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Overexpression of
malonyl-coenzyme A (CoA) decarboxylase as a novel therapeutic approach
to insulin resistance
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.
(source DailyUpdates 9th
March; for a full abstract of the original paper see Nat
Med. 2004 Feb 8 [Epub ahead of print])
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highlights the suppression of endothelial cell
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