Hyperlipidemias
Conditions
Brief 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.
Interventions
DRUGTeduglutide + Normal Saline
Teduglutide 0.05 mg/kg subcutaneous injection; Normal Saline intravenous infusion
DRUGTeduglutide + L-NMMA
Teduglutide 0.05 mg/kg subcutaneous injection; L-NMMA 10 mg/kg intravenous infusion
DRUGPlacebo + L-NMMA
Placebo subcutaneous injection; L-NMMA 10 mg/kg intravenous infusion
Sponsors
University Health Network, Toronto
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Masking description
Single-blinded for participants
Intervention model description
Each participant receives 3 randomized treatments.
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Lipid Levels | 10.5 hours | Lipid levels in plasma and lipoprotein fractions are measured following treatments |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Blood Flow | 3 hours | Mesenteric blood flow rates are measured with ultrasound following treatments |
Countries
Canada
Outcome results
None listed