l-nmma on glp-2 mediated intestinal lipoprotein release

Conditions: Hyperlipidemias

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.

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.