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The gastrointestinal tract and glucose tolerance.

PURPOSE OF REVIEW: The development of incretin hormones and incretin analogues for the therapy of diabetes highlights the importance of the gastrointestinal tract in the maintenance of glucose tolerance. RECENT FINDINGS: The review focuses on recent information on the role of incretins and their breakdown products on insulin secretion, gastric emptying, and satiety. The importance of gastric emptying and its absorptive potential as well as of dietary composition on gastric emptying and glucose tolerance is highlighted. The concept of a portal glucose sensor in humans has been the subject of some controversy but has been recently revisited. SUMMARY: The gastrointestinal tract plays an important part in glucose tolerance. In this review we have examined how factors altering gastric emptying, insulin secretion in response to meal ingestion, and gastric emptying contribute to the maintenance and deterioration of glucose tolerance.

Blood Glucose↗

Pathological studies of the animals replaced totally with the artificial heart. Part II Concerning liver, gastrointestinal tract, kidney, and general discussion.

Twenty-eight goats with an artificial heart (AH) were studied pathologically. Being continued from the previous report, the liver, gastrointestinal tract, and kidneys were taken up in this paper and finally, general discussion was done to get our ideas in shape concerning the pathophysiological status of the goat. Central necrosis of the liver was always observed in the goats which survived for over 140 hours. This finding seemed to be caused mainly by circulatory insufficiency of the portal vein at the latter half of the survival time. Microscopic findings of degeneration, necrosis, and edema were commonly observed at the walls of gastrointestinal tracts, when goats showed poor apetite, mucous feces and constipation. But these problems have been improved by application of a new control method to regulate the output of AH system within a goat's physiological range since October 1974. The lesions seen in the kidneys are classified into 5 groups. The most important findings of them are lower nephron nephrosis and cortical necrosis, both of which indicate the occurrence of long standing vasoconstriction of proximal renal arteries. By means of microangiographic method and others, thrombi were detected frequently in the kidneys. The vascular walls, where thrombi were attached to, were often damaged. Therefore, these thrombi were thought to be formed in the local vessels in situ through renal circulatory insufficiency. The renal pathological lesions have been also improved and severe renal failure from which the previous goats could not escape, has been lessened since the application of a new AH control method. As a whole, the main pathophysiological status of the animals replaced by the AH are thought conclusively to be peripheral circulatory insufficiency. This would be caused by abnormal hemodynamics, so that, the essential clinical etiology is thought to be AH function itself.

Animals↗

Localization of somatostatin receptor subtype mRNA in the rat gastrointestinal tract and regulation of SSTR1 gene expression.

Somatostatin and its receptors are widely distributed in the central nervous system and peripheral tissues including those of the gastrointestinal tract (GI tract). The expression patterns of the five known SSTR genes have been analysed in detail by reverse transcription polymerase chain reaction amplifications and in situ hybridizations using tissues dissected from different parts of rat stomach and gut. While SSTR1 mRNA is present at relatively high amounts throughout the gastrointestinal tract, the levels of SSTR2, 3 and 4 mRNAs vary in different regions and SSTR5 mRNA has not been detected. In situ hybridizations revealed the presence of SSTR3 mRNA in enterocytes and in neurons of the myenteric and submucous plexus. These findings are consistent with a role of SSTR3 in the observed somatostatin-mediated inhibition of acetylcholine release from myenteric neurons and of secretomotor neuron activity in the submucous plexus. Sequence analyses of the SSTR1 gene promoter revealed the absence of the canonical TATA and CAAT motifs and the presence of a variety of potential binding sites for transcriptional regulators. Among these are binding sites for GCF, AP-2, AP-4, response elements for somatostatin (SOM-RE), epidermal growth factor (EGF-RE) and cytocines (GAS and NFIL) as well as for tissue-specific factors such as Pit-1 (pituitary) and IDX-1 (pancreatic cells). Mobility shift assays have confirmed that nuclear proteins of pancreatic RIN1046-38 and pituitary GH3 tumour cells bind to oligonucleotides containing the overlapping Pit-1 and IDX-1 binding sites. Thus, the Pit-1/IDX-1 sites may be critical for the activation of the SSTR1 gene in these cell-types.

Animals↗

[Manifestations of AIDS in the gastrointestinal tract].

