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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Teduglutide + Normal Saline | Placebo Comparator | Teguglutide + (L-NMMA control) |
|
| Teduglutide + L-NMMA | Active Comparator | Tedulgutide + L-NMMA |
|
| Placebo + L-NMMA | Placebo Comparator | (Teduglutide control) + L-NMMA |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Teduglutide + Normal Saline | Drug | Teduglutide 0.05 mg/kg subcutaneous injection; Normal Saline intravenous infusion |
|
| Measure | Description | Time Frame |
|---|---|---|
| Plasma Lipid Levels | Lipid levels in plasma and lipoprotein fractions are measured following treatments | 10.5 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Blood Flow | Mesenteric blood flow rates are measured with ultrasound following treatments | 3 hours |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Tornto General Hospital, UHN | Toronto | Ontario | M5G 1L7 | Canada |
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| ID | Term |
|---|---|
| D006949 | Hyperlipidemias |
| ID | Term |
|---|---|
| D050171 | Dyslipidemias |
| D052439 | Lipid Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| C494910 | teduglutide |
| D000077330 | Saline Solution |
| D019323 | omega-N-Methylarginine |
| ID | Term |
|---|---|
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |
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Each participant receives 3 randomized treatments.
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Single-blinded for participants
| Teduglutide + L-NMMA | Drug | Teduglutide 0.05 mg/kg subcutaneous injection; L-NMMA 10 mg/kg intravenous infusion |
|
|
| Placebo + L-NMMA | Drug | Placebo subcutaneous injection; L-NMMA 10 mg/kg intravenous infusion |
|
|
| D001120 |
| Arginine |
| D024361 | Amino Acids, Basic |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D000599 | Amino Acids, Diamino |
| D000601 | Amino Acids, Essential |