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DRC Director's Report - March 2022

Recently the International Journal of Science featured important research by a member of the FOEDRC, Ayotunde Dokun, MD, PhD, Director of the Division of Endocrinology and Metabolism and his team. Peripheral arterial disease is the narrowing or blockage of the vessels that supply blood to lower extremities. This disease affects millions of individuals with diabetes and is considered a major complication of diabetes which often lead to limb amputation.

How diabetes contributes to the increased risk of limb amputation in individuals with peripheral arterial disease is poorly understood. We know that peripheral arterial disease complications are different in people with type 1 versus type 2 diabetes. 

Therefore, it is very likely that these two forms of diabetes affect worsening of peripheral arterial disease through different processes. We know that a protein called disintegrin and metalloproteinase gene 12 (ADAM12) is expressed at high levels in cells lining the blood vessels where there is poor blood flow. 

ADAM12 plays a key role in the ability to restore blood flow to limbs when there is blockage of blood vessels. Much less is known about how ADAM12 expression is increased or regulated in areas of poor blood flow. In our previous work, we showed that under normal conditions where there is no diabetes the levels of a small ribonucleic acid (RNA) called miR-29a must go down for ADAM12 expression to go up which then helps restore blood flow when there is blockage of blood vessel. 

In our most recent study, we found that following blockage of blood flow in type 2 diabetic limbs miR-29a levels does not go down which prevents increased expression of ADAM12 leading to poor blood flow recovery. We also found that treatment of mice with type 2 diabetes with an inhibitor of miR-29a improved ADAM12 expression and resulted in improved blood flow recovery, reduced skeletal muscle injury and improved muscle function. 

Importantly, we showed similar improvements if we augment ADAM12 expression directly by gene transfer. Therefore, our result has identified a way to possibly improve blood flow to limbs in type 2 diabetes by treating with inhibitors of miR-29a or by augmentation of ADAM12 expression.

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