Lifestyle changes are one key to treating type 2 diabetes. Controlling blood glucose alleviates not only symptoms but also most comorbid conditions – except for atherosclerosis. New research has a good explanation. High blood glucose can imprint our immune system with metabolic memory, and this does not disappear even when blood glucose is sustained at normal levels. The new understanding suggests new targets for diagnosing, preventing and treating complications of diabetes. Researchers think that it will be possible to replace this unhealthy memory.
Elevated blood glucose is the primary danger signal for people with diabetes. Untreated or poorly treated diabetes causes many deaths globally. A common condition, made worse by diabetes, is atherosclerosis, leading to coronary artery disease and its complications, including heart attack. Although raised blood glucose increases the of atherosclerosis, treating blood glucose does not reduce that risk. This has been mysterious, but now researchers have come a step closer to determining why.
“Our experiments show that immune memory is trained when the body is exposed to elevated blood glucose. This memory is imprinted in the bone marrow and in the macrophages of the immune system by inserting small marks into the DNA that remain even if the blood glucose is normalized. We transferred bone marrow stem cells from mice with diabetes to healthy mice and thereby also transferred this type of unhealthy memory. Now we are striving to learn how to replace this memory with positive memory,” explains senior author Robin Choudhury, Professor of Cardiovascular Medicine, University of Oxford, United Kingdom.
Transferring memory
Atherosclerosis is a chronic inflammatory disease in which modified lipoproteins – complexes of fat and protein – are deposited and retained and immune cells accumulate in the walls of large arteries. The arteries become more rigid and inflexible and therefore also rupture more easily. The researchers focused especially on macrophages, immune cells whose normal role is to degrade damaged cells and absorb cellular waste.
“Macrophages are key in all stages of atherosclerosis and are widely regarded as therapeutic targets. They can act in two opposite ways: either repairing tissue or promoting inflammation, and the latter can exacerbate atherosclerosis. We knew that macrophages react strongly to environmental stimuli such as elevation in blood glucose, but we could not understand why their function did not normalize when glucose did,” says Robin Choudhury.
The researchers therefore first grew macrophages in the laboratory in diabetic conditions with high blood glucose. This clearly but expectedly changed the gene expression in the macrophages towards harmful inflammatory conditions. The surprise came when the macrophages were transferred to normal physiological conditions with normal blood glucose.
“Although the conditions normalized, the macrophages retained the unhealthy gene expression as if they created memory of the situation from before the glucose levels normalized. And we found this when we transferred bone marrow cells from diabetic mice to non-diabetic mice. The memory was transferred, causing the non-diabetic mice that had normal blood glucose to develop macrophages with this unhealthy gene expression,” explains Robin Choudhury.
Counteracting with positive memory
Modifications to the access to certain genes explains the stubborn memory of macrophages. Which of the many genes in a cell are actually expressed at a given time is influenced by epigenetic programming – small chemical modifications on the surface of the DNA strands that affect whether they are accessible to the transcription factors that bind before gene expression can take place.
“We found that increased blood glucose results in some very specific modifications at positions that affect the ability of a transcription factor RUNX1 to drive inflammation. Significantly, the macrophages retain the imprinted epigenetic modifications even after the blood glucose normalizes. As a result the macrophages seem to create memory that pushes them away from their healing role and while aggravating atherosclerosis. This helps to explain why treating glucose does not reduce the risk of heart attack,” says Robin Choudhury.
Although many macrophages are quite short lived, the epigenetic marks are imprinted on the bone marrow stem cells and therefore passed on to new macrophages.
“Our study may help to explain why conventional treatments do not work to reduce vascular risk and fundamentally challenges the conventional approach to managing the vascular complications of diabetes. On the other hand, we have now found several potential new therapeutic targets, so we hope to be able to develop new drugs that can remove or modify the chemical marks on the genes. In this way, we hope to rewrite unhealthy macrophage memory and replace it with a new and more positive memory,” concludes Robin Choudhury.
