Pathophysiology of Diabetic Gastroparesis (PATODIAG)

The goal of this study is to explore the pathophysiology of diabetic gastroparesis by conducting an exploratory cohort study. Participants will be type 1 diabetes patients with and without gastroparesis. Investigators will investigate

• Differences in nervefiber density and morphology
• Cellular and transcriptional changes and indices of glucosemetabolism between groups

Study Overview

• Status: Recruiting
• Conditions: Gastroparesis Due to Diabetes Mellitus Type I
• Intervention / Treatment: Diagnostic test: technetium scitigraphy

Detailed Description

Aims To perform an exploratory cohort study including 26 type 1 diabetes (DM1) patients aged 18-85 years with gastroparesis and 26 comparable DM1 diabetes patients without gastroparesis, investigating nerve fibre density and length in the mucosal and submucosal layer of the stomach (fundus, and antrum). A variety of molecular, biochemical and cellular experimental procedures will be performed on bloodsamples and tissue biopsies collected during gastroscopy exploring the pathophysiology of gastroparesis. In addition, we will compare differences in, measures of glucose metabolism in the two patient groups through bloodsamples.

Hypotheses

1. Nerve fibre morphology in the stomach is different in type 1 diabetes patients with diabetic gastroparesis compared to diabetes patient without gastroparesis and associated with differences in glucose metabolism and the severity of autonomic and peripheral neuropathy.
2. Patients with gastroparesis show loss of interstitial cells of Cajal (ICC) in the gastric body, antrum and fundus and have marked morphological changes indicative of injuries.
3. Macrophages are thought to play a central role in diabetic gastroparesis, in which a loss of anti-inflammatory heme-oxygenase-1 (HO-1) positive macrophages leads to decreased protection against oxidative stress, resulting in damage to ICCs.
4. In gastroparesis there is increased presence of fibrosis in the stroma and alteration in inflammatory cells.
5. Patients with gastroparesis may have decreased levels of neurotransmitters such as NO and substance P.
6. Gastroparesis may cause pathological alterations of enteric glial and ganglion cells and the cytoplasm of smooth muscle cells.
7. Patients with gastroparesis have lower pyloric distensibility.
8. Examining transcriptional changes in between groups will reveal new genes associated with disease development. Newly developed in vitro models make it possible to explore and correlate molecular biochemical and cellular factors to disease development and progression.

Study Design All participants will be type 1 diabetes patients attending treatment at Steno Diabetes Center Copenhagen (SDCC) or type 1 diabetes patients referred from other treatment facilities. Patients will fill out the Gastroparesis Cardinal Symptom Index (GCSI) questionnaire and be asked if they have been diagnosed with gastroparesis. Patients with known gastroparesis or with a GCSI score ≥ 1.9 without known gastroparesis will be subject to a technetium scintigraphy. Patients without established gastroparesis and a GCSI score < 1.9 will also undergo technetium scintigraphy. A gastric content above 10%, 4 hours after meal ingestion will be considered the diagnostic threshold for gastroparesis Patients with gastroparesis will be considered as cases and patients without gastroparesis as control. All patients will have a gastroscopy to rule out other causes to gastro-intestinal symptoms. During gastroscopy, 8 biopsies will be obtained and endo-flip will be used to measure distesibility in pylorus. Tissue specimens and blood samples will be collected and used in various research-based analyses to understand the pathophysiology.

• Study Type: Interventional
• Enrollment (Anticipated): 52
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Region Hovedstaden
    • Hvidovre, Region Hovedstaden, Denmark, 2650
      • Recruiting
      • Hvidovre University Hospital
      • Contact: John G Karstensen, MD; Phone Number: +4540944465; Email: john.gasdal.karstensen@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Type 1 diabetes
• age 18-85
• Case group: Gastroparesis verified by technetium scintigraphy and a GCSI score ≥ 1.9
• Control group: Gastroparesis not confirmed by technetium scintigraphy and score GCSI score < 1.9

Exclusion Criteria:

