Carnitine Transporter, Plasma-membrane, Deficiency of Clinical Trial
Official title:
Fat and Carbohydrate Metabolism During Exercise, With and Without L-carnitine Supplementation in Patients With Carnitine Transporter Deficiency
The investigators wish to investigate fat and sugar metabolism during exercise with and
without L-carnitine supplementation in patients with carnitine transporter deficiency (CTD).
Patients with CTD have low plasma- and muscle concentrations of carnitine, which is believed
to lead to an impaired fat oxidation. Presently there is no cure available for these
patients, but daily intake of L-carnitine has been shown to limit the amount of symptoms.
Little is known about the metabolism during exercise and the pathophysiological mechanisms
causing the symptoms.
Studying the fat and sugar metabolism in CTD patients will contribute to the understanding
of the role of the carnitine transporter in the development of symptoms in these patients.
Furthermore, knowledge about the fat and sugar metabolism in these patients can increase the
understanding of the role of the carnitine transporter in the metabolism healthy persons.
The investigators have included 8 patients with genetically verified CTD in the study and a
group of 10 age- and sex-matched controls. Subjects will perform a 1h cycling test,
exercising at a moderate intensity. By measuring the expiration of carbon dioxide (CO2) and
consumption of oxygen (O2), the investigators can determine the total fatty acid and
carbohydrate oxidation during cycling. At the same time the investigators will measure the
patients' whole body palmitate (fat) and glucose (sugar) oxidation rates using stable
isotope technique.
The patient group will repeat the cycling test after 4 days without taking their usual
L-carnitine treatment. During the treatment break, patients will be admitted to be
continuously monitored for heart rhythm disturbances, which is a known but rarely occurring
complication to untreated CTD.
Since the patients have a defect in their fat metabolism, the investigators expect to find
that they have a reduced ability to burn fat, which is the major source of energy during low
intensity exercise. It is therefore likely, that the CTD patients will benefit from
adjustments in their daily diet, whenever they have to perform physically. By learning about
the metabolism of different dietary substances, fat and sugar, these studies can help to
improve the treatment in terms of dietary recommendations for CTD patients. This will have a
direct impact on the daily life of the patients.
8 Patients with verified CTD have been included
- All patients have performed an incremental load exercise test to exhaustion on a cycle
ergometer to determine maximal oxygen comsumption rate (VO2 max)
- One-hour exercise test: Measurement of the total fat and sugar oxidation rates during
exercise using stable isotope tracers.
Subjects arrive at the laboratory after 3-9 hours fasting. One IV-catheter is inserted in
the cubital vein in one arm and another in a peripheral vein in the other hand. The stable
isotope tracers will be given in the cubital vein as a constant infusion of solutions of:
- [U-13C]-palmitate (0.0026 mg x kg-1 x min-1, after a priming bolus of 0.085 mg x kg-1
NaH13CO3)
- [1,1,2,3,3-2H5]-glycerol (0.0049 mg x kg-1 x min-1 )
- [6.6-2H2]-glucose (0.0728 mg x kg-1 x min-1 ) 5 days before the study, subjects must
avoid eating food containing corn. Corn contains larger amounts of C13, which we use as
a tracer, and can therefore disturb the measurements.
For two hours the subjects rest while receiving the infusions until the tracers have
distributed in the body and reached a steady state. After the rest, the subjects exercise on
the cycle-ergometer until exhaustion or for a maximum of 1 hour at an intensity that
corresponds to 60-70% of VO2max.
Every other minute during exercise, the heart rate is recorded and the subject evaluates
his/her degree of exertion (Rate of Perceived Exertion, RPE) on a Borg scale.
Blood and breath samples:
From 20 minutes before exercise until the end of exercise, blood samples are drawn through
the IV-catheter in the hand vein (10-12 mL per sample) and samples of the expired breath are
collected in a Douglas bag (Hans Rudolph inc.) every ten minutes. The breath is transferred
into Vaccutainer-glas for analysis of 13CO2 -enrichment (10 mL). The plasma samples are
anayzed for concentrations of hormones, metabolites, carnitine and acyl-carnitines.
Muscle biopsy:
On this day a muscle biopsy is taken from the vastus lateralis of the thigh to measure the
intramuscular concentrations of carnitine and acylcarnitines.
- Wash-out period: For 4 days patients were admitted for telemetric cardiac monitoring
while they pause their daily oral L-carnitine treatment.
- After the washout period, patients repeat the one-hour exercise test with the stable
isotope tracers. Also the muscle biopsy for intramuscular carnitine and acyl-carnitine
concentrations are repeated-
TRACERS In this study we will use infusions of stable isotopes incorporated into metabolites
as tracers of whole body metabolism. We will use small amounts of fat (palmitate and
glycerol) and sugar (glucose) labelled with stable isotopes of carbon (13C) and hydrogen
(2H). The palmitate and glycerol tracers (98 % enriched, Cambrigde Isotope Laboratories,
Andover, MA, USA) will be dissolved in sterile water and infused through a bacterial filter
into human serum albumin. The glucose tracer (99 % enriched, Cambrigde Isotope Laboratories,
Andover, MA, USA) will be dissolved and injected into a solution of 0.9% saline (NaCl)
through a bacterial filter as well.
These tracers are naturally occurring in food (e.g. in corn) and in the human body. They are
harmless and will be handled and given to the subjects under sterile conditions.
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Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment