Carnitine supplementation improves metabolic flexibility and skeletal muscle acetylcarnitine formation in volunteers with impaired glucose tolerance: A randomised controlled trial

Abstract

Background: Type 2 diabetes patients and individuals at risk of developing diabetes are characterized by metabolic inflexibility and disturbed glucose homeostasis. Low carnitine availability may contribute to metabolic inflexibility and impaired glucose tolerance. Here, we investigated whether carnitine supplementation improves metabolic flexibility and insulin sensitivity in impaired glucose tolerant (IGT) volunteers. Methods: Eleven IGT-volunteers followed a 36-day placebo-and L -carnitine treatment (2 g/day) in a randomised, placebo-controlled, double blind crossover design. A hyperinsulinemic-euglycemic clamp (40 mU/m 2 /min), combined with indirect calorimetry (ventilated hood) was performed to determine insulin sensitivity and metabolic flexibility. Furthermore, metabolic flexibility was assessed in response to a highenergy meal. Skeletal muscle acetylcarnitine concentrations were measured in vivo using long echo time proton magnetic resonance spectroscopy ( 1 H-MRS, TE = 500 ms) in the resting state (7:00AM and 5:00PM) and after a 30-min cycling exercise. Twelve normal glucose tolerant (NGT) volunteers were included without any intervention as control group. Results: Metabolic flexibility of IGT-subjects completely restored towards NGT control values upon carnitine supplementation, measured during a hyperinsulinemic-euglycemic clamp and meal test. In muscle, carnitine supplementation enhanced the increase in resting acetylcarnitine concentrations over the day (delta 7:00 AM versus 5:00 PM) in IGT-subjects. Furthermore, carnitine supplementation increased postexercise acetylcarnitine concentrations and reduced long-chain acylcarnitine species in IGT-subjects, suggesting the stimulation of a more complete fat oxidation in muscle. Whole-body insulin sensitivity was not affected. Conclusion: Carnitine supplementation improves acetylcarnitine formation and rescues metabolic flexibility in IGT-subjects. Future research should investigate the potential of carnitine in prevention/treatment of type 2 diabetes.

Pathophysiological role of metabolic flexibility on metabolic health

“…Taken together, the effect of healthy diets on MetF appears partially dependent on the fasting oxidative response (i.e., fasting RQ). A 36‐day L‐carnitine supplementation in individuals with glucose intolerance did a similar observation 104 …”

L-Carnitine and Acylcarnitines: Mitochondrial Biomarkers for Precision Medicine

“…Since LC is much higher in abundance relative to the ACs, an AC/LC ratio in the blood exceeding 0.4 is thought to represent disturbed mitochondrial metabolism [ 7 ]. Additionally, ratios of ACs and other metabolites, such as free fatty acids, have also been used to assess different metabolic pathways [ 20 , 21 , 22 , 23 ].…”

“…Blood concentrations of C2 reflect intracellular levels and the regulation of acetyl-CoA and free CoA via carnitine acetyl-CoA transferase [ 7 , 24 ]. Increased production of C2 represents a critical mechanism for buffering the metabolic status between fed (glucose oxidation) and fasted (fat oxidation) states, referred to as metabolic flexibility [ 23 , 25 ]. Acetyl-CoA is a known inhibitor of pyruvate dehydrogenase (PDH), a critical enzyme involved in cellular respiration of glucose [ 7 , 26 , 27 ].…”

Metabolomic Profiling After a Meal Shows Greater Changes and Lower Metabolic Flexibility in Cardiometabolic Diseases

“…A separate study found that arachidonoyl-carnitine was associated with greater plasma glucose concentration [ 41 ]. A supplementation study among participants with impaired glucose tolerance showed that 2 g/day of L-carnitine increased acylcarnitine concentrations in skeletal muscle but had no effects on whole-body insulin sensitivity [ 42 ].…”

“…Three dietary supplementation studies have shown that L-carnitine, a natural form found in red meats, improved metabolic flexibility [ 42 , 46 , 47 ]. A randomized, placebo-controlled, double-blind crossover trial showed that L-carnitine supplementation restored metabolic flexibility (evaluated by hyperinsulinemic-euglycemic clamp and high-energy meal challenge) among individuals with impaired glucose tolerance [ 42 ]. Murine studies have also confirmed the links between carnitines and metabolic flexibility [ 48 , 49 ].…”