We studied the influence of Etomoxir on fat and carbohydrate oxidation, and the influence
of these changes on insulin sensitivity in type 2 diabetic patients. Etomoxir is an
oxirane carboxylic acid derivative that specifically inactivates carnitine-acyltransferase
I (CAT I, EC: 2.3.1.21), the key enzyme for the transport of long-chain acyl-CoA compounds
into the mitochondria. Thus, oxidation of fatty acids should be reduced by this drug
and glucose utilisation be increased according to the Randle mechanism. In order to
test this hypothesis, we measured oxidative and non-oxidative glucose utilisation
using the euglycaemic hyperinsulinaemic clamp technique, the isotope dilution mass
spectrometry (IDMS) method with stable isotopes (6,6-D2-glucose) and indirect calorimetry. The clamps lasted 5 hours, indirect calorimetry
was performed during the last hour and calculations of glucose disposal were based
on steady state conditions during the last 30 minutes. Twelve type 2 diabetic patients
were treated with 100 mg etomoxir/per day for 3 days in this placebo-controlled, randomized,
double-blind study. Treatment resulted in a significant increase in carbohydrate oxidation
(from 72 to 113 g/24 h, p = 0.039), decrease in fat oxidation (from 139 to 114 g/24
h, p = 0.037), and decrease of the glucose appearance rate (RA) in the basal state
(from 1.85 to 1,70 mg/kg min., p = 0.014). During the euglycaemic clamp neither RA
(3.30 and 3.20 mg/kg min., p = 0.471) nor the glucose infusion rate (4.28 and 4.53
mg/kg min., p = 0.125) showed significant changes. In addition, no significant changes
in glucose and fat oxidation were detected during the hyperinsulinaemic clamp. Under
basal conditions non-oxidative glucose utilisation was decreased by etomoxir (1.26
and 0.80 mg/kg × min). Thus, we could demonstrate a decrease in fat and increase in
glucose oxidation by etomoxir, but non-oxidative glucose utilisation was decreased,
No significant changes could be demonstrated under clamp conditions.
Key words
Carnitine-acyltransferase - Etomoxir - Insulin resistance - Cori-cycle
