Diabetes? Old cells must go!

Histological cut through fat tissue, illustrative photo.
source: sciencephoto.com, author: Jose Calvo

The disease called diabetes mellitus is divided into two types. The first one is characterized by a lack or complete absence of insulin production in the body. Insulin is a hormone that signals satiety with food. The second type is caused by lowered insulin production combined with insulin resistance. This type is also associated with many other (secondary) problems such as high blood pressure or non-alcoholic liver steatosis. Such fat deposition in tissues is a vicious circle. Deposited fat promotes insulin resistance, which leads to diabetes, which leads to fat deposition, and so on. It is very hard to break the cycle but not impossible. Correct medication and lifestyle changes can alleviate the symptoms of the disease.

So what is the correlation between diabetes and old cells, you might ask? Cellular senescence is caused by cell cycle arrest. The cell is not able to divide but is still metabolically active which means that it still produces various chemicals to influence its surroundings. Unless these cells are effectively removed by the immune system, inflammation forms, and the surrounding tissues get damaged. Diabetes promotes cellular senescence and tissue damage is one of the symptoms of this disease. It is another vicious cycle and the key to breaking it is the removal of senescent cells.

Mitochondria, illustrative photo.
source: sciencephoto.com, author: hybrid medical animation

Targeted elimination of senescent cells by MitoTam could significantly help patients suffering from type 2 diabetes. MitoTam is mitochondrially targeted tamoxifen. Mitochondria are the powerhouses of cells and they play an important role in the process of cellular senescence. MitoTam, which recently passed the first round of clinical trials as an anticancer agent, can significantly damage the structure and function of mitochondria even so that it leads to their complete collapse.

Scientists have studied the effectiveness of MitoTam as a senolytic agent (a compound that can selectively destroy senescent cells) in laboratory mice. Besides the senolytic effect being proven, they also managed to study the exact effects of MitoTam in diabetic mice. The drug is able to lower the animal´s weight and blood sugar level which leads to better glucose tolerance. It also limits the fat deposition in the liver and kidneys which results in breaking the vicious cycle. Thanks to mitochondrial targeting, MitoTam is more effective than its parent substance, tamoxifen itself. Another difference is also that some effects of MitoTam last even weeks after the therapy ends.

Unlike current therapeutic agents, MitoTam targets the cause of the problem and not just its symptoms. Most drugs, that are currently used to treat type 2 diabetes, either promote insulin production or improve the sensibility to this enzyme. Some of them even just remove glucose from the body by supporting its secretion into the urine. MitoTam, although not yet tested as an antidiabetic agent in humans, could thus open new ways to treat and prevent one of the most widespread serious diseases in modern populations.

Vacurova, E., Trnovska, J., Svoboda, P. et al. Mitochondrially targeted tamoxifen alleviates markers of obesity and type 2 diabetes mellitus in mice. Nat Commun 13, 1866 (2022).

Magda Křelinová