Carnitine palmitoyltransferase: a viable target for the treatment of NIDDM?
Inhibition of fatty acid oxidation is well recognized as a potentially effective mechanism for controlling glycemia in non-insulin-dependent diabetes mellitus (NIDDM). However, a direct targeting of inhibition of the intramitochondrial beta-oxidation pathway or an indirect modulation of fatty acid oxidation by inhibition of substrate release from adipose stores has been fraught with lack of efficacy, unacceptable side-effects or both. Focus has therefore recently been directed towards the carnitine palmitoyltransferase (CPT) system, a three-component system necessary for the transfer of long-chain fatty acids into the intramitochondrial matrix. This article will briefly review the background for fatty acid oxidation inhibition in NIDDM and then focus on the progress in the biological understanding and drug discovery targeting of the CPT system for the treatment of NIDDM. Based upon the review, it is concluded that mechanism-based hepatic and myocardial toxicities in normal animals and a potential for a lack of human efficacy may pose insurmountable hurdles for the development of CPT inhibitors for the treatment of NIDDM.
Anderson
R C
RC
Novartis Pharmaceuticals Corporation, Department of Metabolic and Cardiovascular Diseases, Summit, NJ 07901, USA.
D000818:Animals; D002333:Carnitine Acyltransferases / Q000037:antagonists & inhibitors; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D008316:Malonyl Coenzyme A / Q000037:antagonists & inhibitors; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction
D004791:Enzyme Inhibitors; D005227:Fatty Acids; D008316:Malonyl Coenzyme A; D002333:Carnitine Acyltransferases; D002334:Carnitine O-Palmitoyltransferase