Understanding the impact of type 1 diabetes and statin use on vascular cells
Lead Research Organisation:
Imperial College London
Department Name: National Heart and Lung Institute
Abstract
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.
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.
Technical Summary
Diabetes is a serious metabolic disease that reduces life expectancy by increasing cardiovascular events. These mechanisms are incompletely understood but include endothelial and smooth muscle cell dysfunction in vivo in young and elderly people with diabetes. Statins, which lower cholesterol, have revolutionised the preventative treatment for cardiovascular disease and have beneficial pleiotropic effects including improved endothelial dysfunction and anti-inflammatory effects. In 2014, NICE recommended offering statin treatment in all type 1 diabetic (T1D) adults over 40 years or for all type 2 diabetic (T2D) adults with increased risk of cardiovascular disease. However, the risk benefit of statin therapy in diabetes has been questioned since all clinical evidence supporting statin use in people with T1D is inferred from large randomised controlled trials on participants with T2D and so not all patients are happy to comply. My overall aim is therefore to understand how statins affect vascular biomarkers and cellular function in T1D which is critical for translation. With the help of an outstanding group of basic and clinical researchers, I aim to address how statins effect vascular endothelial and smooth muscle cells grown either non-invasively from blood or from the coronary artery of people that are healthy or have T1D. This includes testing their response to inflammation and shear stress and investigating the mechanism by which statins may exert their effects. Using RNA Seq and proteomics I will compare potential target genes/ biomarkers altered by statin/non-statin use in people with T1D. Should this work show statins cause protective anti-inflammatory effects in T1D then this will revolutionise the future use of statins for the treatment of many diseases and provide opportunities for personalised medicine. Ultimately it may provide fact-based data to encourage diabetic patients to take a statin and reduce burden to healthcare.
