Carnitine supplementation as a therapy to improve insulin sensitivity in Type 2 diabetic patients with low carnitine status

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 the hypothesis that carnitine
supplementation in type 2 diabetic patients with initially low carnitine status
enhances metabolic flexibility and insulin sensitivity to a greater extent than
in subjects with an initially high carnitine status. Our novel non-invasive
MRI-based method to determine acetylcarnitine in muscle provides the
opportunity for a priori identification of patients with low acetylcarnitine
status in muscle.

The primary objectives are to investigate which determinants (primarily
carnitine status) determine the effect of carnitine supplementation on
metabolic flexibility and insulin sensitivity in patients with type 2 diabetes.
Furthermore, a secondary objective is to examine the molecular pathways of
carnitine and acetylcarnitine, responsible for muscle insulin sensitivity and
metabolic flexibility as well as the effects of carnitine supplementation in
patients with type 2 diabetes with an initially low carnitine status on
intrahepatic lipid content, acetylcarnitine formation, blood plasma
metabolites, body composition, physical performance and quality of life.

The current study is an intervention study. Subjects will not be blinded for
the intervention since all subjects will receive oral carnitine supplementation

Participants will be asked to take three chewing tablets of L-carnitine
(330mg), three times a day (breakfast, lunch and dinner), for 96 days.

Subjects will first visit the University once for screening purposes during
which length, weight and blood pressure will be measured. An ECG will be
performed, blood will be drawn and they will fill in 2 questionnaires. If
screening was successfully completed, subjects will enter the study and visit
the university for a maximal cycling test (visit 1: 30 minutes). All subjects
assigned to the study willl undergo baseline measurements and subsequently
receive oral carnitine supplementation for a period of 96 days including 3
measurement days in the last week of the supplementation period. Baseline and
post supplementation measurements are identical and include 1H-MRS for
acetylcarnitine determination, questionnaires, physical performance testing and
body composition measurements. Insulin sensitivity and metabolic flexibility
will be determined via a 2-step hyperinsulinemic euglycemic clamp. Before the
clamp intrahepatic lipid content will be determined. Furthermore, at the
beginning and end of the clamp, a muscle biopsy will be obtained. For these
visits, subjects have to report to the university in the morning in the fasted
state. The evenings prior to these three test days, subjects have to eat a
standardize meal (macaroni bolognaise). Muscle biopsies lead to mild discomfort
and there is a risk of hematoma. During the hyperinsulinemic euglycemic clamp,
a risk of hypoglycaemia exists. In summary, we will draw approximately 392ml
blood during the entire study period. During each of the three intervention
trial we draw a maximum of 169 ml blood.