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Gastrointestinal Sensorimotor Dysfunctions in Diabetes Mellitus

30 maart 2019 bijgewerkt door: Adil Bharucha, Mayo Clinic
The purpose of this study is to understand why people with indigestion have gastrointestinal symptoms and in particular to understand whether symptoms are related to increased sensitivity to nutrients in the small intestine and to a hormone (GLP1) which is normally released from the small intestine in response to nutrients. We propose to study the contribution of GLP1 to intestinal sensitivity with a drug (exendin 9-39) that blocks the effects of GLP1.

Studie Overzicht

Toestand

Voltooid

Conditie

Interventie / Behandeling

Gedetailleerde beschrijving

Upper gastrointestinal symptoms (early satiety, pain, nausea, and vomiting) are not uncommon in diabetic (DM) enteropathy. While these symptoms are often attributed to accelerated or delayed gastric emptying, the precise contribution of abnormal gastric emptying to symptoms in patients with DM gastroparesis is often unclear.

The investigators recently observed that approximately 50% of patients with functional dyspepsia have increased sensation to duodenal nutrient (carbohydrate and lipid) perfusion. Another recent study suggests that patients with functional dyspepsia have low-grade mucosal inflammation, abnormalities of cell-to-cell adhesion proteins which predispose to increased epithelial permeability, and a leaky epithelial barrier. Type 1 DM is associated with increased small intestinal permeability even in subjects who do not have celiac disease.

Hence, the investigators proposed to evaluate the overall hypothesis that intestinal chemosensitivity related to increased epithelial permeability and GLP-1 explains symptom severity in patients with functional dyspepsia and in patients with DM and dyspepsia. Healthy subjects, Patients with DM and GI symptoms, and patients with functional dyspepsia underwent assessment of intestinal chemosensitivity during duodenal nutrient perfusion, gastric emptying (by scintigraphy), cardiovascular and GI vagal functions (plasma pancreatic polypeptide response to sham feeding and a comprehensive autonomic reflex screen), in vivo assessment of small intestinal permeability (urinary lactulose:mannitol ratio), and upper endoscopy with assessment of epithelial tight junction proteins and permeability on small bowel biopsies.

During the nutrient infusion, subjects in each group (i.e., healthy subjects, functional dyspepsia and DM) were randomized to lipid infusion and placebo or lipid infusion and exendin 9-39. Hormonal responses (i.e., GLP-1, cholecystokinin (CCK), gastric inhibitory polypeptide (GIP), glucagon, peptide tyrosine tyrosine (PYY), C-peptide, and insulin) and plasma glucose will also be evaluated during enteral nutrient infusion. GI symptoms during each perturbation (meal, nutrient infusion) will be evaluated by validated questionnaires. Blood will be collected for DNA-based genetic analyses, initially to assess the relationship of GI sensorimotor dysfunctions and symptoms with single nucleotide polymorphisms (SNPs) affecting CCK and GLP-1 receptors. The analysis will assess for disturbances in these parameters in functional and DM dyspepsia, investigate associations between symptoms during enteral infusion and hormonal-epithelial functions, and evaluate relationships between daily symptoms and results of testing.

Studietype

Ingrijpend

Inschrijving (Werkelijk)

104

Fase

  • Fase 2

Contacten en locaties

In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.

Studie Locaties

  • Verenigde Staten
    • Minnesota
      • Rochester, Minnesota, Verenigde Staten, 55905
        • Mayo Clinic in Rochester

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

18 jaar tot 70 jaar (Volwassen, Oudere volwassene)

Accepteert gezonde vrijwilligers

Ja

Geslachten die in aanmerking komen voor studie

Allemaal

Beschrijving

Inclusion criteria for controls:

  • Healthy male or non-pregnant, non-breastfeeding female volunteers;
  • 18-70 years old;
  • Able to provide written informed consent before participating in the study;
  • Able to communicate adequately with the investigator and to comply with the requirements for the entire study

Additional inclusion criteria for patients:

  • Symptoms of dyspepsia (i.e., early satiety, postprandial discomfort, nausea, vomiting, regurgitation)
  • Patients in the Diabetes Mellitus (DM) group will also require Type 1 or 2 DM of ≥ 3 years duration; in patients with type 2 DM, the dyspepsia symptoms should have begun or worsened after DM was diagnosed

Exclusion criteria - for patients and controls:

