Year of grant:
Nýtslan av fitisýrum og umsetningurin av karnitini í vøddakyknum hjá sjúklingum við CTD.
Københavns Universitet og Landssjúkrahúsið
Steen Larsen, Allan Meldgaard Lund, Flemming Wibrand, Jan Rasmussen, Jákup Andreas Thomsen og Magni Mohr
Grant from the FRC in DKK:
For several decades multiple cases of sudden death in young Faroese individuals with untreated carnitine transporter deficiency (CTD) have been reported. CTD is a disorder influencing fatty acid β- oxidation by a lack of the carnitine transporter(OCTN2). Skeletal muscle and cardiac muscle utilize fatty .acids as an energy source and low body carnitine levels in these tissues can lead to skeletal muscle myopathy and lethal cardiac arrhythmia. Most CTD patients are being treated with L-Carnitine,however preliminary unpublished data shows that skeletal muscle carnitine concentration of Faroese treated CTD patents is 20 fold lower than normal and this raises the question if the β-oxidation in CTD patients might be impaired even though they are being treated. The regulation of OCTN2 is not fully understood, however hyperinsulinaemia has been associated with increased muscle carnitine content in healthy humans. Human experiments CTD patients with the severe genotype N32S/N32S (n=10), CTD patients with N32S/haplotype (n=10) and healthy control subjects (n=10) will be recruited. The subjects/patients will come to the laboratory on two occasions. The patients/controls will come to the laboratory on two occasions. On the first occasion they will have their health examined. The second visit to the laboratory will be divided into 3 sub studies: STUDY 1: Mitochondrial and metabolic alterations in CTD skeletal muscle Analysis will be done on the muscle in order to answer the following key questions: 1) Is mitochondrial function impaired in CTD skeletal muscle? 2) If so, do the levels of muscle Carnitine inversely correlate to the degree of mitochondrial dysfunction? 3) What is the effect of carnitine deficiency on the metabolic state of skeletal muscle fibers? STUDY 2: Regulation of skeletal muscle carnitine uptake by insulin and, effect of co-administration of insulin and Carnitine on skeletal muscle carnitine levels. The results generated by this study will give us insight on the regulation of OCTN2 and potential alterations found in CTD skeletal muscle. Furthermore, the hypothesis that the insulin-induced upregulation of carnitine transport into skeletal muscle could be explained by OCTN2 intracellular redistribution will be tested. Furthermore, the results will show if the effect of insulin on skeletal muscle carnitine uptake is mediated by OCTN2 and if so, if it is impaired in CTD patients. These results are needed in order to potentially use insulin to enhance the effect of Carnitine supplementation on CTD patients. STUDY 3: Insulin induced enhancement of carnitine uptake in skin fibroblasts In this study analysis will be done on skin biopsies. By culturing fibroblasts from the subjects: 1) The carnitine transport over the plasmalemma can be measured. This will allow for the investigation of the effect that insulin has on carnitine uptake in fibroblasts from CTD patients and healthy controls. 2) The intracellular OCTN2 distribution and potential re-distribution in response to insulin and/or carnitine will be measured. The results generated by this study will give insight on the insulin induced regulation of OCTN2 and a potential deviation found in CTD fibroblasts