Besides central nervous system, pulmonary and cutaneous manifestations, the gastrointestinal tract and the hepatobiliary system are major organs in AIDS. Gastrointestinal symptoms due to opportunistic infections or HIV-associated tumours are common in AIDS patients. Nevertheless, a huge variety of endoscopically diagnosed mucosal lesions may not always be correlated to microbiological findings, clinical symptoms and histological aspects. Cytomegalovirus being the most important opportunistic infection in the GI tract in symptomatic AIDS patients, is correlated with erosive and ulcerative lesions, often accompanied by complications like perforation or bleeding. HIV-associated tumours in the GI tract like Non Hodgkin-lymphoma or Kaposi sarcoma may present with atypical endoscopic findings. Diagnostic procedures should include microbiological and histological investigations of biopsies looking for opportunistic infections. Besides, typical immunological changes involving the mucosa as direct target organ of the HIV virus, are important to understand morphological and functional abnormalities in HIV-patients with GI symptoms.

Acquired Immunodeficiency Syndrome↗

Cis-diaminodichloroplatinum (II) chemotherapy for advanced adenocarcinoma of the upper gastrointestinal tract.

A phase II study of cis-diaminodichloroplatinum (II) (cis-DDP) was carried out in 55 patients with advanced adenocarcinoma of the upper gastrointestinal tract. The drug was given at a dose of 100 mg/m2 i.v. over 2h every 3-4 weeks, with hydration and mannitol diuresis. There were 3 partial responses (6%) among 51 evaluable patients (esophagus 12, stomach 16, pancreas 14, liver 6, and biliary 3). Toxicity was moderate with cumulative nephrotoxicity being the most serious side effect. Myelosuppression was noted in 25% of patients, all having had prior therapy with mitomycin C and nitrosoureas. Activity of cis-DDP as a single agent against adenocarcinoma of the upper gastrointestinal tract in our patient population was minimal.

Adenocarcinoma↗

Differential diagnosis of gastrointestinal stromal tumor and other spindle cell tumors in the gastrointestinal tract based on immunohistochemical analysis.

To confirm the usefulness of an immunohistochemical panel of antibodies for KIT (c-kit/CD117), CD34, desmin, smooth-muscle actin (SMA), h-caldesmon (HCD), S-100 protein, neuron-specific enolase (NSE), and beta-catenin, 297 mesenchymal and peripheral nerve-sheath tumors of the gastrointestinal tract and intra-abdominal locations including 211 gastrointestinal stromal tumors (GISTs), 12 leiomyomas, 18 leiomyosarcomas, 17 solitary fibrous tumors (SFTs), 14 schwannomas, and 25 desmoid-type fibromatoses (DTFs) were analyzed immunohistochemically. Consistent (100%) immunoreactivity for KIT, CD34, desmin and S-100, and nuclear accumulation of beta-catenin were detected in GISTs, SFTs, smooth-muscle tumors, schwannomas, and DTFs, respectively. Immunoreactivity for SMA, HCD, and NSE was observed in a wide range of these tumors. In addition, 418 bone and soft tissue tumors were enrolled in this study for KIT immunostaining. As a result, a limited number of these tumors were KIT positive, including synovial sarcoma that showed morphological similarity to GISTs. These findings suggest that KIT, CD34, desmin, S-100, and beta-catenin are key markers for clinical diagnosis of GISTs and other spindle cell tumors that may involve the gastrointestinal tract, whereas SMA, HCD, and NSE have only limited value.

Antigens, CD34↗

Fluoroscopically controlled examination of the upper gastrointestinal tract using low density barium. A review of 139 endoscopically proven lesions.

120 of 139 endoscopically verified lesions were diagnosed by fluoroscopically controlled examination of the upper gastrointestinal tract (sensitivity 86%). The incidence of false negative results was 19/139 (14%). The lesions most frequently missed were ulcerations of 1 or 2 mm in size, or lesions obscured by gastric contents. All 16 malignancies were diagnosed radiologically. It is concluded that with proper fluoroscopic-radiographic technique the sensitivity of fluoroscopically controlled examination of the upper gastrointestinal tract is comparable to (or better than) that of double contrast studies.

Barium Sulfate↗

Fentanyl and diazepam in endoscopy of the upper gastrointestinal tract.

To compare the effect of fentanyl, a short-acting narcotic analgesic, with that of diazepam as intravenous premedication for endoscopy of the upper gastrointestinal tract, we allocated at random 200 consecutive outpatients requiring elective endoscopy to receive either fentanyl or diazepam; the procedure was evaluated both by the endoscopist and by the patient. The endoscopists' opinion of the ease of the procedure was significantly better for the group of patients who received fentanyl than for the group who received diazepam (P less than 0.001). The patients' opinion of the procedure was not influenced by the premedication used. No serious side effects were observed in either patient group. We concluded that fentanyl has significant advantages over diazepam as premedication for endoscopy of the upper gastrointestinal tract.

Aged↗

Endoscopic examination of the upper gastrointestinal tract in infancy.

