Inhibition by etomoxir of carnitine palmitoyltransferase I reduces hepatic glucose production and plasma lipids in non-insulin-dependent diabetes mellitus.
To determine 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 (mumol/L), beta-hydroxybutyrate (mumol/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 less than .05], 7.8 +/- 0.9, [P v t1 less than .01], 7.9 +/- 1.1 [P v t1 less than .05]), which was reversible in t6 (9.9 +/- 1.1). Mean plasma lipids were reduced (t1 v t5) for triglycerides (-54%, P v t1 less than .01), cholesterol (-24%, P v t1 less than .05), and beta-hydroxybutyrate (-44%, P v t2 less than .01), while free fatty acids increased by 52% (P v t1 less than .05), as did GPT (t1: 17 +/- 3; t5: 32 +/- 7 U/L [P v t1 less than .01]).(ABSTRACT TRUNCATED AT 250 WORDS)
Medizinische Universitätsklinik, Wien, Austria.
K
K
Ratheiser
B
B
Schneeweiss
W
W
Waldhäusl
P
P
Fasching
A
A
Korn
P
P
Nowotny
M
M
Rohac
H P
HP
Wolf
D020155:3-Hydroxybutyric Acid; D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors*; D002784:Cholesterol / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005947:Glucose / Q000096:biosynthesis*; D015309:Glucose Clamp Technique; D006801:Humans; D006885:Hydroxybutyrates / Q000097:blood; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007773:Lactates / Q000097:blood; D019344:Lactic Acid; D008055:Lipids / Q000097:blood*; D008099:Liver / Q000378:metabolism*; D008875:Middle Aged; D014280:Triglycerides / Q000097:blood
D004852:Epoxy Compounds; D005230:Fatty Acids, Nonesterified; D006885:Hydroxybutyrates; D007004:Hypoglycemic Agents; D007773:Lactates; D008055:Lipids; D014280:Triglycerides; D019344:Lactic Acid; D002784:Cholesterol; D002334:Carnitine O-Palmitoyltransferase; D000410:Alanine Transaminase; D005947:Glucose; C054207:etomoxir; D020155:3-Hydroxybutyric Acid