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 x 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.