A team of scientists led by University of Oxford’s Professor Robin Choudhury has found that hyperglycemia alters stem cells in the bone marrow that go on to become white blood cells called macrophages; as a result, these macrophages become inflammatory and contribute to the development of atherosclerotic plaques that can cause heart attacks. The finding explains why people with diabetes are at increased risk of heart attack, even after their blood glucose levels are brought back under control, a paradox that has troubled doctors for years.
Hyperglycemia-induced trained immunity may explain why targeting elevated glucose is ineffective in reducing macrovascular risk in diabetes and suggests new targets for disease prevention and therapy. Image credit: Steve Buissinne.
“Our study is the first to show that diabetes causes long-term changes to the immune system, and how this might account for the sustained increase in the risk of heart attack,” Professor Choudhury said.
“We need to change the way we think about, and treat, diabetes. By focusing too narrowly on a managing a person’s blood sugar levels we’re only addressing part of the problem.”
“Right now, people with diabetes aren’t receiving effective treatment for their increased risk of heart and circulatory disease. These findings identify new opportunities for preventing and treating the complications of diabetes.”
In the study, Professor Choudhury and colleagues investigated the differences in white blood cells in people with and without type 2 diabetes.
The researchers removed the white blood cells from blood samples and grew them in an environment with normal glucose levels.
Those from people with type 2 diabetes showed a greatly exaggerated inflammatory response compared to the cells from people without the condition.
The authors also extracted stem cells from the bone marrow of mice with and without diabetes and transplanted these into mice with normal blood glucose levels.
The bone marrow taken from diabetic mice ‘remembered’ its exposure to high levels of glucose and as a result the mice receiving this bone marrow developed almost double the amount of atherosclerotic plaques.
When they looked at the mouse macrophages in more detail they found that those that had developed from stem cells in the bone marrow of diabetic mice had been permanently altered to become more inflammatory.
The team now plans to explore new avenues for treatments based on this finding and to find out whether short periods of increased blood glucose in people without diabetes have this damaging effect.
“While treatments for diabetes have improved, people with diabetes still have a higher risk of heart attacks,” said Professor Sir Nilesh Samani, medical director at the British Heart Foundation, which funded this study.
“This research may provide part of the explanation for why this is the case and potentially pave the way for new treatments to reduce the risk of heart attack for the millions of people living with diabetes.”
The results were published this week in the journal Circulation.
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Laurienne Edgar et al. Hyperglycaemia Induces Trained Immunity in Macrophages and Their Precursors and Promotes Atherosclerosis. Circulation, published online July 13, 2021; doi: 10.1161/CIRCULATIONAHA.120.046464
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