Identifying the defective vascular repair pathway in diabetes
Research type
Research Study
Full title
Identifying the defective vascular repair pathway in diabetes
IRAS ID
232535
Contact name
Fiona L Wilkinson
Contact email
Sponsor organisation
Manchester Metropolitan University
Duration of Study in the UK
5 years, 0 months, 0 days
Research summary
Research Summary
The worldwide prevalence of diabetes mellitus is increasing and it can affect nerves, skin and blood vessels. Despite glucose, cholesterol and blood pressure control, blood vessel complications are highly prevalent, increasing cardiovascular risk by 4-fold. In diabetes, damage to the nerves can also occur in the lower limbs and feet and patients can lose the sense of touch (neuropathy) and may unknowingly cause damage to the skin, resulting in a foot or leg ulcer. Inadequate blood supply in the lower limb (ischaemia) is a threat to surrounding tissue viability and poor healing of wounds. Open ulcers or wounds are more susceptible to infections, which can spread to bone and beyond and can result in gangrene, amputation or even death.
Damage to the blood vessel lining is an early event in diabetes, triggered by the high glucose, advanced glycation end-products (AGEs; a complication of high glucose and indicator of cardiovascular risk) and inflammation. Stem cells called Endothelial Progenitor Cells (EPCs) help repair the blood vessel lining and maintain healthy blood vessel function; however, they are fewer in number and are less effective in patients with diabetes.
Current treatments for diabetic wounds are not always successful and so we need more research to determine why the EPCs have a damaged repair mechanism and how we can potentially restore these protective pathways with new treatments.
This laboratory-based research will assess the differences in the functional capacity of EPCs isolated from 3 groups of patients; a) diabetes with neuropathy and foot ulcers, b) diabetes with neuroischaemia and foot ulcers and c) healthy controls. This work will allow us to develop innovative drugs to restore EPC repair mechanisms and improve diabetic foot ulcer healing. The ultimate goal of this research is to help patients with diabetes to improve their quality-of-life by reducing wound related complications.Summary of Results
The worldwide prevalence of diabetes mellitus is increasing and it can affect nerves, skin and blood vessels. Despite glucose, cholesterol and blood pressure control, blood vessel complications are highly prevalent, increasing cardiovascular risk by 4-fold. In diabetes, damage to the nerves can also occur in the lower limbs and feet and patients can lose the sense of touch (neuropathy) and may unknowingly cause damage to the skin, resulting in a foot or leg ulcer.
Poor blood supply to the lower limb (ischaemia) is a threat to surrounding tissue viability and poor healing of wounds due to lack of nutrients and oxygen. Open ulcers or wounds are more susceptible to infections, which can spread to bone and beyond and can result in gangrene, amputation or even death. Damage to the blood vessel lining is an early event in diabetes, triggered by the high glucose, advanced glycation end products (AGEs; a complication of high glucose and indicator of cardiovascular risk) and inflammation. Stem cells called Endothelial Progenitor Cells (EPCs) help repair the blood vessel lining and maintain healthy blood vessel function; however, they are fewer in number and are less effective in patients with diabetes. Current treatments for diabetic wounds are not always successful and so we need more research to determine why the EPCs have a damaged repair mechanism and how we can potentially restore these protective pathways with new treatments.
We have performed laboratory-based research to assess the differences in the functional capacity of EPCs isolated from a blood sample taken from patients with diabetes (who also have foot ulcers) and those without diabetes (control). EPCs from patients with diabetes were harder to grow in larger numbers in lab culture conditions compared to control. Therefore, we also exposed EPCs from healthy control donors to high glucose to understand the molecular changes that may occur within a diabetic environment for comparison.
We have generated preliminary data that shows that diabetic conditions lead to an increase in the expression of genes related to inflammation, changes related to the cell cycle, how they respond to a low oxygen environment and the matrix that surrounds cells. We have been developing a novel drug that may be able to help promote EPC repair by targeting some of these pathways. We are advancing this project with mechanistic laboratory experiments that do not require patient samples in the meantime. Our goal now is to use these preliminary data to apply for funding to further investigate these findings. The ultimate goal of this research is to help patients with diabetes to improve their quality-of-life by reducing wound related complications. The research team would also like to sincerely thank the participants who were involved in this study.REC name
HSC REC A
REC reference
17/NI/0238
Date of REC Opinion
1 Dec 2017
REC opinion
Further Information Favourable Opinion