Effects of the Carnitine-acyltransferase Inhibitor Etomoxir on Insulin Sensitivity, Energy Expenditure and Substrate Oxidation in NIDDM

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