RESUMEN
BACKGROUND: Studies on incidence rates of first-time colonic diverticular disease are few, and population-based estimates of lifetime risk are lacking. In this observational study, the incidence, admission rates and lifetime risks of hospitalization and surgery for diverticular disease were investigated. METHODS: Considering the entire Swedish population as an open cohort, incidence and admission rates, and lifetime risk estimates (considering death as a competing risk) of hospitalization and surgery for diverticular disease were calculated using data from cross-linked national registers and population statistics from 1987 to 2010. RESULTS: In total, there were 144 107 hospital admissions for diverticular disease in 95 049 individual patients. Of these, 17 599 were admissions with bowel resection or stoma formation in 16 824 patients. The total number of person-years in the population during the study period was 213 949 897. Age-standardized incidence rates were 47·4 (95 per cent c.i. 47·1 to 47·7) for first-time hospitalization with diverticular disease and 8·4 (8·2 to 8·5) per 100 000 person-years for diverticular disease surgery. The corresponding admission rates (including readmissions) were 70·8 (70·4 to 71·2) and 8·7 (8·6 to 8·9) per 100 000 person-years. Following an increase in 1990-1994, rates stabilized. Based on incidence and mortality rates from 2000 to 2010, the estimated remaining lifetime risk of hospitalization from 30 years of age was 3·1 per cent in men and 5·0 per cent in women. The corresponding risk of surgery was 0·5 per cent in men and 0·8 per cent in women. CONCLUSION: Diverticular disease is a common reason for hospital admission, particularly in women, but rates are stable and the lifetime risk of surgery is low.
Asunto(s)
Diverticulitis del Colon/epidemiología , Diverticulitis del Colon/cirugía , Hospitalización/estadística & datos numéricos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Incidencia , Lactante , Recién Nacido , Almacenamiento y Recuperación de la Información , Masculino , Persona de Mediana Edad , Sistema de Registros , Riesgo , Suecia/epidemiología , Adulto JovenRESUMEN
AIMS: To report four histological-immunohistochemical oesophagitis phenotypes. METHODS: Oesophageal biopsies from 311 patients were stained with H&E and with CD3, a T cell marker. Additional immunohistochemical stains (n=413) were performed in 77 cases. RESULTS: Four histological-immunohistochemical oesophagitis phenotypes were recorded: lymphocytic oesophagitis (LyE, ≥40 CD3+ lymphocytes/HPF in CD3 immunostain), eosinophilic oesophagitis (EoE, ≥15 eosinophils/HPF in H&E stain), lymphocytic infiltration (≤39 CD3+/HPF) and compound lymphocytic oesophagitis-eosinophilic oesophagitis (Co LyE-EoE). At index biopsy, 28.3% (n=88) had LyE, 21.2% (n=66) EoE, 10.6% (n=33) Co LyE-EoE and 39.9% (n=124) lymphocytic infiltration. A persistent oesophagitis phenotype was found in 42.5% (37/87) in the first follow-up biopsy, in 34.4% (21/61) in the second follow-up biopsy and in 48.1% (26/54) in the third follow-up biopsy. Using ßF1 immunostain, two different surface T cell receptors were detected in LyE and Co Lye-EoE: one having ≥40 ßF1+/HPF (ßF1+ high) and the other having <39 ßF1+/HPF (ßF1+ low). CONCLUSIONS: Based on the literature regarding the significance of intraepithelial lymphocytes (IELs) in the initiation of EoE, we submit that the IEL phenotypes in LyE might differ from those found in EoE as they were unable to elicit the same eosinophilic response. Recent studies disclosed that group 2 innate lymphocytes (ILC2s), enriched in EoE, remain undetected in CD3 immunostain as they lack surface markers for T, B, natural killer (NK) or NK T cells. If ILC2s also participate in the lymphocytic infiltration of EoE, then the frequency of cases with Co LyE-EoE here reported might have been much higher. The four oesophagitis phenotypes described are easy to recognise, provided that the dual staining procedure (H&E-CD3) is implemented.
Asunto(s)
Esofagitis Eosinofílica/patología , Esofagitis/patología , Linfocitos/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Inmunohistoquímica , Inmunofenotipificación , Lactante , Masculino , Persona de Mediana Edad , Fenotipo , Adulto JovenRESUMEN
BACKGROUND: Gastroesophageal reflux disease (GERD), the regurgitation of gastric acids often accompanied by heartburn, affects up to 20% of the general population. Genetic predisposition is suspected from twin and family studies but gene-hunting efforts have so far been scarce and no conclusive genome-wide study has been reported. We exploited data available from general population samples, and studied self-reported reflux symptoms in relation to genome-wide single nucleotide polymorphism (SNP) genotypes. METHODS: We performed a GWAS meta-analysis of three independent population-based cohorts from Sweden, Finland, and UK. GERD cases (n=2247) and asymptomatic controls (n=4503) were identified using questionnaire-derived symptom data. Upon stringent quality controls, genotype data for more than 2.5M markers were used for association testing. Bioinformatic characterization of genomic regions associated with GERD included gene-set enrichment analysis (GSEA), in silico prediction of genetic risk effects on gene expression, and computational analysis of drug-induced gene expression signatures using Connectivity Map (cMap). KEY RESULTS: We identified 30 GERD suggestive risk loci (P≤5×10-5 ), with concordant risk effects in all cohorts, and predicted functional effects on gene expression in relevant tissues. GSEA revealed involvement of GERD risk genes in biological processes associated with the regulation of ion channel and cell adhesion. From cMap analysis, omeprazole had significant effects on GERD risk gene expression, while antituberculosis and anti-inflammatory drugs scored highest among the repurposed compounds. CONCLUSIONS: We report a large-scale genetic study of GERD, and highlight genes and pathways that contribute to further our understanding of its pathogenesis and therapeutic opportunities.
