Our main objective is to determine the effect of HO-1 induction by heme arginate infusion on insulin resistance and endothelial dysfunction related to MetS. Secondary objectives are to determine the effect on adipose tissue, adiponectin plasma level…
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Insulin sensitivity assessed by an euglycemic hyperinsulinemic clamp expressed
as M-value. Vasodilation / forearm blood flow in response to acetylcholine,
assessed by venous occlusion strain gauge plethysmography.
Secondary outcome
Vasodilation / forearm blood flow in response to nitroprusside, assessed by
venous occlusion strain gauge plethysmography.Plasma biomarkers of oxidative
stress and vascular inflammation and markers of HO expression and activity.
Background summary
The metabolic syndrome (MetS) is characterized by a combination of
cardiovascular risk factors among which insulin resistance and can be seen as a
pre-stage of type 2 diabetes mellitus (T2DM). Cardiovascular complications are
the leading cause of morbidity and mortality associated with both MetS and
T2DM. Both MetS and T2DM are associated with a stage of low grade inflammatory
activation of adipose tissue and the vascular system. Oxidative stress is
thought to be a key phenomenon in the pathogenesis of this pro-inflammatory
state. As pro-inflammatory cytokines reinforce insulin resistance, a vicious
cycle of cumulating exposure to risk factors and inflammation of the vascular
system and adipose tissue occurs. The cytoprotective enzyme heme oxygenase
(HO-1), is well known for its powerful antioxidant and anti-inflammatory
capacities. In vitro and animal studies convincingly show the beneficial effect
of HO activity with regard to T2DM related insulin resistance and vascular
dysfunction. We thus hypothesize that short term HO-1 induction by heme
arginate infusion ameliorates insulin resistance and endothelial dysfunction in
subjects with MetS.
Study objective
Our main objective is to determine the effect of HO-1 induction by heme
arginate infusion on insulin resistance and endothelial dysfunction related to
MetS. Secondary objectives are to determine the effect on adipose tissue,
adiponectin plasma level, markers for oxidative stress and vascular
inflammation and indicators of HO activity.
Study design
Single-centre, randomized, controlled, cross-over study.
Intervention
Three day treatment with heme arginate (3 mg/kg with a maximum of 250 mg,
intravenously administered on day 1 and 3 of one treatment period) in a
randomized and cross-over design with a washout period of two months. The
control treatment will consist of a three day treatment with L-arginine (3,2
mg/kg with a maximum of 267 mg, intravenously administered on day 1 and 3 of
the other treatment period).
Study burden and risks
Subjects will visit our department 7 times. The first visit relates to the
medical screening, the next six visits include the administration of trial
medication (either heme arginate or arginine) and/or the assessments among
which plethysmography and clamps. Total burden of time will be 20 hours
approximately. In daily clinical practice, heme arginate is used for the
treatment of acute porphyria. The substance is hardly associated with side
effects, but infusion may cause local irritation of the vene. Instructions
given by the manufacturer to avoid these effects will be complied with
obviously. Side effects due to the euglycemic hyperinsulinemic clamp are
infrequent. Plethysmography will cause temporary and completely reversible
numbness and discomfort in both hands due to inflation of the wrist-cuffs. The
adipose tissue biopsy is preceded by infiltration with local anaesthetics, but
may induce a hematoma. The subjects will not benefit from participating in this
study. A subject fee is to be provided.
Postbus 9101
6500 HB Nijmegen
NL
Postbus 9101
6500 HB Nijmegen
NL
Listed location countries
Age
Inclusion criteria
At least 18 and not older than 70 years of age on the day of the first dosing.
Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
Metabolic syndrome defined by at least three out of five criteria:
Elevated waist circumference (women >= 88, men >= 102 cm).
Elevated triglycerides or drug treatment (>= 1.7 mmol/L).
Reduced HDL-cholesterol or drug treatment (women < 1.3 mmol/L, men < 1.0 mmol/L).
Elevated blood pressure (systolic >= 130 mm Hg and/or diastolic >= 85 mm Hg)
Elevated fasting glucose (>= 6.1 mmol/L)
Exclusion criteria
History of smoking within the past year.
History of or current abuse of drugs, alcohol or solvents.
Known diabetes mellitus
Repeated systolic blood pressure >= 180 mm Hg in all subjects, >= 160 mm Hg in women >= 65 yrs old and >= 140 mm Hg in men >= 65 yrs old
Fasting plasma glucose > 7.0 mmol/L or HbA1c > 6.2%
Pregnancy or breast feeding (contraception for at least 3 months before inclusion is required for fertile women)
Current use of antihypertensive, cardiac or other vasoactive medication
Current use of acetylsalicylic acid and/or statin
Use of antioxidant vitamin supplements
Clinical evidence of cardiac or pulmonary disease
Laboratory evidence of renal or hepatic abnormalities, defined as results exceeding twice the upper limit of normal range.
Unconjugated hyperbilirubinemia (total bilirubin level > 10 µmol/L and a normal direct bilirubin level) suggesting the Gilbert Syndrome.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-020875-22-NL |
| CCMO | NL32656.091.10 |