Diabetes

Sweet Sweet Memories: Why Defeating Diabetes Means Looking Beyond Blood Sugar

Posted on 8 November 2022

Over one in ten US adults have diabetes. China and India, whose populations together form over a third of humanity, also have a rate of diabetes of around one in ten. Millions more will have undiagnosed diabetes or prediabetes – it has been estimated that about half of all people with diabetes have not yet been diagnosed.

Most of this diabetes is type II diabetes, and is the result of the body’s inability to properly control blood glucose (sugar) levels, which happens when cells stop responding well to the blood sugar-lowering hormone insulin. Type I diabetes, on the other hand, is the consequence of insufficient insulin production by the pancreas.

Elevated blood sugar can damage blood vessels and organs, and can even kill you. However, having diabetes also increases your risk of almost all age-related diseases, including atherosclerosis – the build up of fatty material within the walls of the arteries. Diabetics have a similar risk of future cardiovascular events as someone who has already suffered a heart attack. Yet researchers have noticed something odd: even if you treat someone’s diabetes and restore their blood sugar to normal levels, their risk of cardiovascular problems shows little to no reduction. Scientists are now beginning to understand why, and what they’ve found suggests that in order to defeat this epidemic, we might need to look deeper than blood sugar – towards the genes themselves.

Why Do Diabetics Get More Cardiovascular Disease?

Atherosclerosis is the result of cholesterol becoming trapped within the walls of the arteries. These deposits narrow the blood vessels they occur in, and can block off blood vessels entirely by causing a blood clot to form, or by breaking apart and blocking smaller vessels downstream from the deposit. If this happens in the coronary artery (the artery that supplies blood to the heart muscle), the result is a heart attack, in which a portion of the heart is starved of oxygen.

If these harmful deposits are made mainly from cholesterol, how does having high blood sugar make them grow faster? It turns out that cells of the immune system play an important role in atherosclerosis – particularly the white blood cells called macrophages. Macrophages are the ‘scavengers’ of the immune system. Their role is to ‘eat’ and digest pathogens, debris, and anything else that shouldn’t be found within the tissues they are patrolling. When macrophages detect cholesterol in the walls of an artery, they try to ‘eat’ it, but are unable to break it down, and release inflammatory molecules to call other macrophages to help. This creates a vicious cycle of inflammation that makes the fatty deposit grow faster.

Macrophages can boost or suppress inflammation, depending on the situation.
Source of immune cell depiction: Zahn Bariring
GNU Free Documentation License

Not all macrophages promote inflammation – macrophages can switch between two ‘modes’. The first ‘mode’, called M1, drives inflammation as described above. The second ‘mode’, called M2, does the reverse – it quells inflammation and attempts to repair damaged tissue. It appears that M1 macrophages rely more heavily on glucose (sugar) for energy, while M2 macrophages consume more fatty acids. Higher levels of glucose can encourage macrophages to behave more like M1 macrophages, which are responsible for driving atherosclerosis. However, the question remains: why doesn’t bringing someone’s blood sugar back to normal lower their risk of atherosclerosis?

The Immune System ‘Remembers’ High Blood Sugar

The switch between M1 and M2 macrophages is controlled by the expression of different genes. One of the ways in which gene expression is controlled is through epigenetic changes. If the genetic code within each cell is akin to an instruction book, then epigenetic changes can be likened to bookmarks indicating which pages are important for a given cell. A heart cell looks very different from a brain cell because they express a very different set of genes, and this is mainly because of mostly permanent epigenetic changes that took place early during development.

Researchers at Oxford University wanted to investigate whether such epigenetic changes might occur in the macrophages of diabetics. They began by looking at mouse models. Since macrophages don’t live for very long and don’t divide, any epigenetic changes would have to occur in the stem cells of the bone marrow (which give rise to new macrophages) in order to have any long-lasting consequences. Because of this, they took bone marrow cells from diabetic mice with high blood sugar and from non-diabetic mice. They then placed these cells in an environment with normal glucose levels and made them develop into macrophages. Sure enough, the cells taken from diabetic mice showed more features of M1 macrophages when stimulated. They ‘remembered’ the high levels of glucose they were previously exposed to, and this appeared to prime them to become M1 macrophages. They were also better at sticking to artery walls and consumed more cholesterol than cells from non-diabetic mice. In line with this, when bone marrow from diabetic mice was transplanted into healthy mice, those mice developed atherosclerosis at a much higher rate than mice receiving bone marrow from non-diabetic mice.

This image shows a cross section of the aorta from a mouse that received bone marrow from an non diabetic mouse (top) and one that received bone marrow from a diabetic mouse (bottom). The green and red colours both indicate the presence of more macrophages in the fatty plaques of the mouse receiving bone marrow from a diabetic donor. Graph D shows that plaques were generally larger in mice receiving bone marrow from diabetic donors.
Hyperglycemia Induces Trained Immunity in Macrophages and Their Precursors and Promotes Atherosclerosis

Next, the researchers took a closer look at the DNA of macrophages derived from bone marrow cells exposed to elevated glucose. They found that high levels of glucose altered the way the DNA of these cells was packaged. Within the nucleus of each cell, DNA is coiled upon itself many times into a structure called chromatin. Depending on how tightly packed this chromatin is, genes can be made accessible or inaccessible for reading. By changing which regions of chromatin were more ‘open’, cells exposed to higher levels of glucose made genes related to inflammation more accessible.

What Does This Mean For Humans?

Of course, we can’t do the kinds of experiments described above in humans. However, the researchers were able to look at macrophages taken from humans with type II diabetics and from fatty plaques taken from human arteries, and found that their behaviours and gene expression changes are very similar to those observed in mice. This is both good news and bad news for humans with type II diabetes.

The bad news is that, even if someone’s diabetes is well controlled with normal blood sugar, their bone marrow is still producing macrophages that are ‘primed’ to seek out fatty deposits and promote atherosclerosis.

The good news is that we now know more about the underlying epigenetic changes, and can start looking for ways to reverse them. During their investigations, researchers found that a molecule called RUNX1 was involved in promoting the expression of many of the genes that were upregulated in primed macrophages. This could one day be a therapeutic target, and in the less distant future, as a way of measuring someone’s risk of atherosclerosis.

Until then, there may be other ways to reverse the changes brought about by high blood sugar. We mentioned earlier that M1 macrophages rely more on glucose for energy, while M2 macrophages rely more on fatty acids. When bone marrow cells consume more glucose, this results in the production of cells primed to become M1 macrophages. Perhaps by forcing these cells to metabolise more fatty acids instead of glucose, these changes could be reversed. This can be reliably achieved through dietary restriction techniques such as fasting, though this can have additional risks for diabetics and has to be done with care.

Regardless of where this research leads next, it’s a good example of why the ongoing diabetes epidemic is such a disaster for public health. The health effects of diabetes run deep, and we’re going to need new, innovative ways to treat it if we want to tackle the crisis head-on.


References

Hyperglycemia Induces Trained Immunity in Macrophages and Their Precursors and Promotes Atherosclerosis: https://doi.org/10.1161/CIRCULATIONAHA.120.046464

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