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.
The 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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