• Ongoing cancer treatment or other concurrent illness that will make the patient unable to attend the study on the discretion of the investigator.
• Recent gastrointestinal surgery
• Active duodenal/gastric ulcer disease,
• Diseases in the ventricle or previously complicated upper abdominal surgery
• Pregnancy or breast feeding
• Persons who, in the judgement of the investigator, may be unable to follow the protocol.
• Parkinson disease
• metoclopramide 48 hours prior to scintigraphy
• domperidone 48 hours prior to scintigraphy
• macrolide antibiotics 48 hours prior to scintigraphy
• anti-cholinergic agents
• Tricycliv antidepressants
• Glucagon-like peptide-1 analogues
• Lithium
• Diphenhydramine
• dopamine agonists
• progesterone, L-dopa
• calcitonine
• ocreotide
• Interferon alfa
• sucralsulfate
• botulinum toxin injections (eg, Botox®) by pyloric injection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: cases with gastroparesis; patients with a gastroparesis symptom score index (GCSI) of > 1.9 will be considered as cases with gastroparesis and will be subjected to technetium-scintigraphy and gastroscopy with tissuesamples from antrum and fundus and bloodsamples of glucosemetabolism	Diagnostic test: technetium scitigraphy; patients will have a technetium scintraphy confirming or ruling out gastroparesis. Then the patients will have a gastroscopy with tissue samples from antrum and fundus. During gastroscopy an endo-flip ballon will meassure the distensibility in pylorus.; Other Names: gastroscopy with tissuesamples
Active Comparator: Controls without gastroparesis; patients with a gastroparesis symptom score index (GCSI) of < 1.9 will be considered as controls without gastroparesis and will be subjected to technetium-scintigraphy and gastroscopy with tissuesamples from antrum and fundus and bloodsamples of glucosemetabolism	Diagnostic test: technetium scitigraphy; patients will have a technetium scintraphy confirming or ruling out gastroparesis. Then the patients will have a gastroscopy with tissue samples from antrum and fundus. During gastroscopy an endo-flip ballon will meassure the distensibility in pylorus.; Other Names: gastroscopy with tissuesamples

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mucosal nerve length density (MNLD)	differences in mucosal nerve length density (MNLD) of the gastric fundus and antrum in diabetes patients with and without gastroparesis. MNLD will be assessed by confocal microscopy of mucosal biopsies obtained by oesophago-gastro-duodenoscopy.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nerve fibre morphology	Nerve fibre morphology assessed by confocal microscopy of mucosal biopsies obtained by esophago-gastro-duodenoscopy	24 months
Differences in histology	Hematoxylin and eosin (HE) staining and c-KIT staining of immune cells, interstitial cells, glia cells, ganglion cells and smooth muscle cells and visualization under a microscope	24 months
Transcriptional changes	Altered transcriptional changes in mRNA by NanoString.	24 months
Differences in cell populations	Differences in cell populations by fluorescence-activated cell sorting (FACS).	24 months
Differences in pyloric distensibility	Pyloric distensibility measurements by Endo-Flip.	24 months
Differences in glucose metabolism	plasma glucose in mmol/L, HbA1c in mmol/mol, proinsulin C-peptide in pmol/L	24 months
Differences in gastric emptying time	Gastric emptying time assessed by technetium scintigraphy.	24 months
Differences in neuropathy measures	sensory tests that record sensation of touch, vibration, cooling and heat.	24 months
Immunohistochemical differences	Immunohistochemical staining that uses antibodies to visualize the localization of particular proteins within single cells.	24 months

Collaborators and Investigators

• Sponsor: Hvidovre University Hospital
• Collaborators: Zealand University Hospital; Steno Diabetes Center Copenhagen

Study record dates

Study Major Dates

• Study Start (Actual): February 16, 2023
• Primary Completion (Anticipated): December 31, 2024
• Study Completion (Anticipated): June 1, 2025

Study Registration Dates

• First Submitted: December 12, 2022
• First Submitted That Met QC Criteria: February 6, 2023
• First Posted (Actual): February 8, 2023

Study Record Updates

• Last Update Posted (Actual): April 14, 2023
• Last Update Submitted That Met QC Criteria: April 12, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: gastroparesis
• Additional Relevant MeSH Terms: Digestive System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Neurologic Manifestations; Endocrine System Diseases; Gastrointestinal Diseases; Stomach Diseases; Diabetes Mellitus; Paralysis; Diabetes Mellitus, Type 1; Gastroparesis
• Other Study ID Numbers: SJ-980

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No