  • Major abdominal surgery (i.e., appendectomy, cholecystectomy, tubal ligation, hysterectomy, and limited colonic resection are permissible)
  • Clinical evidence (including physical exam and EKG) of significant cardiovascular, respiratory, renal, hepatic, gastrointestinal, hematological, neurological, psychiatric or other disease that may interfere with the objectives of the study and/or pose safety concerns
  • Opiates, alpha adrenergic agonists, metoclopramide, and high doses of anticholinergic agents (e.g., amitriptyline greater than 50 mg daily). If medically safe, these drugs may be discontinued for four half lives prior to study assessments
  • Treatment with glucagon-like peptide-1 (GLP-1) agonists and amylin which cause vagal blockade and may affect central processing of pain
  • Use of tobacco products within the past six months or NSAIDs or aspirin within the past week (since they all may affect intestinal permeability)
  • Bleeding or clotting disorders or medications that increase risk of bleeding from mucosal biopsies
  • Positive tissue transglutaminase antibodies (TTG)
  • For two days prior to studies, subjects will be instructed to avoid ingestion of artificial sweeteners such as sucralose (SplendaTM), aspartame (NutrasweetTM), foods containing lactulose or mannitol
  • Pregnant or breast-feeding females
  • Known intolerance or allergy to eggs
  • Poor peripheral venous access, if central venous access is not available
  • Any other condition or prior therapy that, in the opinion of the investigator, would make the patient unsuitable for the study

Exclusion criteria for controls only:

• Current symptoms of a functional gastrointestinal disorder assessed by questionnaire

Exclusion criteria for patients only:

  • Severe vomiting that would preclude tube placement or participation in the study
  • Structural cause for symptoms by endoscopy within the past 48 months
  • Patients with gastric pacemakers

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

  • Primair doel: Fundamentele wetenschap
  • Toewijzing: Gerandomiseerd
  • Interventioneel model: Parallelle opdracht
  • Masker: Verdrievoudigen

Wapens en interventies

Deelnemersgroep / Arm
Interventie / Behandeling
Experimenteel: Healthy Controls Exendin 9-39

Exendin 9-39 was administered intravenously (1,200 pmol/kg bolus followed by infusion at 300 pmol/kg/min).

Lipid infusion 66.7 mL Microlipid (0.5 gm/mL diluted in water to 222 ml).
Geneesmiddel: Exendin 9-39
Exendin 9-39 will be administered intravenously (1,200 pmol/kg bolus followed by infusion at 300 pmol/kg/min).
Geneesmiddel: Microlipid
Lipid infusion {66.7 mL Microlipid (0.5 gm/mL diluted in water to 222 ml).
Placebo-vergelijker: Healthy Controls Placebo
Normal saline infusion was prepared to match the appearance of Exendin 9-39. Lipid infusion 66.7 mL Microlipid (0.5 gm/mL diluted in water to 222 ml).
Geneesmiddel: Microlipid
Lipid infusion {66.7 mL Microlipid (0.5 gm/mL diluted in water to 222 ml).
Geneesmiddel: Placebo
Normal saline infusion will be prepared to match the appearance of Exendin 9-39
Experimenteel: Diabetics Exendin 9-39

Exendin 9-39 was administered intravenously (1,200 pmol/kg bolus followed by infusion at 300 pmol/kg/min).

Lipid infusion 66.7 mL Microlipid (0.5 gm/mL diluted in water to 222 ml).
Geneesmiddel: Exendin 9-39
Exendin 9-39 will be administered intravenously (1,200 pmol/kg bolus followed by infusion at 300 pmol/kg/min).
Geneesmiddel: Microlipid
Lipid infusion {66.7 mL Microlipid (0.5 gm/mL diluted in water to 222 ml).
Placebo-vergelijker: Diabetics Placebo
Normal saline infusion was prepared to match the appearance of Exendin 9-39. Lipid infusion 66.7 mL Microlipid (0.5 gm/mL diluted in water to 222 ml).
Geneesmiddel: Microlipid
Lipid infusion {66.7 mL Microlipid (0.5 gm/mL diluted in water to 222 ml).
Geneesmiddel: Placebo
Normal saline infusion will be prepared to match the appearance of Exendin 9-39
Experimenteel: Functional Dyspepsia Exendin 9-39

Exendin 9-39 was administered intravenously (1,200 pmol/kg bolus followed by infusion at 300 pmol/kg/min).

