How immunity causes diabetes

The immune cells in the adipose tissue disrupt the metabolism by exosomes – microbubbles with regulatory molecules that spread throughout the body.

In case of diabetes of the second type (it makes 85–90% of all types of diabetes mellitus), the tissues stop responding normally to insulin, which helps them to absorb glucose. The pancreas begins to produce more insulin, but this does not help, because the problem is in the tissues and not in insulin. In the end, the pancreas wears out and can no longer produce insulin.

The fact that diabetes usually accompanies overweight, the researchers found out a long time. There is also an intermediate link that connects one with another: a chronic inflammatory reaction. Previously, we have already written about some of the mechanisms that trigger the inflammatory reaction in obesity. However, how exactly the inflammation violates the sensitivity of cells to insulin, for a long time remained incomprehensible.

Researchers at the University of California at San Diego were able to trace what happens. It turned out that the immune system suppresses insulin sensitivity with the help of exosomes – microscopic bubbles that serve as cells for communication. Exosomes contain miRNAs – regulatory molecules that affect protein synthesis. A cell packs its miRNA into an exosome and sends it to another cell, as a result, the molecular processes in the target cell change in one direction or another.

In chronic inflammation, many macrophage immune cells come to the adipose tissue, which secrete a variety of molecules associated with the inflammatory response. Among what macrophages emit, there are “bad” exosomes that so affect the cellular metabolism that the cells become insensitive to insulin.

Inflammatory exosomes also act outside adipose tissue: the researchers were able to trace how they enter the bloodstream and go to the muscles and the liver. Inflammatory exosomes were taken from obese mice and injected into healthy animals, and as a result, insulin sensitivity was disturbed in healthy animals.

When reverse manipulation was performed, that is, “healthy” exosomes were injected into sick animals, then those insulin sensitivities was restored — in spite of the persistence of obesity, their metabolism returned to normal. Human cells of the liver and adipose tissue behaved in the same way: when they were treated with “bad” exosomes, the cells lost insulin sensitivity – and, conversely, insulin sensitivity was restored when the cells were treated with “good” exosomes. Full research results are published in Cell.

If we understand exactly which miRNA from exosomes cause the clinical picture of diabetes, we will find molecular targets for drugs. Researchers estimate that exosomes contain several hundred varieties of miRNAs, but in this case only about 20–30 of them are of interest.

One microRNA seems to have already been calculated – it disrupts the synthesis of a well-known protein called PPARγ. This protein regulates glucose metabolism – the accumulation of fatty acids in the cells of adipose tissue. (Researchers note that effective anti-diabetes drugs already exist, the mechanism of action of which is associated with PPARγ, but the problem is that they cause side effects that are unacceptable in clinical practice; in any case, there are still about two to three dozen miRNAs that can be more successful targets.)

In addition, exosomal miRNAs are easy to isolate from the blood, so they are suitable for the role of biomarkers of diabetes. A blood test can then determine whether a person has a risk of diabetes in the near future, as well as which drugs will best help him if the disease has already begun to develop. The analysis for exosomes (more precisely, the analysis for miRNA from exosomes) could also replace such an unpleasant procedure as tissue biopsy, when we want to find out what state the tissue is in.

According to the researchers, it is important to continue exploring the exosomes also because they are likely to be involved in the development of not only diabetes, but also other obesity complications not related to metabolism.

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