Asunto(s)
Reflujo Gastroesofágico/epidemiología , Reflujo Gastroesofágico/genética , Estudio de Asociación del Genoma Completo/métodos , Vigilancia de la Población/métodos , Finlandia/epidemiología , Reflujo Gastroesofágico/diagnóstico , Humanos , Suecia/epidemiología , Estudios en Gemelos como Asunto/métodos , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: In animal and human studies glucagon-like peptide-2 (GLP-2) has been shown to increase blood flow in the superior mesenteric artery and the portal vein. This study describes the effect of GLP-2 measured directly on the intestinal mucosal blood flow by laser Doppler flowmetry (LDF) in end-jejunostomy short bowel syndrome (SBS) patients. METHODS: In five SBS patients with end-jejunostomy a specially designed laser Doppler probe was inserted into the stoma nipple, and blood flow measured directly on the jejunal mucosa for 105 min in relation to no treatment, systemic saline infusion, topical adrenaline application and a subcutaneous injection of 800 µg native GLP-2. RESULTS: The GLP-2 injection increased jejunal mucosal blood flow by 79±37% compared to conditions, where no treatment was given (p<0.001). The significant effect was present at least 105 min. Systemic saline infusion and topical, mucosal adrenaline application did not affect mucosal microcirculation. CONCLUSIONS: GLP-2 raises jejunal microcirculation in SBS patients with end-jejunostomy. This may explain the redness and increase in the end-jejunostomy nipple size imminently after commencing GLP-2 injections. The potential beneficial effects of this GLP-2-mediated increase of blood flow in the mesenteric bed should be investigated in clinical conditions other than the short bowel syndrome.
Asunto(s)
Péptido 2 Similar al Glucagón/fisiología , Mucosa Intestinal/irrigación sanguínea , Yeyuno/fisiopatología , Microcirculación/fisiología , Síndrome del Intestino Corto/fisiopatología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Yeyuno/cirugía , Flujometría por Láser-Doppler , Masculino , Persona de Mediana Edad , Proyectos Piloto , Síndrome del Intestino Corto/cirugíaRESUMEN
Microscopic colitis, comprising collagenous colitis and lymphocytic colitis, is epitomized by chronic watery diarrhea, endoscopically normal colonic mucosa, and characteristic histopathological features. Reports on chromoendoscopic findings in microscopic colitis are scarce and in this paper we describe such findings. We have examined 13 patients with microscopic colitis by means of chromoendoscopy with indigo carmine 0.2 %â- 0.5 %. In all 13 cases continuous mucosal changes were seen, with disappearance of innominate grooves or with irregularity of grooves. The segmental distribution of abnormal chromoendoscopic findings corresponded almost completely with the microscopic features. A diffuse mosaic pattern was found in five of 10 cases of collagenous colitis and in all three cases of lymphocytic colitis. Uneven surface was seen in four cases of collagenous colitis, one of collagenous colitis in remission, and one of lymphocytic colitis, and a nodular surface was recorded in five cases of collagenous colitis but in none of the lymphocytic colitis cases. If these findings can be reproduced in larger series of microscopic colitis cases, the need for biopsies as a diagnostic tool might be restricted to patients where chromoendoscopy shows clear mucosal changes, thereby saving costs and limiting possible complications associated with multiple biopsies.
Asunto(s)
Colitis Microscópica/diagnóstico , Colonoscopía , Colorantes , Carmin de Índigo , Adulto , Anciano , Anciano de 80 o más Años , Colitis Colagenosa/diagnóstico , Colitis Linfocítica/diagnóstico , Colitis Microscópica/patología , Femenino , Humanos , Mucosa Intestinal/patología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Colon cancer and diverticular disease are most common in the Western world and their incidences tend to increase with advancing age. The association between the diseases remains unclear. AIM: To analyse the risk of colon cancer after hospitalisation for diverticular disease. METHODS: Nationwide case-control study. A total of 41,037 patients with colon cancer during 1992-2006, identified from the Swedish Cancer Register were included. Each case was matched with two control subjects. From the Swedish Inpatient Register, cases and control subjects hospitalised for diverticular disease were identified. Odds ratios (OR) and confidence intervals for receiving a diagnosis of colon cancer after hospital discharge for diverticular disease were calculated. Colon cancer mortality was compared between patients with or without diverticular disease. RESULTS: Within 6months after an admission due to diverticular disease, OR of having a colon cancer diagnosis were up to 31.49 (19.00-52.21). After 12 months, there was no increased risk. The number of discharges for diverticular disease did not affect the risk. Colon cancer mortality did not differ between patients with and without diverticular disease. CONCLUSIONS: Diverticular disease does not increase the risk of colon cancer in the long term, and a history of diverticular disease does not affect colon cancer mortality. The increased risk of colon cancer within the first 12months after diagnosing diverticular disease is most likely due to surveillance and misclassification. Examination of the colon should be recommended after a primary episode of symptomatic diverticular disease.
