Scientists believe they have uncovered the link between diabetes and circulatory problems which causes thousands of Britons to need a limb amputation each year.
A protein in cells could be responsible for leg ulcers and gangrene in diabetics, which lead to them needing amputation, they said.
Experts from the British Heart Foundation (BHF) said the study could pave the way for a new drug to cut down the risks.
About 5,000 diabetics a year in the UK - or 100 a week - have a limb amputated.
Experts carried out experiments on mice and found that a protein called p75NTR was present in the cells of diabetics but not in the cells of healthy mice.
When they stopped the protein working in diabetic cells, they found that circulation to the lower limbs improved.
But when the protein was introduced into cells, circulation worsened, suggesting the important role played by the protein.
Jeremy Pearson, associate medical director at the British Heart Foundation (BHF), which funded the study, said: "The researchers have found that there is an increased expression of this protein in the cells of diabetics.
"The problem with diabetics is that they get all sorts of circulation problems and can suffer things like gangrene in their toes.
"People have never understood before exactly why this is."
Professor Peter Weissberg, medical director at the BHF, added: "This BHF-funded group in Bristol have made an important discovery in identifying a molecule that leaves diabetics at risk of awful conditions such as leg ulcers and gangrene that can require amputation.
"This vital finding may pave the way for the development of a drug to knock out the molecule - or its effects.
"Such a treatment would have enormously beneficial effects on one of the most devastating and life-threatening complications of diabetes."
Diabetics are 15 times more likely to need a lower limb amputation than those without the disease.
About seven out of 10 people having an amputation will die within five years as a result of possible complications and their condition, figures suggest.
Diabetics are far more likely to develop foot problems, including ulcers, which can get infected and even lead to gangrene. More than one in 10 foot ulcers results in an amputation.
There are currently 2.3 million people in the UK with Type 1 and 2 diabetes.
Type 1 usually develops in childhood while Type 2 is linked to lifestyle factors such as obesity.
An extra 500,000 people in the UK have Type 2 diabetes but are unaware of it.
The experiments looked at the cells lining blood vessels.
Dr Iain Frame, director of research at Diabetes UK, said the results of experiments in mice should be interpreted with caution, but welcomed the study.
"Finding out more about what can lead to ulcers, amputations and other serious complications in people with diabetes is vital to protect long-term health," he said.
"If this research is proven in humans, a treatment could be developed to remove the p75NTR protein from which many people with diabetes could benefit.
"More research is needed, as we do not yet know why the protein seems to prevent the growth of new blood vessels in people with diabetes.
"We look forward to the researchers doing more work on the protein to help with the development of improved treatments in the future."
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