Ciprofibrate and Pre-diabetes

Free fatty acids (FFA) are the main fuel source in a healthy adult heart, since they are responsible for 70-80% of the myocardial ATP production. Plasma FFA and triglycerides (TG) levels are elevated in obesity and diabetes, evoking substrate competition in the heart: the increased availability of lipids will lead to fat accumulation in the heart, which is associated with cardiac insulin resistance and will therefore restrain insulin-stimulated cardiac glucose oxidation. It is shown that a lower myocardial glucose uptake correlates with decreased diastolic function. The benefits of counterbalancing this lipid overload is proven by previous research in pre-diabetes, which showed the reversibility of impaired myocardial substrate metabolism and improvement of function and structure after modest weight loss induced by lifestyle changes.

Ciprofibrates are a ligand of the peroxisome proliferator-activated receptor (PPAR) α and are considered to be a major regulator of the lipid metabolism and promote fat oxidative capacity. They are not only effective in normalizing lipid-lipoprotein levels in patients with the metabolic syndrome, but improve also their insulin sensitivity. We therefore hypothesize that ciprofibrate administration in subjects with impaired glucose metabolism (IGM) influence the myocardial substrate metabolism (via the PPARα pathway) and thereby improve myocardial insulin sensivity.

Objectives: The main objective of the study is to investigate whether ciprofibrate treatment can improve myocardial insulin sensitivity in subjects with IGM. As secondary objectives we want to investigate whether ciprofibrate treatment also improves diastolic and myocardial mitochondrial function and decreases intracardiomyocellular lipid content. Futhermore, since ciprofibrate could also affect cardiac metabolism indirectly, we want to investigate the effect of ciprofibrate on skeletal and hepatic glucose uptake, hepatic lipid storage and composition.

Study design: In a randomized, double-blind, cross-over design, the effects of ciprofibrate supplementation on myocardial insulin sensitivity will be compared to placebo in humans with IGM.

Study population: Twelve male, overweight (BMI \> 27 kg/m2), insulin-resistant subjects, aged between 40 and 70 years, without cardiac disease, will participate in this study.

Intervention: Subjects will be asked to take one pill of ciprofibrate 100mg, or placebo, once daily (at dinner), for 35 days.

Main study parameters/endpoints: The main study endpoint is the difference in myocardial insulin sensitivity (measurement of glucose uptake using radio-active labeled 18F-FDG tracer in PET-MRI) after ciprofibrate administration compared to the placebo trial.

Eligibility Criteria:
Inclusion Criteria:

* Race: caucasian
* Sex: male
* Age: 40-70 years
* BMI: 27-35 kg/m2
* Stable dietary habits: no weight gain or loss \> 5kg in the last three months
* Insulin resistant: glucose clearance rate below \< 360 ml/kg/min, as determined using OGIS120

Exclusion Criteria:

* Patients with a cardiac disease or with instable angina
* Patients with hepatic or renal failure
* Haemoglobin \<7.8 mmol/l
* In case of an abnormal ECG in rest: this will be discussed with the responsible medical doctor
* HbA1c \> 6.5%
* Diagnosed with type 1 or type 2 diabetes mellitus
* Patients with alcohol abuse
* Use of a fibrate
* Medication use known to interfere with glucose homeostasis/metabolism
* Use of anti-coagulants, excluding platelet aggregation inhibitors
* Subjects who do not want to be informed about unexpected medical findings during the screening /study, or do not wish that their physician is informed, cannot participate in the study.
* Subjects who intend to donate blood during the intervention or subjects who have donated blood less than three months before the start of the intervention.
* Participation in another biomedical study within 1 month before the first screening visit
* Any condition, disease or abnormal laboratory test result that, in the opinion of the Investigator, would interfere with the study outcome, affect trial participation or put the subject at undue risk
* Any contra-indication to MRI scanning. These contra-indications include patients with following devices:

  * Electronic implants such as pacemakers or defibrillator or neurostimulator
  * Central nervous system aneurysm clip
  * Some hearing aids (such as cochlear implant) and artificial (heart) valves which are contraindicated for MRS
  * Iron containing corpora aliena in the eye or brains
  * Claustrophobia
* Participation in earlier research or medical examinations in the past 3 months that included PET/MRI scanning