Asunto(s)
Neoplasias del Colon/etiología , Divertículo/complicaciones , Factores de Edad , Anciano , Estudios de Casos y Controles , Neoplasias del Colon/mortalidad , Femenino , Humanos , Masculino , Oportunidad Relativa , Factores de Riesgo , SueciaRESUMEN
BACKGROUND: Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are major incretins with important effects on glucoregulatory functions. The aim of this study was to investigate effects of GIP and GLP-1 on gastric emptying and appetite after a mixed meal, and effects on insulin secretion and glucose disposal in humans. METHODS: Randomized crossover single-blind study in 17 healthy volunteers receiving GIP (2 or 5 pmol kg(-1) min(-1), n = 8), GLP-1 (0.75 pmol kg(-1) min(-1), n = 9) or NaCl for 180 min with a radionuclide-labeled omelette and fruit punch (370 kcal). Outcome measures were gastric emptying rate, insulinogenic index, hunger, satiety, desire to eat, and prospective food consumption. Blood was analyzed for GIP, GLP-1, glucagon, C-peptide, peptide YY (PYY) and ghrelin. KEY RESULTS: Glucose-dependent insulinotropic polypeptide 2 and 5 pmol kg(-1) min(-1) decreased gastric half-emptying time from 128.5 ± 34.0 min in controls to 93.3 ± 6.3 and 85.2 ± 11.0 min (P < 0.05). Glucose-dependent insulinotropic polypeptide 5 pmol kg(-1) min(-1) decreased postprandial glucose (P < 0.001) and insulin (P < 0.05) with increased insulinogenic index. Glucose-dependent insulinotropic polypeptide had no effects on hunger, desire to eat, satiety or prospective consumption. Glucagon-like peptide-1 0.75 pmol kg(-1) min(-1) increased half-emptying time from 76.6 ± 7.6 min to 329.4 ± 71.6 (P < 0.01). Glucagon-like peptide-1 decreased plasma glucose and insulin (both P < 0.05-0.001), and increased insulinogenic index markedly. Hunger, desire to eat and prospective consumption were decreased (P < 0.05), and satiety borderline increased (P < 0.06). CONCLUSION & INFERENCES: The incretin effect of GIP and GLP-1 differs as GLP-1 exerts a strong glucoregulatory incretin through inhibition of gastric emptying, which GIP does not. Thus, GLP-1 as incretin mimetic may offer unique benefits in terms of weight loss in treatment of type 2 diabetes.
Asunto(s)
Apetito/efectos de los fármacos , Glucemia/metabolismo , Vaciamiento Gástrico/efectos de los fármacos , Polipéptido Inhibidor Gástrico/farmacología , Péptido 1 Similar al Glucagón/farmacología , Homeostasis/efectos de los fármacos , Incretinas/metabolismo , Insulina/metabolismo , Adulto , Péptido C/sangre , Estudios Cruzados , Método Doble Ciego , Femenino , Polipéptido Inhibidor Gástrico/sangre , Ghrelina/sangre , Glucagón/sangre , Péptido 1 Similar al Glucagón/sangre , Humanos , Hambre/efectos de los fármacos , Inmunoensayo , Masculino , Péptido YY/sangre , Respuesta de Saciedad/efectos de los fármacosRESUMEN
Peptide tyrosine-tyrosine (PYY) is a prandially controlled hormone in endocrine ileal and colonic mucosa cells. In plasma, PYY appears as full-length PYY1-36 and truncated PYY3-36. Both have different pharmacological profile, and PYY3-36 seems to inhibit food intake. We aimed at investigating the effect of intravenously administered PYY1-36 and PYY3-36 on gastric emptying and short-term metabolic control. Eight healthy adults were studied in single-blinded, randomized design. At separate occasions, intravenous infusion of saline, PYY1-36 or PYY3-36 (0.8 pmol kg(-1) min(-1)) and a radio-labelled omelette were given. Gastric emptying (scintigraphy), appetite ratings (VAS), and plasma concentrations of insulin, glucose, GLP-1 and PYY were measured. PYY3-36 and PYY1-36 both inhibited gastric emptying, PYY3-36 most effectively. Half-emptying time was prolonged from 63.1+/-5.2 (saline) to 87.0+/-11.5 min (PYY3-36), whereas retention at 120 min was 2.5+/-1.4% for saline, 10.7+/-4.4 for PYY1-36 and 15.8+/-4.4 for PYY3-36. Neither form influenced glucose or GLP-1 concentrations, but both decreased the postprandial rise in insulin. PYY3-36 induced nausea (VAS increase 47.5+/-22.6 mm) and decreased prospective consumption (VAS change 39.5+/-7.7 mm). In conclusion, PYY3-36's reducing effect upon food intake might be mediated by a decreased gastric emptying rate.
