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Insulin resistance syndrome (or insulin resistance) is defined as a state of decreased cellular and tissue response to insulin. Often associated with excess weight (with a dominant abdominal distribution of adipose tissue), it is a major risk factor for type 2 diabetes. However, strategies to reduce insulin resistance are limited. Researchers have found that removing old dysfunctional cells from human fat can reduce hallmarks of diabetes. This could lead to new treatments for type 2 diabetes and other metabolic diseases.

Type 2 diabetes results from improper use of insulin by the body; it represents the majority (90%) of cases of diabetes, a disease that today affects 537 million people worldwide (or one in ten adults) according to the International Diabetes Federation (FID). IDF projections show that by 2045, 783 million adults will be living with diabetes, or one in eight adults. This exponential increase in the number of patients is due to a complex interaction of several factors: poor diet, lower levels of physical activity (sedentary lifestyle) and an increase in the prevalence of overweight and obesity.

But according to a team from theUConn School of Medicine, affiliated with the University of Connecticut, senescent cells of body fat are also closely linked to the development of type 2 diabetes. Experiments carried out on mice carrying human adipose implants have indeed shown that the elimination of these cells appear to mitigate the negative effects of fat on metabolism. In a press release, the researchers evoke “a spectacular result”.

A combination of drugs against the senescence of fat cells

The body’s cells are constantly renewing themselves, the oldest ones aging and dying as new cells appear. But sometimes, this process goes awry and damaged cells persist: these cells, called senescent cells, interfere with the proper functioning of the cells that are nearby. They can, for example, change the way neighboring cells handle sugars or proteins and thus cause metabolic problems.

Ming Xu, assistant professor at UConn Center on Aging, and his colleagues set out to target these senescent cells via a combination of two experimental drugs, dasatinib and quercetin. Dasatinib is already used to treat some forms of leukemia; quercetin (or quercetol), a powerful antioxidant, is an organic compound found in many medicinal plants. In previous research, Xu had already shown that the combination of these two substances made it possible to improve the health and extend the lifespan of elderly mice.

In this study, cultures of human adipose tissue – taken from obese people with metabolic disorders – were transplanted into mice, which was enough to cause persistent physical dysfunction and spread cell senescence to rodent tissues. But after treatment with dasatinib and quercetin, the harmful effects of fat tissue were almost eliminated. ” The senolytic cocktail, dasatinib plus quercetin, which results in selective elimination of senescent cells, decreased the number of natural senescent cells and their secretion of pro-inflammatory cytokines linked to fragility in human adipose tissue explants ”, Summarized the authors of this study, in 2018.

« These drugs can make human fat healthy, and that could be great. The results were very impressive and paved the way for potential clinical trials Xu said. That’s why he and his team explored the effect of drugs on type 2 diabetes in a clinical trial. The first results are encouraging, but large-scale trials will have to be conducted to assess the efficacy and safety of the treatment in humans before their clinical use.

A relevant target for future treatments

The researchers focused on a very specific population of senescent cells that had never been explored until now. These cells express high levels of p21, a protein that inhibits cyclin-dependent kinases – proteins that play a major role in cell cycle regulation, which are key markers of cell senescence in particular.

The elimination of senescent cells strongly expressing the protein p21 in obese mice, by a treatment combining dasatinib and quercetin, made it possible to attenuate insulin resistance and the symptoms characteristic of diabetes. © L. Wang et al.

Using a mouse model specifically developed for this research (endowed with cells strongly expressing the p21 inhibitor), Xu’s team demonstrated that eliminating these senescent cells, once a month, is effective both in slowing the development of diabetes (by reducing resistance to insulin), and also to relieve diabetic symptoms developed in obese mice. ” Our findings lay the groundwork for further targeting of cells expressing high levels of p21 as a novel therapy to alleviate insulin resistance “, Summarize the researchers.

The team’s results show that intermittent clearance of high p21 cells may confer long-term protection against obesity-induced metabolic dysfunction. In addition, the timing of clearance can be quite flexible, thus improving potential clinical applicability. Previous studies have focused on different cellular markers, but the beneficial effects of eliminating cells expressing strongly p21 were so pronounced that Xu believes this marker should be the subject of much more research. ” Reducing the negative effects of fat on the metabolism has been a dramatic achievement. If any therapy worked this well in humans, it would be a breakthrough treatment for diabetes », Concluded the researchers.

Source : Cell Metabolism, L. Wang et al.

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