Dyspepsia, Diabetes Mellitus With Gastrointestinal Symptoms
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGExendin 9-39
Exendin 9-39 will be administered intravenously (1,200 pmol/kg bolus followed by infusion at 300 pmol/kg/min).
DRUGMicrolipid
Lipid infusion {66.7 mL Microlipid (0.5 gm/mL diluted in water to 222 ml).
DRUGPlacebo
Normal saline infusion will be prepared to match the appearance of Exendin 9-39
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Intestinal Chemosensitivity to Lipids Perfusion | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | 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. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from Mayo Clinic in Rochester, Minnesota.
Participants by arm
| Arm | Count |
|---|---|
| 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). | 13 |
| 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). | 11 |
| 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). | 20 |
| 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). | 20 |
| 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). | 20 |
| 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). | 20 |
| Total | 104 |
Baseline characteristics
| Characteristic | Healthy Controls Exendin 9-39 | Healthy Controls Placebo | Diabetics Exendin 9-39 | Diabetics Placebo | Functional Dyspepsia Exendin 9-39 | Functional Dyspepsia Placebo | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 36 years STANDARD_DEVIATION 12.6 | 42 years STANDARD_DEVIATION 14.3 | 45 years STANDARD_DEVIATION 15.7 | 45 years STANDARD_DEVIATION 11.6 | 44 years STANDARD_DEVIATION 13.2 | 39 years STANDARD_DEVIATION 13 | 42.3 years STANDARD_DEVIATION 13 |
| BMI | 26 kg/m2 STANDARD_DEVIATION 4.4 | 26 kg/m2 STANDARD_DEVIATION 5.3 | 29 kg/m2 STANDARD_DEVIATION 6.6 | 27 kg/m2 STANDARD_DEVIATION 4.5 | 26 kg/m2 STANDARD_DEVIATION 6.4 | 27 kg/m2 STANDARD_DEVIATION 6.9 | 26.8 kg/m2 STANDARD_DEVIATION 5.2 |
| Race and Ethnicity Not Collected | — | — | — | — | — | — | 0 Participants |
| Region of Enrollment United States | 13 participants | 11 participants | 20 participants | 20 participants | 20 participants | 20 participants | 104 participants |
| Sex: Female, Male Female | 8 Participants | 6 Participants | 16 Participants | 15 Participants | 15 Participants | 16 Participants | 76 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 4 Participants | 5 Participants | 5 Participants | 4 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 11 | 0 / 20 | 0 / 20 | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 0 / 13 | 0 / 11 | 2 / 20 | 1 / 20 | 1 / 20 | 0 / 20 |
| serious Total, serious adverse events | 0 / 13 | 0 / 11 | 0 / 20 | 0 / 20 | 0 / 20 | 0 / 20 |
Outcome results
Primary
Mean Intestinal Chemosensitivity to Lipids Perfusion
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.
Time frame: Day 1, approximately 2 hours after infusion
Population: Functional Dyspepsia arm - enteral lipid infusion was not performed because a nasoduodenal tube could not be placed in 2 functional dyspepsia placebo subjects and 3 functional dyspepsia exendin 9-39 subjects.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls Exendin 9-39 | Mean Intestinal Chemosensitivity to Lipids Perfusion | 0.22 score on a scale | Standard Deviation 0.05 |
| Healthy Controls Placebo | Mean Intestinal Chemosensitivity to Lipids Perfusion | 0.36 score on a scale | Standard Deviation 0.13 |
| Diabetics Exendin 9-39 | Mean Intestinal Chemosensitivity to Lipids Perfusion | 0.55 score on a scale | Standard Deviation 0.11 |
| Diabetics Placebo | Mean Intestinal Chemosensitivity to Lipids Perfusion | 0.65 score on a scale | Standard Deviation 0.17 |
| Functional Dyspepsia Exendin 9-39 | Mean Intestinal Chemosensitivity to Lipids Perfusion | 1.4 score on a scale | Standard Deviation 0.9 |
| Functional Dyspepsia Placebo | Mean Intestinal Chemosensitivity to Lipids Perfusion | 1.2 score on a scale | Standard Deviation 0.9 |
Comparison: Mean GI symptom score during lipid infusion in controls vs diabetics adjusted for treatment status (ie, exendin or placebo)p-value: 0.06ANOVA
Comparison: Mean GI symptom score during lipid infusion in controls vs functional dyspepsia adjusted for treatment status (ie, exendin or placebo)p-value: 0.0001ANOVA
Secondary
Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo
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.