Asunto(s)
Vaciamiento Gástrico/efectos de los fármacos , Péptido YY/farmacología , Adulto , Apetito/efectos de los fármacos , Glucemia/análisis , Femenino , Péptido 1 Similar al Glucagón/sangre , Humanos , Insulina/sangre , Masculino , Náusea/inducido químicamente , Fragmentos de Péptidos , Péptido YY/efectos adversos , Péptido YY/sangre , Método Simple CiegoRESUMEN
Incretin hormones often display inhibitory actions on gut motility. The aim of this study was to investigate if altered responsiveness to glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) as regards insulin release and small bowel motility could bring further clarity to the pathophysiology of diabetes in the Goto-Kakizaki (GK) rat. The isolated perfused pancreas was studied in male GK and Wistar rats (controls) under euglycemic and hyperglycemic conditions. Glucose-dependent insulinotropic peptide (10 nmol L(-1)) or GLP-1 (10 nmol L(-1)) were added to the medium and perfusate was collected and analysed for insulin. Moreover, GK and Wistar rats were supplied with bipolar electrodes in the small bowel and myoelectric activity was recorded during intravenous administration of GIP (1-400 pmol kg(-1) min(-1)) or GLP-1 (0.1-20 pmol kg(-1) min(-1)). Finally, tissue was collected from GK and Wistar rats for RNA extraction. Under euglycemia, GIP and GLP-1 stimulated the initial insulin response by 10-fold in GK rats (P < 0.05). At later hyperglycemia, the insulin response to GIP and GLP-1 was blunted to about one-third compared with controls (P < 0.05). In the bowel GLP-1 was about 2.6-16.7 times more potent than GIP in abolishing the migrating myoelectric complex in the GK and control rats. Polymerase chain reaction (PCR) showed GIP and GLP-1 receptor gene expression in pancreatic islets and in small bowel. The initially high, but later low insulin responsiveness to stimulation with GIP and GLP-1 along with inhibition of small bowel motility in the GK rat indicates a preserved incretin response on motility in diabetes type 2.
Asunto(s)
Polipéptido Inhibidor Gástrico/farmacología , Motilidad Gastrointestinal/efectos de los fármacos , Péptido 1 Similar al Glucagón/farmacología , Insulina/metabolismo , Intestino Delgado , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Animales , Diabetes Mellitus Experimental/metabolismo , Polipéptido Inhibidor Gástrico/genética , Polipéptido Inhibidor Gástrico/metabolismo , Hormonas Gastrointestinales/metabolismo , Hormonas Gastrointestinales/farmacología , Motilidad Gastrointestinal/fisiología , Péptido 1 Similar al Glucagón/genética , Péptido 1 Similar al Glucagón/metabolismo , Intestino Delgado/efectos de los fármacos , Intestino Delgado/fisiología , Masculino , Complejo Mioeléctrico Migratorio/efectos de los fármacos , Complejo Mioeléctrico Migratorio/fisiología , Páncreas/citología , Ratas , Ratas EndogámicasRESUMEN
Glucagon-like peptide-1 (GLP-1) is released after food intake to act as an incretin. GLP-1 also inhibits gastric emptying and increases satiety. In rats, GLP-1 inhibits small bowel motility. Our aim was to study the effects of GLP-1 on gastrointestinal motility in healthy subjects and patients with irritable bowel syndrome (IBS). Antro-duodeno-jejunal manometry was carried out during a 4-h control period with saline, followed by a 4-h period with intravenous GLP-1 (healthy: 0.7 and 1.2 pmol kg(-1) min(-1) (n = 16); IBS, 1.2 and 2.5 pmol kg(-1) min(-1) (n = 14). Plasma was analysed for GLP-1 and gut hormones, and gut tissue expression of GLP-1 receptor was studied. In healthy subjects, GLP-1 0.7 pmol kg(-1) min(-1) reduced the migrating motor complexes (MMCs) from a median of 2 (range 2-3) to 0.5 (0-2), and motility index from 4.9 +/- 0.1 to 4.3 +/- 0.3 ln Sigma(mmHg*s min(-1)) in jejunum, while GLP-1 1.2 pmol kg(-1) min(-1) diminished MMCs from 2 (2-3) to 1.5 (1-2.5), and motility index from 5.2 +/- 0.2 to 4.4 +/- 0.2. In IBS patients, GLP-1 1.2 pmol kg(-1) min(-1) reduced the MMCs from 2.5 (2-3.5) to 1 (0-1.5) without affecting motility index. At 2.5 pmol kg(-1) min(-1) GLP-1 decreased MMCs from 2 (1.5-3) to 1 (0.5-1.5), and motility index from 5.2 +/- 0.2 to 4.0 +/- 0.5. Motility responses to GLP-1 were similar in antrum and duodenum. Presence of the GLP-1 receptor in the gut was verified by reverse transcriptase PCR. In conclusion, the gut peptide GLP-1 decreases motility in the antro-duodeno-jejunal region and inhibits the MMC in healthy subjects and IBS patients.
