L-NMMA on GLP-2 Mediated Intestinal Lipoprotein Release
Condition: Hyperlipidemias
MeSH terms: Hyperlipidemias
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      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: 
      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.
    

Intervention name(s): Teduglutide + Normal Saline; Teduglutide + L-NMMA; Placebo + L-NMMA
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Teduglutide 0.05 mg/kg subcutaneous injection; Normal Saline intravenous infusion; Teduglutide 0.05 mg/kg subcutaneous injection; L-NMMA 10 mg/kg intravenous infusion; Placebo subcutaneous injection; L-NMMA 10 mg/kg intravenous infusion
Other intervention name(s): L-NMMA control; active treatments; Teduglutide control
Intervention MeSH terms: Teduglutide; omega-N-Methylarginine
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Each participant receives 3 randomized treatments.
Masking: Single (Participant)
Primary purpose: Basic Science