Understanding the impact of type 1 diabetes and statin use on vascular cells

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Diabetes is a disease where sugar (glucose) levels cannot be controlled properly because the pancreas, which makes the cells that produce glucose, does not work. People with diabetes have serious complications effecting the heart and blood vessels (cardiovascular system) resulting in a poor quality of life and shorter life expectancy compared to people that are healthy or do not have diabetes. There are 537 million people worldwide that have diabetes so understanding why cardiovascular complications occur and how we can prevent these complications is not only important to patients and caregivers, but also to society and healthcare. To prevent cardiovascular complications, in 2014, NICE recommended that adults with diabetes take statins, a class of drugs that reduce the level of bad cholesterol/ lipids. This recommendation was based on extensive clinical study data looking at statin use mainly in people with type 2 diabetes (T2D) not type 1 diabetes (T1D). This is important because T2D is a very different disease to T1D. T2D, which makes up approximately 90% of cases, is influenced by age, diet and lifestyle factors and has been shown to improve/ reverse with weight loss. T1D, which makes up approximately 8% of cases, can develop at a young age (childhood), requires life-long treatment with injections and cannot be prevented or reversed to a point where medication is no longer needed. Importantly, the lipid profile is different between T1D and T2D; people with T1D have higher levels of lipids that are protective to the cardiovascular system whereas people with T2D have higher levels of 'bad' cholesterol. For people with T1D, the lack of clinical evidence has resulted in worry about statin-use to the point where they are refusing to start statin therapy. Similarly, for clinicians, this lack of evidence has made it difficult to decide if and when to start their patients on a statin.This project aims to use cells that can be grown non-invasively from blood, and provide a 'window into the vasculature', to further understand how T1D and statin use effects the vasculature. I have shown that in control (healthy) donors statins reduce inflammatory responses of endothelial cells (cells that make up blood vessels) grown from blood (called blood outgrowth endothelial cells; BOECs) in response to infection. I will now expand on this work to look at BOECs and coronary artery endothelial and smooth muscle cells (cells that also make up blood vessels) grown from people with T1D. Firstly, I will test how BOECs and coronary artery cells grown from controls respond to inflammation when a statin is added. I will look specifically at how statins effect the ability of the cells to do their job, such as; (i) how fast these cells grow within a certain time, (ii) how quickly they move from one area to another, (iii) the things they release when drugs are added to them and (iv) how 'sticky' they are. Secondly, I will repeat these experiments in cells plated in static conditions and under directional flow to mimic the flow of blood in the body. Thirdly, I will run a small clinical study where I will compare head-to-head the responses above from people with T1D that are either on statin therapy or not on statin therapy. Finally in order to better understand if and how certain genes/ proteins change in T1D, how statin use effects this expression and ultimately identify potential biomarkers, I will use techniques called RNA Sequencing and O-link. This will allow me to confirm how statins effect BOECs in T1D.Overall, the findings from this project impacts people with not only T1D but also T2D and other diseases where statins have been shown to be beneficial such as cancer and infection. The use of BOECs for research in T1D provides opportunities for personalised medicine and fast and effective drug screening and reduces the need for animals in research.