Asunto(s)
Motilidad Gastrointestinal/fisiología , Péptido 1 Similar al Glucagón/fisiología , Péptido 1 Similar al Glucagón/uso terapéutico , Síndrome del Colon Irritable/fisiopatología , Complejo Mioeléctrico Migratorio/fisiología , Adolescente , Adulto , Duodeno/efectos de los fármacos , Duodeno/inervación , Duodeno/fisiología , Femenino , Motilidad Gastrointestinal/efectos de los fármacos , Péptido 1 Similar al Glucagón/administración & dosificación , Humanos , Síndrome del Colon Irritable/tratamiento farmacológico , Yeyuno/efectos de los fármacos , Yeyuno/inervación , Yeyuno/fisiología , Masculino , Persona de Mediana Edad , Complejo Mioeléctrico Migratorio/efectos de los fármacos , Antro Pilórico/efectos de los fármacos , Antro Pilórico/inervación , Antro Pilórico/fisiologíaRESUMEN
AIM: To investigate the effects of members of the pancreatic polypeptide family on migrating myoelectric complexes in rats in vivo. METHODS: Rats were supplied with bipolar electrodes at 5 (duodenum), 15 and 25 cm (jejunum) distal to pylorus for electromyography. The natural ligands neuropeptide Y, pancreatic polypeptide, peptide YY1-36 and peptide YY3-36 were infused IV at doses of 0.5-400 pmol kg(-1) min(-1). The mechanisms of action were studied after pre-treatment with N(omega)-nitro-L-arginine (L-NNA) 1 mg kg(-1), guanethidine 3 mg kg(-1) and in bilaterally vagotomized animals. RESULTS: PP inhibited myoelectrical activity dose-dependently in both the duodenum (ED50 5.8 pmol kg(-1) min(-1)) and jejunum (2.6 pmol kg(-1) min(-1)). PYY1-36 and PYY3-36 also had inhibitory effect in the jejunum (4.4 and 130 pmol kg(-1) min(-1), respectively). PYY1-36 had no significant effect in the duodenum, whereas PYY3-36 stimulated myoelectrical activity at the highest doses. NPY was without effect. In the jejunum neither L-NNA, guanethidine or vagotomy had any significant influence on the inhibitory effects of PP, PYY1-36 and PYY3-36. In the duodenum, the effect of PP was inhibited by guanethidine, but not L-NNA or vagotomy. The stimulatory effect of PYY3-36 in the duodenum was blocked by L-NNA and vagotomy, whereas guanethidine was without effect. CONCLUSION: Peptides of the PP family modulate small bowel motility differentially. Whereas their general effect is inhibitory in the jejunum, the mixing duodenal compartment is stimulated by PYY3-36, suggested to reflect receptor distribution distinction in the gut. This implicates distribution of distinct receptors in the gut being activated by either peptide.
Asunto(s)
Duodeno/efectos de los fármacos , Yeyuno/efectos de los fármacos , Polipéptido Pancreático/farmacología , Animales , Relación Dosis-Respuesta a Droga , Duodeno/fisiología , Electromiografía/métodos , Guanetidina/farmacología , Intestino Delgado/efectos de los fármacos , Intestino Delgado/fisiología , Yeyuno/fisiología , Masculino , Neuropéptido Y/farmacología , Fragmentos de Péptidos , Péptido YY/farmacología , Ratas , Ratas Sprague-Dawley , VagotomíaRESUMEN
CONTEXT: Ghrelin is produced primarily by enteroendocrine cells in the gastric mucosa and increases gastric emptying in patients with gastroparesis. MAIN OBJECTIVE: The objective of the study was to evaluate the effect of ghrelin on gastric emptying, appetite, and postprandial hormone secretion in normal volunteers. DESIGN: This was a randomized, double-blind, crossover study. SUBJECTS: Subjects included normal human volunteers and patients with GH deficiency. INTERVENTION: Intervention included saline or ghrelin (10 pmol/kg.min) infusion for 180 min after intake of a radioactively labeled omelette (310 kcal) or GH substitution in GH-deficient patients. MAIN OUTCOME MEASURES: Measures consisted of gastric empty-ing parameters and postprandial plasma levels of ghrelin, cholecystokinin, glucagon-like peptide-1, peptide YY, and motilin. RESULTS: The emptying rate was significantly faster for ghrelin (1.26 +/- 0.1% per minute), compared with saline (0.83% per minute) (P < 0.001). The lag phase (16.2 +/- 2.2 and 26.5 +/- 3.8 min) and half-emptying time (49.4 +/- 3.9 and 75.6 +/- 4.9 min) of solid gastric emptying were shorter during ghrelin infusion, compared with infusion of saline (P < 0.001). The postprandial peak in plasma concentration for cholecystokinin and glucagon-like peptide-1 occurred earlier and was higher during ghrelin infusion. There was no significant effect of ghrelin on plasma motilin or peptide YY. There was no difference in gastric emptying before and after GH substitution. CONCLUSION: Our results demonstrate that ghrelin increases the gastric emptying rate in normal humans. The effect does not seem to be mediated via GH or motilin but may be mediated by the vagal nerve or directly on ghrelin receptors in the stomach. Ghrelin receptor agonists may have a role as prokinetic agents.
