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.