Time frame: Day 1
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Healthy Controls Exendin 9-39 | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of solids | Rapid emptying | 1 Participants |
| Healthy Controls Exendin 9-39 | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of solids | Normal emptying | 10 Participants |
| Healthy Controls Exendin 9-39 | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of solids | Delayed emptying | 2 Participants |
| Healthy Controls Exendin 9-39 | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of liquids | Rapid emptying | 2 Participants |
| Healthy Controls Exendin 9-39 | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of liquids | Normal emptying | 11 Participants |
| Healthy Controls Exendin 9-39 | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of liquids | Delayed emptying | 0 Participants |
| Healthy Controls Placebo | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of solids | Normal emptying | 8 Participants |
| Healthy Controls Placebo | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of liquids | Rapid emptying | 2 Participants |
| Healthy Controls Placebo | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of liquids | Delayed emptying | 0 Participants |
| Healthy Controls Placebo | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of solids | Rapid emptying | 3 Participants |
| Healthy Controls Placebo | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of solids | Delayed emptying | 0 Participants |
| Healthy Controls Placebo | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of liquids | Normal emptying | 9 Participants |
| Diabetics Exendin 9-39 | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of liquids | Delayed emptying | 1 Participants |
| Diabetics Exendin 9-39 | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of liquids | Normal emptying | 19 Participants |
| Diabetics Exendin 9-39 | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of liquids | Rapid emptying | 0 Participants |
| Diabetics Exendin 9-39 | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of solids | Delayed emptying | 8 Participants |
| Diabetics Exendin 9-39 | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of solids | Rapid emptying | 0 Participants |
| Diabetics Exendin 9-39 | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of solids | Normal emptying | 12 Participants |
| Diabetics Placebo | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of liquids | Rapid emptying | 1 Participants |
| Diabetics Placebo | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of solids | Normal emptying | 10 Participants |
| Diabetics Placebo | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of solids | Delayed emptying | 5 Participants |
| Diabetics Placebo | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of liquids | Delayed emptying | 1 Participants |
| Diabetics Placebo | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of liquids | Normal emptying | 18 Participants |
| Diabetics Placebo | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of solids | Rapid emptying | 5 Participants |
| Functional Dyspepsia Exendin 9-39 | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of solids | Rapid emptying | 2 Participants |
| Functional Dyspepsia Exendin 9-39 | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of liquids | Normal emptying | 19 Participants |
| Functional Dyspepsia Exendin 9-39 | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of solids | Normal emptying | 16 Participants |
| Functional Dyspepsia Exendin 9-39 | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of solids | Delayed emptying | 2 Participants |
| Functional Dyspepsia Exendin 9-39 | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of liquids | Rapid emptying | 1 Participants |
| Functional Dyspepsia Exendin 9-39 | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of liquids | Delayed emptying | 0 Participants |
| Functional Dyspepsia Placebo | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of liquids | Rapid emptying | 1 Participants |
| Functional Dyspepsia Placebo | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of solids | Delayed emptying | 3 Participants |
| Functional Dyspepsia Placebo | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of liquids | Normal emptying | 19 Participants |
| Functional Dyspepsia Placebo | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of liquids | Delayed emptying | 0 Participants |
| Functional Dyspepsia Placebo | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of solids | Normal emptying | 14 Participants |
| Functional Dyspepsia Placebo | Rate of Gastric Emptying (GE t 1/2) in Patients With Diabetes Mellitus (DM) or Non-ulcer Dyspepsia (NUD) Compared to Placebo | GE of solids | Rapid emptying | 3 Participants |