Asunto(s)
Vaciamiento Gástrico/efectos de los fármacos , Hambre/efectos de los fármacos , Hormonas Peptídicas/farmacología , Adulto , Colecistoquinina/sangre , Estudios Cruzados , Método Doble Ciego , Femenino , Vaciamiento Gástrico/fisiología , Mucosa Gástrica/metabolismo , Ghrelina , Péptido 1 Similar al Glucagón/sangre , Hormona de Crecimiento Humana/sangre , Hormona de Crecimiento Humana/deficiencia , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Hambre/fisiología , Masculino , Persona de Mediana Edad , Motilina/sangre , Hormonas Peptídicas/sangre , Hormonas Peptídicas/genética , Péptido YY/sangre , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Ghrelina , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estómago/efectos de los fármacosRESUMEN
BACKGROUND: The timing of the migrating motor complexes (MMC) at food intake may influence gastric emptying and release of regulatory hormones. This report studies the relationships between phases I (motor quiescence) and II (intermediate frequency contractions) of MMC and prandial gut hormone response. MATERIALS AND METHODS: Seven fasting volunteers ingested a meal during phase I or II of MMC verified by manometry, using paracetamol as a marker for gastric emptying. Blood was sampled before, during and 210 min after food intake for analysis of ghrelin, motilin, insulin and paracetamol. RESULTS: The basal level of ghrelin during phase I was 127.5 +/- 25.4 pmol L(-1) and during phase II was 132.4 +/- 24.8 pmol L(-1). After food intake during phase I, ghrelin fell to 77.2 +/- 10 pmol L(-1); in phase II it fell to 82.7 +/- 17.8 pmol L(-1) within 60 min and returned to baseline levels after 120 min. Baseline levels of motilin were 16 +/- 2 pmol L(-1) and 18 +/- 3 pmol L(-1) during phases I and II, respectively. After food, motilin decreased to 8.5 +/- 0.7 pmol L(-1) and 8.7 +/- 1.0 pmol L(-1) within 60 min and returned to baseline after 90 min. Insulin levels in phases I and II were 8.1 +/- 1.2 mU L(-1) and 8.6 +/- 0.7 mU L(-1), respectively, reaching 138.9 +/- 35.6 mU L(-1) and 167.4 +/- 30.0 mU L(-1) at 45 min postprandially. CONCLUSIONS: The nutritional status of the gastrointestinal tract at food intake had only a limited impact on plasma ghrelin. After food intake, plasma ghrelin drops, similar to motilin, and resumes preprandial levels within 120 min.
Asunto(s)
Ingestión de Alimentos/fisiología , Complejo Mioeléctrico Migratorio/fisiología , Hormonas Peptídicas/sangre , Acetaminofén/sangre , Adulto , Analgésicos no Narcóticos/sangre , Vaciamiento Gástrico/fisiología , Fármacos Gastrointestinales/sangre , Ghrelina , Humanos , Insulina/sangre , Masculino , Motilina/sangreRESUMEN
CONTEXT: Previous studies using pancreatic polypeptide (PP) infusions in humans have failed to show an effect on gastric emptying, glucose metabolism, and insulin secretion. This might be due to the use of nonhuman sequences of the peptide. OBJECTIVE: The objective of this study was to use synthetic human PP to study gastric emptying rates of a solid meal and postprandial hormone secretion and glucose disposal as well as the gastric emptying rate of water. DESIGN: This was a single-blind study. SETTING: The study was performed at a university hospital. PARTICIPANTS: Fourteen healthy adult subjects were studied. INTERVENTIONS: Infusion of saline or PP at 0.75 or 2.25 pmol/kg.min was given to eight subjects (gastric emptying of solid food), and infusion of saline or PP at 2.25 pmol/kg.min was given to six subjects (gastric emptying of water). MAIN OUTCOME MEASURES: The main outcome measures were gastric emptying of solids (scintigraphy), hunger ratings (visual analog scale), and plasma concentrations of PP, insulin, glucagon, somatostatin, glucagon-like peptide 1, glucose, and gastric emptying of plain water (scintigraphy). RESULTS: PP prolonged the lag phase and the half-time of emptying of the solid meal. The change in hunger rating, satiety, desire to eat after the meal, or prospective consumption was not affected. The postprandial rise in plasma glucose was prolonged by PP. The postprandial rise in insulin was also delayed by PP. PP had no significant effect on the emptying of water. CONCLUSIONS: PP inhibits gastric emptying of solid food and delays the postprandial rise in plasma glucose and insulin. PP is suggested to have a physiological role in the pancreatic postprandial counterregulation of gastric emptying and insulin secretion.
