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Gastrointestinal Sensorimotor Dysfunctions in Diabetes Mellitus

30. mars 2019 oppdatert av: 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.

Studieoversikt

Status

Fullført

Forhold

Intervensjon / Behandling

Detaljert beskrivelse

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

Intervensjonell

Registrering (Faktiske)

104

Fase

  • Fase 2

Kontakter og plasseringer

Denne delen inneholder kontaktinformasjon for de som utfører studien, og informasjon om hvor denne studien blir utført.

Studiesteder

  • Forente stater
    • Minnesota
      • Rochester, Minnesota, Forente stater, 55905
        • Mayo Clinic in Rochester

Deltakelseskriterier

Forskere ser etter personer som passer til en bestemt beskrivelse, kalt kvalifikasjonskriterier. Noen eksempler på disse kriteriene er en persons generelle helsetilstand eller tidligere behandlinger.

Kvalifikasjonskriterier

Alder som er kvalifisert for studier

18 år til 70 år (Voksen, Eldre voksen)

Tar imot friske frivillige

Ja

Kjønn som er kvalifisert for studier

Alle

Beskrivelse

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

Studieplan

Denne delen gir detaljer om studieplanen, inkludert hvordan studien er utformet og hva studien måler.

Hvordan er studiet utformet?

Designdetaljer

  • Primært formål: Grunnvitenskap
  • Tildeling: Randomisert
  • Intervensjonsmodell: Parallell tildeling
  • Masking: Trippel

Våpen og intervensjoner

Deltakergruppe / Arm
Intervensjon / Behandling
Eksperimentell: 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).
Legemiddel: Exendin 9-39
Exendin 9-39 will be administered intravenously (1,200 pmol/kg bolus followed by infusion at 300 pmol/kg/min).
Legemiddel: Microlipid
Lipid infusion {66.7 mL Microlipid (0.5 gm/mL diluted in water to 222 ml).
Placebo komparator: 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).
Legemiddel: Microlipid
Lipid infusion {66.7 mL Microlipid (0.5 gm/mL diluted in water to 222 ml).
Legemiddel: Placebo
Normal saline infusion will be prepared to match the appearance of Exendin 9-39
Eksperimentell: 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).
Legemiddel: Exendin 9-39
Exendin 9-39 will be administered intravenously (1,200 pmol/kg bolus followed by infusion at 300 pmol/kg/min).
Legemiddel: Microlipid
Lipid infusion {66.7 mL Microlipid (0.5 gm/mL diluted in water to 222 ml).
Placebo komparator: 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).
Legemiddel: Microlipid
Lipid infusion {66.7 mL Microlipid (0.5 gm/mL diluted in water to 222 ml).
Legemiddel: Placebo
Normal saline infusion will be prepared to match the appearance of Exendin 9-39
Eksperimentell: 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).
Legemiddel: Exendin 9-39
Exendin 9-39 will be administered intravenously (1,200 pmol/kg bolus followed by infusion at 300 pmol/kg/min).
Legemiddel: Microlipid
Lipid infusion {66.7 mL Microlipid (0.5 gm/mL diluted in water to 222 ml).
Placebo komparator: 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).
Legemiddel: Microlipid
Lipid infusion {66.7 mL Microlipid (0.5 gm/mL diluted in water to 222 ml).
Legemiddel: Placebo
Normal saline infusion will be prepared to match the appearance of Exendin 9-39

Hva måler studien?

Primære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Mean Intestinal Chemosensitivity to Lipids Perfusion
Tidsramme: 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

Sekundære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo
Tidsramme: 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

Samarbeidspartnere og etterforskere

Det er her du vil finne personer og organisasjoner som er involvert i denne studien.

Sponsor

Mayo Clinic

Samarbeidspartnere

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

Etterforskere

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

Publikasjoner og nyttige lenker

Den som er ansvarlig for å legge inn informasjon om studien leverer frivillig disse publikasjonene. Disse kan handle om alt relatert til studiet.

Generelle publikasjoner

Hjelpsomme linker

Studierekorddatoer

Disse datoene sporer fremdriften for innsending av studieposter og sammendragsresultater til ClinicalTrials.gov. Studieposter og rapporterte resultater gjennomgås av National Library of Medicine (NLM) for å sikre at de oppfyller spesifikke kvalitetskontrollstandarder før de legges ut på det offentlige nettstedet.

Studer hoveddatoer

Studiestart

1. juni 2014

Primær fullføring (Faktiske)

17. november 2017

Studiet fullført (Faktiske)

17. november 2017

Datoer for studieregistrering

Først innsendt

20. juni 2014

Først innsendt som oppfylte QC-kriteriene

20. juni 2014

Først lagt ut (Anslag)

23. juni 2014

Oppdateringer av studieposter

Sist oppdatering lagt ut (Faktiske)

23. april 2019

Siste oppdatering sendt inn som oppfylte QC-kriteriene

30. mars 2019

Sist bekreftet

1. mars 2019

Mer informasjon

Begreper knyttet til denne studien

Ytterligere relevante MeSH-vilkår

Andre studie-ID-numre

  • 14-002098
  • P01DK068055 (U.S. NIH-stipend/kontrakt)

Legemiddel- og utstyrsinformasjon, studiedokumenter

Studerer et amerikansk FDA-regulert medikamentprodukt

Ja

Studerer et amerikansk FDA-regulert enhetsprodukt

Nei

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