Gastrointestinal Sensorimotor Dysfunctions in Diabetes Mellitus
Condition: Dyspepsia; Diabetes Mellitus With Gastrointestinal Symptoms
MeSH terms: Diabetes Mellitus; Dyspepsia
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Exendin 9-39; Microlipid; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Exendin 9-39 will be 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).; Normal saline infusion will be prepared to match the appearance of Exendin 9-39
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Basic Science