At the Jagiellonian University in Poland we are helping to understand the biology of vascular cell damage in diabetes.
The World Health Organization (WHO) has called diabetes the epidemic of the 21st century. WHO estimates that more than 180 million people worldwide suffer from diabetes today and predicts that the number will double before 2030. The economic and health burden of this disease will be enormous.
Diabetes is characterized by hyperglycemia, an elevated concentration of sugar, or glucose, in the blood. Elevated blood glucose has a damaging impact on endothelial cells, the thin layer of cells that line the interior surface of blood vessels and form the interface – the endothelium – between circulating blood and the rest of the vessel wall. Endothelial cells line the entire human circulatory system, from the heart to the smallest blood vessel.
Under normal circumstances, endothelial cells are able to metabolize circulating blood glucose, providing the energy that the body needs to function. In hyperglycemia, however, too many glucose molecules in the blood cause endothelial cells to malfunction, damaging the body’s circulatory system and resulting in serious complications that can range from kidney failure and heart disease, to blindness. Prolonged hyperglycemia can result in death.
The endothelium has a unique ability to repair and regenerate itself with the help of a group of specialized cells called endothelial progenitor cells (EPCs). Endothelial progenitor cells are found in bone marrow and, in response to a signal from damaged endothelial tissue, are recruited into the bloodstream to help repair an injured vessel. Endothelial progenitor cells can act both directly and indirectly at the site of blood vessel injury by integrating into vessel walls and releasing growth factors that help form new blood vessels at the site of the injury.
In individuals with diabetes, circulating endothelial progenitor cells are exposed to abnormal levels of blood sugar. It has been demonstrated that patients with diabetes not only have fewer endothelial progenitor cells than healthy individuals, but the function of the endothelial progenitor cells that they do have is impaired.
To investigate the role of elevated blood glucose level on endothelial progenitor cell function, we have been examining the mechanisms and effects of diabetes and anti-diabetic drugs on endothelial progenitor cells at the Jagiellonian University in Poland.
There is no question that diabetes has a negative effect on endothelial progenitor cells but researchers are still not sure why so many mechanisms of EPCs function are impaired in diabetes.
We tested the viability of endothelial progenitor cells in mice and found that, after adding glucose to the medium in which the EPCs were being cultured, the cells from diabetic animals were more prone to oxidative stress and cell death than control cells. Glucose also impaired other cell functions such as their ability to connect with neighboring cells to form new blood vessels.
By measuring the number of connections between cells - connections, which are necessary to form vessels by cells later on - we found that hyperglycemia impaired the ability of EPCs to form new blood vessels. The cells from healthy mice formed 40% more connections than those from diabetic mice.
In our studies we examined how thiazolidinediones, a class of drugs that sensitize cells to insulin, affect the functions of endothelial progenitor cells those were isolated from healthy and diabetic mice.
Among diabetic mice that were fed for two weeks with rosiglitazone – a commonly used anti-diabetic drug – their hyperglycaemia decreased and the capability of their endothelial progenitor cells to migrate improved to the level of control cells. The EPCs obtained from the rosiglitazone-treated diabetic mice were also more resistant to oxidative stress than cells isolated from their untreated counterparts.
We know that a thiazolidinedione such as rosiglitazone can improve the viability and migration capability of endothelial progenitor cells. Now we have to look at the biological mechanism of its action on these cells.
The goal of our research is to better understand the biology of endothelial progenitor cells and use our findings to improve EPC functions. We want to know which pathways are impaired in diabetes and which can be modified pharmacologically. The better endothelial progenitor cells function, the better blood vessels will function. And the better blood vessels function, the healthier individuals with diabetes will be.
Since patients with diabetes suffer from so many vascular complications and diseases, this research is very important. Even today there is no successful therapy for diabetic foot disease resulting from blood vessels malfunction. In many cases the only one option, the only one “cure” is to amputate patients’ leg. We hope that our studies will help to change the odds for diabetic patients.
