Insulin resistant subjects and type 2 diabetic patients are characterized by a decreased
metabolic flexibility: a reduced capability to switch from fat oxidation in the basal state
to carbohydrate oxidation in the insulin-stimulated state. This metabolic inflexibility is an
early hallmark in the development of diabetes. Recent evidence suggests that a low carnitine
availability may limit acetylcarnitine formation, thereby reducing metabolic flexibility.
Thus, when substrate flux in the muscle is high, acetyl-CoA concentrations increase, leading
to inhibition of pyruvate dehydrogenase (PDH) and thereby reducing glucose oxidation. The
conversion of acetyl-CoA to acetylcarnitine relieves this acetyl-CoA pressure on PDH. To
provide more direct insight into the effect of carnitine in preventing metabolic
inflexibility and insulin resistance and to further explore the mechanism of action is the
focus of this research. Here, we hypothesize that the capacity to form acetylcarnitine may
rescue lipid-induced insulin resistance. To this end, insulin resistance will be induced by
lipid infusion in healthy volunteers and it will be tested whether carnitine co-infusion can
alleviate insulin resistance.