Lipid infusion 66.7 mL Microlipid (0.5 gm/mL diluted in water to 222 ml).
Geneesmiddel: Exendin 9-39
Exendin 9-39 will be administered intravenously (1,200 pmol/kg bolus followed by infusion at 300 pmol/kg/min).
Geneesmiddel: Microlipid
Lipid infusion {66.7 mL Microlipid (0.5 gm/mL diluted in water to 222 ml).
Placebo-vergelijker: Functional Dyspepsia Placebo
Normal saline infusion was prepared to match the appearance of Exendin 9-39. Lipid infusion 66.7 mL Microlipid (0.5 gm/mL diluted in water to 222 ml).
Geneesmiddel: Microlipid
Lipid infusion {66.7 mL Microlipid (0.5 gm/mL diluted in water to 222 ml).
Geneesmiddel: Placebo
Normal saline infusion will be prepared to match the appearance of Exendin 9-39

Wat meet het onderzoek?

Primaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Mean Intestinal Chemosensitivity to Lipids Perfusion
Tijdsspanne: Day 1, approximately 2 hours after infusion
Intestinal chemosensitivity was recorded by evaluating symptoms during duodenal lipid infusion (0.5 gm/mL diluted in water to 222 mL) and placebo or the glucagon like peptide 1 (GLP-1) receptor antagonist exendin 9-39 over 2 hours. Participants reported the severity of 6 symptoms (nausea, fullness, bloating, abdominal pain, belching, and burning) at 15 minute intervals using a Visual Analogue Scale (VAS) marked 0 (minimum value) - 4 (maximum value): absent (0), light (1), moderate (2), severe (3) and intolerable(4). The scores recorded for nausea, fullness, bloating, and abdominal pain over the 2 hour infusion were averaged and reported as the mean symptom score. Higher scores mean a worse outcome.
Day 1, approximately 2 hours after infusion

Secundaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo
Tijdsspanne: Day 1
The time for half of the ingested solids or liquids to leave the stomach. Following a meal consisting of two eggs labeled with technetium Tc 99m sulfur colloid (1 mCi) served on one slice of bread with milk labeled with indium In111 diethylenetriaminepentaacetate (0.1 mCi), gastric emptying of solids and liquids was assessed with scintigraphy. Rapid emptying is defined as ≥ 36% emptied at one hour and delayed emptying is defined as < 76% emptied at four hours. Normal emptying is defined as amount less than rapid emptying definition but greater than delayed emptying definition.
Day 1

Medewerkers en onderzoekers

Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.

Sponsor

Mayo Clinic

Medewerkers

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Onderzoekers

  • Hoofdonderzoeker: Adil Bharucha, MBBS, MD, Mayo Clinic

Publicaties en nuttige links

De persoon die verantwoordelijk is voor het invoeren van informatie over het onderzoek stelt deze publicaties vrijwillig ter beschikking. Dit kan gaan over alles wat met het onderzoek te maken heeft.

Algemene publicaties

Nuttige links

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Studie start

1 juni 2014

Primaire voltooiing (Werkelijk)

17 november 2017

Studie voltooiing (Werkelijk)

17 november 2017

Studieregistratiedata

Eerst ingediend

20 juni 2014

Eerst ingediend dat voldeed aan de QC-criteria

20 juni 2014

Eerst geplaatst (Schatting)

23 juni 2014

Updates van studierecords

Laatste update geplaatst (Werkelijk)

23 april 2019

Laatste update ingediend die voldeed aan QC-criteria

30 maart 2019

Laatst geverifieerd

1 maart 2019

Meer informatie

Termen gerelateerd aan deze studie

Aanvullende relevante MeSH-voorwaarden

Andere studie-ID-nummers

  • 14-002098
  • P01DK068055 (Subsidie/contract van de Amerikaanse NIH)

Informatie over medicijnen en apparaten, studiedocumenten

Bestudeert een door de Amerikaanse FDA gereguleerd geneesmiddel

Ja

Bestudeert een door de Amerikaanse FDA gereguleerd apparaatproduct

Nee

Deze informatie is zonder wijzigingen rechtstreeks van de website clinicaltrials.gov gehaald. Als u verzoeken heeft om uw onderzoeksgegevens te wijzigen, te verwijderen of bij te werken, neem dan contact op met register@clinicaltrials.gov. Zodra er een wijziging wordt doorgevoerd op clinicaltrials.gov, wordt deze ook automatisch bijgewerkt op onze website .

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