INHIBITION BY ETOMOXIR OF CARNITINE PALMITOYLTRANSFERASE-I REDUCES HEPATIC GLUCOSE-PRODUCTION AND PLASMA-LIPIDS IN NONINSULIN-DEPENDENT DIABETES-MELLITUS

To detemine the therapeutic effect of the carinitine palmitoyltransferase I (CPT-I) inhibitor, etomoxir, eight hospitalized obese non-insulin-dependent diabetes mellitus (NIDDM) patients were studied (body mass index [BMI], 28.7 ± 1.3 kg/m2; age, 54 ± 8 years [means ± SE]) at baseline (placebo = t1), and after oral etomoxir (50 mg/d = t2, 100 mg = 3, 150 mg = t4, 200 mg = t5, placebo = t6). Fasting blood glucose (mmol/L), triglycerides (mmol/L), cholesterol (mmol/L), free fatty acids (μmol/L), β-hydroxybutyrate (μmol/L), and alanine aminotransferase (GPT, U/L) were determined (t1 to t6), as were glucose utilization (M value; indirect calorimetry) and hepatic glucose production during a 10 mU/kg · min euglycemic clamp (t1 and t4). A dose-dependent decrease was induced by etomoxir in fasting blood glucose (t1 to t5: 9.5 ± 0.7, 8.7 ± 1.0, 8.3 ± 1.1, [P v t1 < .05], 7.8 ± 0.9, [P v t1 < .01], 7.9 ± 1.1 [P v t1 < .05]), which was reversible in t6 (9.9 ± 1.1). Mean plasma lipids were reduced (t1 v t5) for triglycerides (-54%, P v t1 < .01), cholesterol (-24%, P v t1 < .05), and β-hydroxybutyrate (-44%, P v t2 < .01), while free fatty acids increased by 52% (P v t1 < .05), as did GPT (t1: 17 ± 3; t5: 32 ± 7 U/L [P v t 1 < .01]). In parallel, hepatic glucose production (mg/min · m2) decreased ( t1 t4: 88 ± 7 73 ± 8 [P v t1 < .05]), whereas M values, ( 263 ± 27 268 ± 29 mg/min · m2), carbohydrate oxidation ( 90 ± 8 74 ± 9 mg/min · m2), and fat oxidation ( 21 ± 7 28 ± 6 mg/min · m2) remained unchanged during the 10-mU/kg · min euglycemic clamp. It is concluded that etomoxir reduces hepatic glucose production, fasting blood glucose, and lipidemia-triglycerides, cholesterol, and β-hydroxybutyrate included-without affecting glucose utilization (M value) during a hyperinsulinemic euglycemic clamp. Such a pharmacologic profile might be helpful in treating hyperlipidemic NIDDM. © 1991.