 nM stimulated both ([Ca2+]i) and cAMP, while CI-988 alone at 100 nM had no effect, but blocked the gastrin-stimulated increases in both mediators. Therefore, using the AR42J pancreatic tumour cell line as a model, the dipeptoid CCK-B/gastrin receptor ligand CI-988 behaves as an antagonist towards gastrin receptor-stimulated signal transduction pathways and cell proliferation in vitro.

Animals↗
PubMed1987

The role of immunohistochemistry, electron microscopy, and ultrastructural cytochemistry in the diagnosis of mixed carcinoma-neuroendocrine neoplasms.

We studied four mixed carcinoma-neuroendocrine neoplasms from gastrointestinal tract and pancreas by routine light microscopy (LM), immunohistochemistry (IH), electron microscopy (EM), and ultrastructural cytochemistry (UC). By LM, the individual tumors showed fairly pure neuroendocrine (carcinoid) or epithelial (papillary) patterns, mixed neuroendocrine-carcinoma features and poorly-differentiated tumor in sheets and nests which did not lend itself to morphologic characterization. IH demonstrated mixed expression, within different areas of the same neoplasm, of epithelial antigens (keratins and carcinoembryonic antigen [CEA]) and neuroendocrine markers (neuron-specific enolase [NSE], bombesin and neurohormonal peptides). By EM, each tumor showed ultrastructural features of epithelial and neuroendocrine differentiation which varied substantially in terms of number of cells involved and their distribution; two of the neoplasms showed biphasic differentiation within single cells. The nature of the neurosecretory granules was verified with the uranaffin reaction (UR). This study illustrates the value of combining LM, IH, EM and UC for the identification of mixed carcinoma-neuroendocrine lesions.

Aged↗
PubMed2000

The use of complex polysaccharides in the management of metabolic diseases: the case of Solanum lycocarpum fruits.

In the Brazilian cerrado, a preparation obtained from the fruits of Solanum lycocarpum St.-Hil. (Solanaceae), popularly known as 'fruta-de-lobo' (wolf-fruit), have been widely employed for diabetes management, obesity and to decrease cholesterol levels. The medicinal preparation consists of the green fruits which are ground in aqueous solution and filtered. The white 'gum' deposited is decanted and slowly dried providing a powder which is commercialized in capsules with the name of 'polvilho-de-lobeira'. Through phytochemical analysis of this phytomedicine and the fruit of S. lycocarpum we found polysaccharides as the main component. Some polysaccharides slow gastric emptying and act on the endocrinous system affecting the liberation of gastrointestinal hormones, lowering blood glucose levels. The hypocholesterolemic activity could be due to the increased fecal bile acid excretion as well as to the action of the short-chain fatty acids, coming from fermentation, on the synthesis of delta-aminolevulinate and by the increase of the cholesterol 7-alpha-hydroxylase and 3-hydroxy-3-methylglutaryl CoA reductase synthesis.

Brazil↗
PubMed2002

Effects of secretin on TCDCA- or TDCA-induced cholestatic liver injury in the rat.

Secretin, a gastrointestinal hormone, is known to act on bile duct epithelial cells and has been thought to have no effects on the bile acid transport in the liver. However, secretin was proved recently to stimulate biliary secretion of taurocholic acid (TCA) and elevate the maximum hepatic transport capacity of TCA. In this study, to evaluate the effect of secretin on the biliary secretion of taurochenodeoxycholic acid (TCDCA) or taurodeoxycholic acid (TDCA), which are known as cytotoxic bile acids, changes in bile flow, biliary excretions of bile acids and serum levels of TCDCA or TDCA were studied in a TCDCA- or TDCA-induced cholestatic rat model with and without secretin administration. Secretin prevented the decrease in bile flow and enhanced biliary excretions of bile acids and bicarbonate, but serum levels of TCDCA or TDCA at the end of the study showed no significant changes in the secretin group as compared with controls. Serum levels of alanine and asparate aminotransferases were highly elevated in all rats given TCDCA or TDCA. These data indicate secretin is a possible treatment for patients with prolonged intrahepatic cholestasis.

Journal Article↗
PubMed2000

Structural determinants for activity of glucagon-like peptide-2.

Glucagon-like peptide-2 (GLP-2) is a 33 amino acid gastrointestinal hormone that regulates epithelial growth in the intestine. Dipeptidylpeptidase IV cleaves GLP-2 at the position 2 alanine, resulting in the inactivation of peptide activity. To understand the structural basis for GLP-2 action, we studied receptor binding and activation for 56 GLP-2 analogues with either position 2 substitutions or alanine replacements along the length of the peptide. The majority of position 2 substitutions exhibited normal to enhanced GLP-2 receptor (GLP-2R) binding; in contrast, position 2 substitutions were less well tolerated in studies of receptor activation as only Gly, Ile, Pro, alpha-aminobutyric acid, D-Ala, or nor-Val substitutions exhibited enhanced GLP-2R activation. In contrast, alanine replacement at positions 5,6,17, 20, 22, 23, 25, 26, 30, and 31 led to diminished GLP-2R binding. Position 2 substitutions containing Asp, Leu, Lys, Met, Phe, Trp, and Tyr, and Ala substitutions at positions 12 and 21 exhibited normal to enhanced GLP-2R binding but greater than 75% reduction in receptor activation. D-Ala(2), Pro(2) and Gly(2), Ala(16) exhibited significantly lower EC(50)s for receptor activation than the parent peptide (p < 0.01-0.001). Circular dichroism analysis indicated that the enhanced activity of these GLP-2 analogues was independent of the alpha-helical content of the peptide. These results indicate that single amino acid substitutions within GLP-2 can confer structural changes to the ligand-receptor interface, allowing the identification of residues important for GLP-2R binding and receptor activation.

Amino Acid Sequence↗
PubMed2001

Regulation of cholangiocyte proliferation.

Intrahepatic bile duct epithelial cells (i.e., cholangiocytes) are the target cells of chronic cholestatic liver diseases (i.e., cholangiopathies), which makes these cells of great interest to clinical hepatologists. This review will focus on "typical" cholangiocyte proliferation, whereas "atypical" (extension of cholangiocyte proliferation into parenchyma), and premalignant "oval" cell proliferation are reviewed elsewhere. The bile duct ligated (BDL) rat model, where most of the known mechanisms of cholangiocyte proliferation have been illustrated, was the first and remains the prototype animal model for "typical" cholangiocyte proliferation. Following a short overview of cholangiocyte functions, we briefly discuss the: (i) in vivo models [i.e., BDL (Fig. 1 and 4), chronic alpha-naphthylisothiocyanate (ANIT) or bile acid feeding (Fig. 2), acute carbon tetrachloride (CCl4) feeding and partial hepatectomy; and (ii) in vitro experimental tools [e.g., purified cholangiocytes and isolated intrahepatic bile duct units (IBDU)] that are key to the understanding of the mechanisms of "typical" cholangiocyte growth. In the second part of the review, we discuss a number of potential factors or conditions [e.g., gastrointestinal hormones, nerves, estrogens, blood supply, and growth factors] as well as the intracellular mechanisms [e.g., adenosine 3',5'-monophosphate (cAMP), and protein kinase C (PKC)] that may regulate "typical" cholangiocyte hyperplasia.

Animals↗