Asunto(s)
Glucemia/metabolismo , Vaciamiento Gástrico/efectos de los fármacos , Hormonas/metabolismo , Polipéptido Pancreático/farmacología , Periodo Posprandial/fisiología , Adulto , Apetito , Estudios Cruzados , Ingestión de Alimentos , Femenino , Alimentos , Glucagón/sangre , Hormonas/sangre , Humanos , Insulina/sangre , Masculino , Dimensión del Dolor , Polipéptido Pancreático/sangre , Polipéptido Pancreático/síntesis química , Valores de Referencia , Saciedad/efectos de los fármacos , Método Simple Ciego , Agua/metabolismoRESUMEN
High-pressure liquid chromatography of extracts of rat pineal glands, followed by radio immunological analysis with antibodies against tachykinins, demonstrated the presence of substance P, neurokinin A and neurokinin B in the superficial rat pineal gland. Immunohistochemistry on perfusion-fixed rat brain sections showed substance P and neurokinin A to be present in nerve fibers located both in the perivascular spaces as well as intraparenchymally between the pinealocytes. After extracting total RNA, followed by reverse transcription and polymerase chain reaction amplification with primers specific for NK1-, NK2- and NK3-receptors, agarose gel analysis of the reaction products showed the presence of mRNA encoding all three neurokinin receptors. Immunohistochemical analysis showed NK1 receptor to be located in the interstitial cells of the gland. This location was confirmed by use of in situ hybridization using radioactively labeled antisense oligonucleotide probes. Double immunohistochemical stainings showed that the NK1-immunoreactive cells were not a part of the macrophages or antigen-presenting cells of the gland. Our study suggests that tachykinins, after release from intrapineal nerve fibers, are involved in an up to now unknown function, different from that of melatonin synthesis.
Asunto(s)
Glándula Pineal/metabolismo , Taquicininas/metabolismo , Animales , Cartilla de ADN , Células Dendríticas/metabolismo , Inmunohistoquímica , Macrófagos/metabolismo , Masculino , Neuroquinina A/metabolismo , Ratas , Ratas Wistar , Receptores de Neuroquinina-1/metabolismo , Receptores de Neuroquinina-3/metabolismo , Receptores de Taquicininas/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sustancia P/metabolismoRESUMEN
BACKGROUND: Cholecystokinin inhibits the secretion of gastrin from antral G cells, an effect that is speculated to be mediated by D cells secreting somatostatin. The aim of the study was to test directly whether cholecystokinin inhibition of antral gastrin secretion is mediated by somatostatin. METHODS: The effects of CCK on gastrin and somatostatin secretion were studied in isolated vascularly perfused preparations of pig antrum before and after immunoneutralization brought about by infusion of large amounts of a high affinity monoclonal antibody against somatostatin. RESULTS: CCK infusion at 10(-9) M and 10(-8) M decreased gastrin output to 70.5% +/- 7.6% (n = 8) and 76.3% +/- 3.6% (n = 7) of basal output, respectively. CCK at 10(-10) M had no effect (n = 6). Somatostatin secretion was dose-dependently increased by CCK infusion and increased to 268 +/- 38.2% (n = 7) of basal secretion during infusion of CCK at 10(-8) M. Immunoneutralization of somatostatin caused a doubling of the basal secretion of gastrin, but did not affect the CCK-induced decrease in gastrin secretion. CONCLUSION: CCK inhibits gastrin secretion independently of paracrine somatostatin secretion.
Asunto(s)
Colecistoquinina/fisiología , Gastrinas/antagonistas & inhibidores , Gastrinas/metabolismo , Comunicación Paracrina/fisiología , Antro Pilórico/metabolismo , Somatostatina/metabolismo , Animales , Colecistoquinina/farmacología , Células Secretoras de Gastrina/fisiología , Radioinmunoensayo , Células Secretoras de Somatostatina/fisiología , PorcinosRESUMEN
Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are secreted in parallel to the circulation after a meal. Intravenous (IV) GLP-1 has an inhibitory effect on gastric emptying, hunger and food intake in man. In rodents, central administration of GLP-2 increases satiety similar to GLP-1. The aim of the present study was to assess the effect of IV administered GLP-2 on gastric emptying and feelings of hunger in human volunteers. In eight (five men) healthy subjects (age 31.1+/-2.9 years and BMI 24.1+/-1.0 kg m(-2)), scintigraphic solid gastric emptying, hunger ratings (VAS) and plasma concentrations of GLP-2 were studied during infusion of saline or GLP-2 (0.75 and 2.25 pmol kg(-1) min(-1)) for a total of 180 min. Concentrations of GLP-2 were elevated to a maximum of 50 and 110 pmol l(-1) for 0.75 and 2.25 pmol kg(-1) min(-1) infusion of GLP-2, respectively. There was no effect of GLP-2 on either the lag phase (29.5+/-4.4, 26.0+/-5.2 and 21.2+/-3.6 min for saline, GLP-2 0.75 or 2.25 pmol kg(-1) min(-1), respectively) or the half emptying time (84.5+/-6.1, 89.5+/-17.8 and 85.0+/-7.0 min for saline, GLP-2 0.75 or 2.25 pmol kg(-1) min(-1), respectively). The change in hunger rating after the meal to 180 min was also unaffected by infusion of GLP-2. GLP-2 does not seem to mediate the ileal brake mechanism.
