Preservation of metabolic flexibility by acetylcarnitine formation

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. We propose to test the hypothesis that metabolic inflexibility in pre-diabetic subjects and diabetic patients is due to a reduced capacity to form acetylcarnitines. To test this hypothesis we will use a novel non-invasive 1H-Magnetic Resonance Spectroscopy (1H-MRS) protocol to determine in vivo, and in time, the formation of acetylcarnitine in skeletal muscle and do so in healthy subject and in prediabetic subjects. Additionally, we will examine whether carnitine supplementation improves the capacity to form acetylcarnitine and improves metabolic flexibility. This might explain the documented positive effects of carnitine supplementation on glucose tolerance. Using the novel non-invasive MRS based tool, this project will provide important information on the role of acetylcarnitine formation in muscle in the etiology of diabetes and reveal if carnitine supplementation can alleviate metabolic inflexibility.

This project is financed by a grant from the European Foundation for the Study of Diabetes (EFSD)
PhD student: Yvonne Bruls