Forty endoscopic examinations of the upper gastrointestinal tract were performed in 38 infants with an age range from 2 days to 12 months. The main indications were upper gastrointestinal bleeding, chronic intractable vomiting, and small intestinal biopsy. Duodenal ulcer, hemorrhagic gastritis, and gastric erosions were the most common causes of upper gastrointestinal bleeding in infancy. An acute viral infection with fever, aspirin ingestion, and diarrhea frequently preceded gastrointestinal bleeding from duodenal ulcer and gastric erosion. Four of the 27 bleeding patients demonstrated no abnormality endoscopically.

Duodenal Diseases↗

Quantity and distribution of eosinophils in the gastrointestinal tract of children.

There are a lack of data on the quantity and location of eosinophils in the gastrointestinal tract of healthy individuals. Accordingly, we examined gastrointestinal biopsies obtained during endoscopic evaluation of pediatric patients. Biopsies were previously interpreted as having no diagnostic abnormality. The presence of extracellular eosinophil constituents and the quantity of eosinophils in atopic versus nonatopic individuals was determined. In the esophagus, eosinophils were present in only 2.7% of high-power fields (hpf), with a mean value of 0.03+/-0.10 eosinophils/hpf (mean+/-standard deviation) and a maximum of 1 eosinophil/hpf. Examination of the antrum and fundus revealed similar numbers of eosinophils in the lamina propria (1.9+/-1.3 and 2.1+/-2.4 eosinophils/hpf, respectively), with no eosinophils observed in the surface epithelium. In the small intestine, there were 9.6+/-5.3 (maximum, 26 eosinophils/hpf) and 12.4+/-5.4 eosinophils/hpf (maximum, 28 eosinophils/hpf) in the intercryptal lamina propria of the duodenum and ileum, respectively. The number of eosinophils in the surface epithelium and crypt epithelium was minimal. In the large intestine, the highest concentration of eosinophils was observed in the cecum (20.3+/-8.2 eosinophils/hpf; maximum, 50 eosinophils/hpf), and there were lower concentrations in the transverse and sigmoid colon (16.3+/-5.6 and 8.3+/-5.9 eosinophils/hpf, respectively). The percentage of fields demonstrating extracellular eosinophil granules in all gastrointestinal segments was 70% to 93%, and extracellular granules were most numerous at the edge of the biopsy (P<0.05). Atopic and nonatopic patients had comparable numbers of eosinophils. These data establish baseline gastrointestinal eosinophil values in pediatric patients without apparent pathological disease.

Adolescent↗

Metabolism of estrogens in the gastrointestinal tract of swine. I. Instilled estradiol.

One minute after instillation of 14C-estradiol-17 beta (14C-E2 17 beta) into selected sections of the gastrointestinal tract of swine, radioactive estradiol metabolites were present in blood collected from the portal and jugular veins. Ether was used to extract free but not conjugated estrogens. The percentage of plasma radioactivity that was ether extractable (EE) was low in portal plasma and even lower in jugular plasma following instillation of 14C-E2 17 beta into the stomach, ileum and colon. EE radioactivity was not detectable in either portal or jugular plasma when estradiol was instilled into the duodenum or jejunum. Therefore, estrogens were conjugated either in the lumen of the gastrointestinal tract or as they crossed the intestinal mucosa. The liver played only a minor role in conjugation of these steroids, since the estrogen metabolites present in portal plasma were very similar to those in jugular plasma, and metabolites in the urine were similar to those in plasma. The principal estrogen conjugate found in both portal and jugular plasma, regardless of the gastrointestinal section into which 14C-E2 17 beta was instilled, was estrone glucuronide. There was no uniform metabolic pattern observed in the metabolites of estradiol that remained in the lumen of each gastrointestinal section; however, many metabolic transformations occurred. We concluded that almost all estrogens absorbed were metabolized during the absorption process. The liver was active only in the metabolism of estrogens that escaped conjugation in the intestinal mucosa.

Animals↗

Detection of circulating tumor cells in patients with gastrointestinal tract cancer using RT-PCR and its clinical implications.

To investigate the relationship between the presence of circulating tumor cells in different stages of gastrointestinal tract cancer and the subsequent relapse or distant metastasis, circulating levels of CEA mRNA was serially examined at an interval of 10.6+/-4.5 or 13.7+/-3.0 months in gastric or colorectal cancer patients, respectively. CEA mRNA was measured by means of RT-PCR amplification as an indicator for micrometastatic malignant cells. Seven of twenty-nine respectable gastric cancer patients (24.1%) [EGC: 2/9 (22.2%), AGC IIIa: 1/5 (20.0%), AGC IIIb: 4/15 (26.6%)] were positive for CEA mRNA on the initial test and 10 of 29 patients (34.4%) [EGC: 2/ 9 (22.2%), AGC IIIa: 1/5 (20.0%), AGC IIIb: 7/15 (46.7%)] were positive on a follow-up test. Only in AGC IIIb, the positive rate for CEA mRNA increased about twice and 6 of 7 positive cases (85.7%) relapsed within 2.6+/-2.4 months after the follow-up test. In colorectal cancer, 4 of 19 patients (21.1%) [B2: 1/6 (16.7%), C2: 3/13 (23.0%)] were positive on the initial test and 10 of 19 patients (52.6%) [B2: 4/6 (66.7%), C2: 6/13 (46.2%)] were positive on a follow-up test showing an increase in positive rates during a follow-up, however, no significant correlation between CEA mRNA positivity and subsequent relapse was demonstrated. These results suggest that an early tumor cell dissemination may occur in gastrointestinal tract cancer without subsequent relapse, however, the serial regular examination of CEA mRNA level may contribute to predicting a subsequent relapse in AGC IIIb in gastric cancer.

