Vascular find opens opportunity for different diabetes treatment

A new study shows a cellular connection between diabetes and blood vessel narrowing that boosts one's risk of chronic and potentially fatal health conditions, including stroke and heart disease.


A team of researchers at the University of California has found a link between diabetes and vascular disease, one of its major complications.


The researchers hope that the findings of the study can help formulate new treatments for diabetes, beyond just controlling and monitoring blood glucose levels. The cellular level connection may help new treatments target the molecular source of high blood glucose's damaging effects on the blood vessels.


In the past, the team conducted a similar study, analyzing hyperglycemia or high blood glucose and how it triggers an enzyme known as protein kinase A (PKA), which in turn, boosts calcium channel action, resulting in blood vessel constriction.


"This was a surprise since PKA is typically associated with blood vessel widening and wasn't really on our radar. We wanted to understand the molecular processes that created this opposite reaction," Manuel Navedo, Professor of Pharmacology at UC Davis Health, said.


But the mechanism by which glucose activates PKA remains unclear, the researchers noted. In the study published in The Journal of Clinical Investigation, they showed that elevating extracellular glucose triggers cyclic adenosine monophosphate (cAMP), the second messenger that's vital for biological processes with a critical role in vascular cell function and production in arterial myocytes, which was particularly dependent on adenylyl cyclase 5 (AC5) activity.


The team performed experiments on the impact of elevated glucose on arterial cells and cerebral blood vessels, which control and maintain blood flow in the vessels. The researchers tested these on laboratory mice, two mouse models of diabetes and a genetically modified mouse.


Specifically, they focused on the connection between PKA and adenylyl cyclase (AC), an enzyme involved in cyclic AMP (cAMP) production. They found that AC5 facilitated cAMP and PKA activation, stimulating increased calcium channel activity and subsequent blood vessel vasoconstriction. Also, they discovered that AC5 was crucial for blood vessel vasoconstriction during diabetes.


Vascular complications during diabetes are the main risk factors for cardiovascular illnesses, such as hypertension, heart disease, and stroke. These complications are often associated with increased blood glucose levels or hyperglycaemia.


The team anticipates doing further tests on the impact of the AC5 chain reaction in humans. The study may pave the way for new treatment approaches that target the reduction of vascular complications of diabetes.


The study on vascular effects of elevated blood glucose levels at the cellular level could open the doors for new treatment modalities to combat diabetes and cardiovascular diseases.


Journal reference:

Syed, A., Reddy, G., Ghosh, D., Prada, M. P., Nystoriak, M., Morotti, S., Grandi, E., Sirish, P., Chaimvimonvat, N., Hell, J., Santana, L., Xiang, Y., Nieves-Cintron, M., and Navedo, M. (2019). Adenylyl cyclase 5-generated cAMP controls cerebral vascular reactivity during diabetic hyperglycemia. The Journal of Clinical Investigation.

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