Rationale: 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. In humans, carnitine supplementation is sometimes also beneficial, but not in everyone. Here we aim to test whether carnitine improves insulin sensitivity, furthermore, whether acetylcarnitine concentration at baseline or other characteristics are associated with the response (in insulin sensitivity) to carnitine supplementation. Furthermore, we will examine the potentially positive effect of carnitine supplementation in type 2 diabetes patients on intrahepatic lipid content, acetylcarnitine formation, blood plasma metabolites, body composition, physical performance and quality of life Objective: The primary objective is to investigate whether carnitine improves insulin sensitivity, furthermore, whether acetylcarnitine concentration at baseline or other characteristics are associated with the response (in insulin sensitivity) to carnitine supplementation. Furthermore, we will examine the potentially positive effect of carnitine supplementation in type 2 diabetes patients on intrahepatic lipid content, acetylcarnitine formation, blood plasma metabolites, body composition, physical performance and quality of life Study design: The current study is an interventional design with one study arm. Subjects will not be blinded for the intervention since all subjects will receive oral carnitine supplementation.~Study population: n=32, patient with type 2 diabetes (BMI 25-38, age 40-75 years) male and female will be included. Only subjects with relatively well-controlled non-insulin depended diabetes will be included.~Intervention (if applicable): Participants will be asked to take three chewing tablets of L-carnitine (330mg), three times a day (breakfast, lunch and dinner), for 96 days.~Main study parameters/endpoints: The primary study endpoints are insulin sensitivity and metabolic flexibility, measured by the hyperinsulinemic-euglycemic clamp. Secondary endpoints are maximal acetylcarnitine concentrations after exercise, Intrahepatic lipid content, body composition, metabolites in the blood before (i.e. glucose, free fatty acids, triglycerides, cholesterol, insulin), functional markers of physical performance, cognition, quality of life and quality of sleep.
the results from animal studies and preliminary human studies show that carnitine availability and acetylcarnitine concentrations are low in insulin resistant states such as with type 2 diabetes mellitus. However, in humans, carnitine supplementation is sometimes beneficial, but not in everyone. We hypothesize that this variability in response might be due to differences between individuals in the amount of carnitine in the muscle i.e. subjects with a low initial carnitine status will benefit more from supplementation. The state of the art non-invasive magnetic resonance spectroscopy method allows us to identify patients muscle acetylcarnitine status. Here we aim to test whether carnitine improves insulin sensitivity, furthermore, whether acetylcarnitine concentration at baseline or other characteristics are associated with the response (in insulin sensitivity) to carnitine supplementation. Furthermore, we will examine the potentially positive effect of carnitine supplementation in type 2 diabetes patients on intrahepatic lipid content, acetylcarnitine formation, blood plasma metabolites, body composition, physical performance and quality of life