Gastrointestinal Sensorimotor Dysfunctions in Diabetes Mellitus

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.

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.

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).

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).

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).

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).

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).

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).

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

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.

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.

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

Chakraborty S, Halland M, Burton D, Desai A, Neja B, Low P, Singer W, Camilleri M, Zinsmeister AR, Bharucha AE. GI Dysfunctions in Diabetic Gastroenteropathy, Their Relationships With Symptoms, and Effects of a GLP-1 Antagonist. J Clin Endocrinol Metab. 2019 Jun 1;104(6):1967-1977. doi: 10.1210/jc.2018-01623.