L-NMMA on GLP-2 Mediated Intestinal Lipoprotein Release

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.

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.

Eligibility Criteria:
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.