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. 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 the hypothesis that metabolic inflexibility in pre-diabetic subjects
and diabetic patients is due to a reduced capacity to form acetylcarnitines: We
aim to investigate whether glucose intolerant subjects have a lower capacity to
form acetyl-carnitine than matched, glucose tolerant subjects. Furthermore, the
effect of carnitine supplementation will be investigated.

Subjects with impaired glucose tolerance will be included in this study and
will be compared to age-, BMI- and sex- matched glucose tolerant subjects with
respect to insulin sensitivity, metabolic flexibility and the capacity for
acetyl-carninitine formation. The subjects with impaired glucose tolerance will
follow a placebo controlled carnitine intervention during 36 days and the
effect of carnitine supplementation will be evaluated.

carnitine/placebo supplementation with 2g carnitine per day (three times daily;
1 capsule of 500mg at breakfast, 1 capsul of 500mg at lunch, 2 capsules of
500mg at diner)

Subjects will come to the university for a screening visit and (in case of
participation) three times for the study measurements at baseline (in the case
of normal glucose tolerant subjects) and at the end of each of the two
interventional periods (in the case of subjects with impaired glucose
tolerance). Therefore, normal glucose tolerant subjects that are included come
in total five times to the MUMC: twice for the screening visit and three times
for the three test days. Subjects with impaired glucose tolerance will report
to the MUMC ten times in total (twice for the screening, twice for a fasted
blood draw at the start of each intervention periode, 8 times for the weekly
blood draw (4 times every intervention period), and 2x3 times for the three
test days after two interventional periods). Blood will be taken repeatedly
(maximally 410 ml) and two muscle biopsies will be taken.
No increased health risk, no direct benefit for the individual subject.