L-NMMA on GLP-2 Mediated Intestinal Lipoprotein Release

Study Overview
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Brief Summary
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The gut is able to retain some fat for many hours after a fatty meal. The gut hormone glucagon-like peptide-2 (GLP-2) is known to release these fat stores in the gut, but it is not known how GLP-2 achieves this. One possibility is that GLP-2 increases blood flow in the gut. NG-monomethyl-L-arginine (L-NMMA) is a substance that inhibits nitric oxide synthase (an enzyme that helps make nitric oxide which increases blood flow). This protocol examines whether blocking gut blood flow with L-NMMA is able to prevent GLP-2 from releasing gut lipid stores. Healthy participants will be treated with a combination of Teduglutide (a resistant form of GLP-2) and L-NMMA, and their respective controls. Blood lipid levels will be measured following treatments.

Detailed Description
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This is a single-blind, cross over, Phase 3b clinical study. The protocol aims to study 15 healthy, lean, non-diabetic males and females for three studies each, in random order, approximately four weeks apart, as follows. Study A (L-NMMA + Teduglutide study): Volunteers will receive high-fat nutritional drink and seven hours later a subcutaneous injection of Teduglutide (0.05mg/kg of body weight, which is the FDA-approved route and daily dose for the treatment of short bowel syndrome).Thirty minutes prior to Teduglutide, the subject will receive an intravenous infusion of L-NMMA up to a maximum amount of 10 mg/kg, to inhibit nitric oxide synthesis. Lipid and lipoprotein levels will be measured at regular intervals for 3 hours following the injection of Teduglutide. Mesenteric blood flow will be measured at regular intervals by ultrasonography on some volunteers. Study B (Teduglutide + normal saline): The design is identical to study A, except that, instead of L-NMMA, normal saline of the same volume will be infused. Study C (Placebo + L-NMMA): The design is identical to study A, except that, instead of Teduglutide, a placebo will be injected subcutaneously. Mesenteric Blood Flow measurement: Mesenteric blood flow will be measured at the bedside for some of the volunteers by ultrasonography in each study (A, B, C) before, during and after the administration of L-NMMA and Teduglutide. The first evaluation will begin 15 min before the start of the L-NMMA infusion and periodically afterwards.

Official Title
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Role of a Nitric Oxide Synthase Inhibitor on GLP-2 Mediated Intestinal Lipoprotein Release

Conditions
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Hyperlipidemias

Intervention / Treatment
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* Drug: Teduglutide + Normal Saline
* Drug: Teduglutide + L-NMMA
* Drug: Placebo + L-NMMA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women, aged 18 to 60 years Body mass index 20 kg/m2 to 30 kg/m2 Hemoglobin above 130g/L. Normal glucose tolerance in response to a 75g, 2-hr oral glucose tolerance test Exclusion Criteria: Subject has a history of hepatitis/hepatic disease that has been active within the previous two years. Any significant active (over the past 12 months) disease of the gastrointestinal, pulmonary, neurological, renal (creatinine > 1.5 mg/dL), genitourinary, hematological systems, or has severe uncontrolled treated or untreated hypertension (sitting diastolic blood pressure > 100 or systolic > 180) or proliferative retinopathy History of diabetes or oral glucose tolerance indicative of diabetes or impaired glucose tolerance. Any history of a myocardial infarction or clinically significant, active, cardiovascular history including a history of arrhythmia's or conduction delays on electrocardiogram, unstable angina, or decompensated heart failure. Any laboratory values: aspartate transaminase > 2x upper limit of normal; alanine aminotransferase > 2x upper limit of normal; thyroid-stimulating hormone > 6 miliunit/l Current addiction to alcohol or substances of abuse as determined by the investigator. Mental incapacity, unwillingness or language barrier precluding adequate understanding or cooperation Taking any prescription or non-prescription medications at the time of the study Having donated blood three months prior to and three months post study procedures A pregnancy test will be performed 1 to 3 days prior to each study in all female research participants. Those who test positive for pregnancy will be excluded.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Each participant receives 3 randomized treatments.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Teduglutide + Normal Saline<br>Teguglutide + (L-NMMA control) | Drug: Teduglutide + Normal Saline<br>* Teduglutide 0.05 mg/kg subcutaneous injection; Normal Saline intravenous infusion<br>* Other names: L-NMMA control;|
| Active Comparator: Teduglutide + L-NMMA<br>Tedulgutide + L-NMMA | Drug: Teduglutide + L-NMMA<br>* Teduglutide 0.05 mg/kg subcutaneous injection; L-NMMA 10 mg/kg intravenous infusion<br>* Other names: active treatments;|
| Placebo Comparator: Placebo + L-NMMA<br>(Teduglutide control) + L-NMMA | Drug: Placebo + L-NMMA<br>* Placebo subcutaneous injection; L-NMMA 10 mg/kg intravenous infusion<br>* Other names: Teduglutide control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Lipid Levels | Lipid levels in plasma and lipoprotein fractions are measured following treatments | 10.5 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Flow | Mesenteric blood flow rates are measured with ultrasound following treatments | 3 hours |