Overexpression of malonyl-coenzyme A (CoA) decarboxylase as a novel therapeutic approach to insulin resistance


DailyUpdates 9th March 2004 -

Insulin resistance frequently results from the ingestion of high-fat diets and contributes to the development of serious health problems including diabetes.  In their March Nature Medicine paper Dr Chris Newgard and colleagues from Duke University Medical Center report that hepatic expression of malonyl-CoA decarboxylase reverses insulin resistance offering a new therapeutic approach to this condition.

Obesity and comorbid type 2 diabetes are two frequent and growing global problems. The insulin resistance syndrome was first described in 1988 and contributes to both conditions and indeed is generally accepted to represent a pathophysiological link between the two. It is estimated that this syndrome affects 70 to 80 million Americans and is characterized by a failure of insulin to stimulate glucose utilization and uptake into tissues. Considerable attention has been paid to the development of molecules able to reduce insulin resistance.

In their March Nature Medicine paper Dr Chris Newgard and colleagues from Duke University Medical Center show that, in rats fed a high-fat diet, whole-animal, muscle and liver insulin resistance is ameliorated following hepatic overexpression of malonyl-coenzyme A (CoA) decarboxylase (MCD), an enzyme that catalyzes the conversion of malonyl-CoA to acetyl-CoA and carbon dioxide and which is thought to be involved in aspects of lipid biosynthesis, oxidation and partitioning.

Mechanistic studies revealed that MCD overexpression decreased circulating free fatty acid and liver triglyceride content. In skeletal muscle, levels of triglyceride and long-chain acyl-CoA (LC-CoA)-two candidate mediators of insulin resistance were either increased or unchanged. Instead, metabolic profiling revealed a unique decrease in the concentration of one lipid-derived metabolite, beta-OH-butyrate, in muscle of MCD-overexpressing animals.

he authors suggest that hepatic expression of MCD lowered circulating FFA levels, which led to lowering of muscle beta-OH-butyrate levels and improvement of insulin sensitivity.  This important data suggests therefore that gene therapy approaches to the overexpression of MCD or indeed small molecule inhibition of enzymes involved in the production of muscle beta-OH-butyrate may represent novel approaches to the treatment of insulin resistance.

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