Scientists have reported a link between the Miro1 protein and insulin resistance

American scientists have discovered that the accumulation of Miro1 protein in skeletal muscles may be involved in the development of insulin resistance in type 2 diabetes mellitus. In preclinical models, the removal of this protein improved the muscle response to insulin, and in patients, its content decreased after a course of physical training. How cellular energy, movement and blood sugar control are related and what the finding can change in the treatment of diabetes — in the Izvestia article.

Why Muscles are Important for Sugar Control

With type 2 diabetes, the body uses insulin worse, a hormone of the pancreas that helps glucose enter cells and serve as an energy source. Therefore, increased blood sugar may be associated with both insufficient insulin production and a weakening of the tissue response to its action.

Decreased sensitivity to the hormone is called insulin resistance. It affects, among other things, muscles, adipose tissue and the liver. If the pancreas eventually stops providing the body's insulin needs, the concentration of glucose in the blood increases. This is how the US National Institute of Diabetes, Digestive and Kidney Diseases explains this connection.

The work of muscles in this system is of fundamental importance: a violation of their response to insulin affects the body's ability to absorb glucose. However, the general concept of "decreased sensitivity" hides specific changes inside the cells. Researchers are trying to determine which of them accompany the disease, and which ones themselves support metabolic disorders. The new work focuses on one of these possible mechanisms — protein accumulation on the surface of mitochondria, cellular structures that provide energy production.

What was found on the surface of mitochondria

The study was carried out by a team led by John Kirwan. The work was conducted at the Pennington Biomedical Research Center at Louisiana State University. Kirwan is currently the head of the Harold Hamm Diabetes Center at the University of Oklahoma.

The focus was on Miro1, a protein of the outer membrane of mitochondria. In people with type 2 diabetes, researchers have found increased levels of it in skeletal muscles. To understand the significance of this finding, they combined studies of human tissue samples with experiments on cells and animals.

The comparative part of the work involved people with normal body weight, overweight or obese, without diabetes, and with diabetes. Accumulation of Miro1 was observed specifically in the group with the disease.

The authors also attributed this process to a violation of the interaction of Miro1 and AKT, a protein involved in insulin signaling. According to their data, the insufficient interaction of these proteins on the surface of mitochondria partially explains the accumulation of Miro1 in muscles.

How the role of protein was tested

By itself, the increased content of any protein in the disease does not allow it to be considered the cause of the disorder. It may be the result of other changes. Therefore, the researchers tested what would happen to the muscle's response to insulin if Miro1 were removed.

In experiments on mice, protein was removed from skeletal muscles. Separate experiments were conducted on cells. Reducing its content improved insulin sensitivity and the ability of mitochondria to provide energy processes.

This approach allowed us to move from observation to function verification: interference with the work of Miro1 changed the studied indicators. This reinforces the assumption that protein accumulation itself is involved in disrupting the insulin response.

What has changed after training

The clinical part of the work was devoted to physical activity. To do this, we conducted a randomized controlled trial involving people with obesity and type 2 diabetes. The participants were divided between an aerobic training group and a standard medical care group.

The program lasted 12 weeks. The trained participants walked or ran on the track five days a week for an hour under the supervision of specialists. Before and after the program, researchers assessed insulin sensitivity and obtained muscle tissue samples during biopsy.

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In the exercise group, the Miro1 content in the muscles decreased. At the same time, insulin sensitivity and mitochondrial energy function improved. This part of the work connects the laboratory finding with the changes that can be observed in humans. Researchers have shown that protein accumulation can be changed during exercise, and a decrease in its content is accompanied by an improvement in metabolic parameters.

At the same time, the study of training alone does not establish how much of its beneficial effect falls on Miro1. Physical activity causes many changes in the body, so the coincidence of several improvements still requires testing a specific mechanism.

How the discovery can help in the treatment

The authors consider Miro1 as a potential therapeutic target, a protein that could improve muscle response to insulin. The point of this approach is to interfere with a specific cellular mechanism involved in glucose metabolism disorders.

However, in the presented study, people were not given a drug that reduces the content of Miro1. The clinical part concerned training, and direct intervention in protein function was tested in preclinical models. Therefore, the results do not yet show how effective and safe the drug effect on this target will be in humans.

For the transition to therapy, it is necessary to establish whether this process can be controlled in patients and whether such an intervention will bring lasting benefits. A separate issue is the reproducibility of the detected effects in the further study of the disease.

The researchers themselves emphasize the need to continue working. Kirwan intends to develop this area at the Harold Hamm Diabetes Center by combining laboratory experiments with research in humans.