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.

Determination of the turnover rates of glucose gives a more dynamic view of carbohydrate metabolism. Using 2H- or 13C-labelled glucose, stable isotope methods have been established which are free of risk for volunteers or patients and are in accordance with the legal requirements for radiation protection. The aim of the present study was to determine the main parameters of glucose turnover in vivo by using two stable-isotope-labelled glucose molecules, [6,6-2H]glucose and [U-13C]glucose. Under steady state conditions, the following parameters were analysed: glucose turnover rate, glucose oxidation rate, recycling of glucose, hepatic glucose production rate, and glucose clearance. In healthy volunteers the following data were obtained for the glucose turnover rate: 2.42 +/- 0.11 mg/kg x min, glucose oxidation rate 1.34 +/- 0.08 mg/kg x min, glucose clearance 3.04 +/- 0.17 ml/kg x min, and glucose recycling 24.7% (about 0.6 mg/kg x min). Under conditions of the euglycaemic-hyperinsulinaemic clamp (insulin levels about 80 mU/l) the glucose turnover rate increased to 9-10 mg/kg x min, and the hepatic glucose production rate was totally suppressed. Under these conditions identical glucose turnover rates were measured by rate of appearance Ra and euglycaemic-hyperinsulinaemic clamp. These data clearly demonstrate that by using differentially labelled glucose molecules at least five parameters of glucose metabolism may be determined in vivo. High insulin levels (70-80 mU/l) stimulate glucose turnover rate by 300-400%, and the glucose infusion rate agrees well with the rate of appearance (Ra) of glucose, determined with [6,6-2H]glucose. Thus, this glucose tracer provides relevant and presumably accurate data under basal and under hyperinsulinaemic conditions.