Asunto(s)
Vaciamiento Gástrico/efectos de los fármacos , Péptidos/administración & dosificación , Péptidos/farmacología , Saciedad/efectos de los fármacos , Adulto , Regulación del Apetito/efectos de los fármacos , Estudios Cruzados , Péptido 1 Similar al Glucagón , Péptido 2 Similar al Glucagón , Humanos , Infusiones Intravenosas , MasculinoRESUMEN
BACKGROUND: The involvement of nitric oxide (NO) in vagal control and vasoactive intestinal polypeptide (VIP)-induced effects on antral motility was studied using isolated perfused preparations of porcine gastric antrum with intact vagal innervation. METHODS: The presence of NO and VIP-producing neurons was studied using immunohistochemistry and histochemical techniques. Widespread, but not total, co-localization of NO and VIP immunoreactivity was found in the submucosa and in the muscle layers. RESULTS: Electrical stimulation of the vagus nerves for 5 min (8 Hz, 10 mA, 4 msec) increased the motility index from 2.47 = 0.44 to 11.50 +/- 2.02 (n = 5). This effect was not influenced by the two NO synthase inhibitors N-nitro-L-arginine methyl ester (10(-4) M) and NG-nitro-L-arginine (10(-5) M). However, infusion of inhibitors increased the spontaneous motility index from 2.40 +/- 0.08 to 5.36 +/- 1.08 (P < 0.05) and 3.05 +/- 1.10 to 4.14 +/- 1.04 (P < 0.05), respectively. The addition of L-arginine reversed this effect. Infusion of VIP 2 x 10(-9)M decreased the motility index from 2.32 +/- 0.43 to 1.32 +/- 0.27 (P < 0.05), an effect that was preserved during NO synthase inhibition. Electrical vagus stimulation increased the release of VIP to the venous effluent, an effect that persisted during NO synthase inhibitors. CONCLUSION: We conclude that NO-producing nerves seem to have a tonic inhibitory action on the porcine antral motility, but are not involved in the motor effects of vagal stimulation or VIP infusion.
Asunto(s)
Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico/metabolismo , Antro Pilórico/metabolismo , Nervio Vago/metabolismo , Péptido Intestinal Vasoactivo/metabolismo , Animales , Estimulación Eléctrica/métodos , Inmunohistoquímica , Óxido Nítrico/antagonistas & inhibidores , PorcinosRESUMEN
BACKGROUND: The two tachykinins substance P and neurokinin A are abundantly present in the gastrointestinal tract. Substance P preferring neurokinin 1 receptors are mainly found in submucosal blood vessels while neurokinin A preferring neurokinin 2 receptors seem to be confined to smooth muscle cells. Tachykinin effects on intestinal mucosal blood flow in humans are not known. AIM: To study the effects of substance P and neurokinin A on small bowel mucosal blood flow in humans. METHODS: A manometry tube supplied with single fibre microprobes recorded mucosal blood flow in the proximal small bowel using laser Doppler flowmetry, concomitant with luminal manometry, defining phases I, II, and III of the migrating motor complex. Simultaneously, flowmetry of temporal skin was performed. Under fasting conditions saline was infused intravenously over four hours followed by infusion of substance P, neurokinin A, or saline. RESULTS: During phase I, substance 1-6 pmol/kg/min increased mucosal blood flow dose dependently by a maximum of 158%. Blood flow of the temporal skin increased in parallel. Neurokinin A 6-50 pmol/kg/min increased mucosal blood flow maximally by 86% at 25 pmol/kg/min while blood flow of temporal skin increased at all doses. Substance P at all doses and neurokinin A at the highest dose only, increased pulse rate. Systolic blood pressure was unchanged by either peptide while substance P at the highest dose decreased diastolic pressure. CONCLUSION: Tachykinins increase blood flow of the small bowel and temporal skin. With substance P being more potent than neurokinin A, these effects are probably mediated through neurokinin 1 receptors.
Asunto(s)
Mucosa Intestinal/efectos de los fármacos , Intestino Delgado/efectos de los fármacos , Neuroquinina A/farmacología , Sustancia P/farmacología , Adolescente , Adulto , Presión Sanguínea/efectos de los fármacos , Diástole , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Infusiones Intravenosas , Mucosa Intestinal/irrigación sanguínea , Intestino Delgado/irrigación sanguínea , Flujometría por Láser-Doppler/instrumentación , Flujometría por Láser-Doppler/métodos , Masculino , Manometría , Complejo Mioeléctrico Migratorio , Pulso Arterial , Flujo Sanguíneo Regional/efectos de los fármacos , Piel/irrigación sanguínea , Estadísticas no Paramétricas , Estimulación QuímicaRESUMEN
BACKGROUND: We studied the effects of tachykinin receptor antagonists on fluid-induced, spontaneous net aboral propulsive complexes in isolated, vascularly perfused porcine ileal segments. METHODS: Fluid was instilled at a constant rate into the proximal opening of the segment, resulting in regular, rapidly propagating propulsive complexes along the entire ileal segment in the aboral direction. RESULTS: NKI, NK2 or NK3 receptor antagonists (CP99994, SR48968 and SR 142801 all at 10(-6) M) had no effect on the frequency of propulsive complexes. Atropine (10(-6) M) abolished the propulsive complexes for 15.0 +/- 1.3 min (n = 18). In spite of continued atropine infusion, the propulsive complexes reappeared. Infusion of the NK1 receptor antagonist CP99994 (10(-6) M) during continued atropine infusion blocked net aboral propulsive complexes in 5 experiments for 12.2 +/- 2.4 min and resulted in motor paralysis in 2 experiments. SP release, measured in the venous effluent, was significantly increased in relation to propulsive complexes during atropine infusion. CONCLUSION: We conclude that, in the porcine ileum, tachykinins mediate atropine-resistant net aboral propulsive complexes acting on NKI receptors.