Adult↗

Identification and distribution of 5-HT3 recognition sites in the rat gastrointestinal tract.

1. Tritiated derivatives of the potent and selective 5-HT3 receptor antagonists GR65630 and LY278584 were used to identify 5-HT3 recognition sites in the rat gastrointestinal tract. 2. Binding studies were carried out in homogenates of the rat oesophagus, the cardia, fundus, body and antrum of the stomach, regions of the small intestine, caecum and large intestine. The specific binding of a single concentration of GR65630 (0.5 nM) defined by granisetron (10 microM) in these areas indicated that the density of 5-HT3 recognition sites varied from 2.4 +/- 1.0 to 10.1 +/- 1.0 fmol mg-1 protein. 3. Saturable binding of [3H]-GR65630 could only be demonstrated in the terminal regions of the small intestine (Bmax in the range of 13.83 +/- 4.54-21.19 +/- 0.89 fmol mg-1 protein; mean +/- s.e. mean) and of high affinity (Kd in the range of 0.42 +/- 0.18-0.79 +/- 0.24 nM). Use of [3H]-LY278584 revealed a similar binding density (Bmax 19.54 +/- 0.26 fmol mg-1 protein) and affinity (Kd 1.04 +/- 0.07 nM) in the terminal small intestine. 4. Binding of [3H]-GR65630 and [3H]-LY278584 to the terminal region of the small intestine was inhibited by 5-HT3 receptor ligands ondansetron and S-zacopride (and 5-hydroxytryptamine), but not by 5-HT1, 5-HT2, catecholamine, gamma-aminobutyric acid and opioid receptor ligands. 5. These data demonstrate that there are regional variations in the density of 5-HT3 recognition sites within the rat gastrointestinal tract. Such data are relevant to the potential use of 5-HT3 receptor ligands to modify secretory and contraction responses in the gastrointestinal system.

Affinity Labels↗

Endoscopic hemostasis of bleeding of the upper gastrointestinal tract by local injection of ninety-eight per cent dehydrated ethanol.

Endoscopic dehydrated ethanol injection was attempted in 48 patients with substantial bleeding of the upper gastrointestinal tract; most of the patients had associated serious medical conditions. The causes of bleeding were: gastric ulcer in 17; duodenal ulcer in 11; gastric or duodenal vascular ectasias, or both, in five; Mallory-Weiss tear in three; acute gastric mucosal lesion in six; esophageal ulcer in two; marginal ulcer in two; gastric leiomyoma in one, and carcinoma of the stomach in one. The mean age was 57 years old (a range of 18 to 91 years old). The mean amount of blood loss prior to time of injection was 4.5 units (a range of 3 to 10 units). Ethanol injection was initially successful in 45 of 48 patients but rebleeding occurred within 72 hours in three of these patients. All instances of treated vascular ectasia disappeared by the time of follow-up endoscopy. No complications were attributable to the injections. Endoscopic local ethanol injection may be the treatment of choice in selected patients with bleeding of the upper gastrointestinal tract.

Adolescent↗

Results of operative treatment of gastrointestinal tract tumors in patients over 80 years of age.

Between 1981 and 1986, 140 patients over 80 years of age were operated on for a gastrointestinal tract tumor in our service. There were 24 gastric, one small-bowel, 91 colonic, and 24 rectal cancers. Only 40% of the patients were preoperatively free of any systemic disorder other than tumor. We performed surgical procedures with a curative intent for 90 (64%) of them. Our mean overall postoperative mortality was 17%, but this rate could be decreased by performing elective operations on well-prepared patients. Over 80% of the deaths were related to systemic organ failures. Eighty-three percent of the survivors (96 patients) returned to their homes; 82% (94 patients) had normal activities for their age. The actuarial survival curve showed a 50% survival rate at three years, all tumoral stages included. These results support the view that surgery is a safe, valid option in the face of gastrointestinal tract tumors in the elderly.

Actuarial Analysis↗