The action of the most common drug against type 2 diabetes depends on a protein

Type 2 diabetes is a complex metabolic disorder characterized primarily by excessive amounts of glucose in the blood due to the body’s inability to respond adequately to the actions of insulin—a process known as insulin resistance—or to produce insulin. hormone. During the development of this pathology, cellular stress occurs that causes an increase in the secretion of cytokines in response to this process —for example, GDF15— that activate mechanisms to counteract processes such as inflammation or insulin resistance.

Despite the fact that metformin is the most widely used drug to treat type 2 diabetes, the mechanisms responsible for its antidiabetic effects have been largely unknown or not at all. The situation has now begun to change thanks to a study led by a group from the Network Biomedical Research Center for Diabetes and Associated Metabolic Diseases (CIBERDEM) in Spain, made up of scientists from the University of Barcelona (UB) and the Research Institute Sant Joan de Déu (IRSJD) in Barcelona, ​​with the collaboration of a team from the Alberto Sols Biomedical Research Institute (of the Higher Council for Scientific Research (CSIC) and the Autonomous University of Madrid (UAM)) in Spain.

The authors of the study set out to find out if the action of metformin depends on the stress response protein GDF15, according to Professor Manuel Vázquez-Carrera, head of the CIBERDEM group at the Faculty of Pharmacy and Food Sciences and the Institute of Biomedicine of the UB (IBUB), and coordinator of the work. «GDF15 is a cellular stress response cytokine —with increased levels in many diseases, such as heart failure, cancer, fatty liver or diabetes itself— that has been proposed as a potential biomarker of many diseases, and in this specific work we have studied its participation in the activation of AMPK by metformin”, details the researcher.

For her part, Ángela M. Valverde, head of the CIBERDEM group at the Alberto Sols Biomedical Research Institute, and co-author of this work, considers that “our findings suggest that the activation of AMPK by metformin increases the levels of GDF15 and In turn, this cytokine contributes to maintaining increased AMPK activity.”

There are drugs in common use, including metformin, whose mechanism of action has long been shrouded in mystery. (Photo: Amazings/NCYT)

To draw these conclusions, the researchers used wild-type mice that express GDF15 and also mice that lacked this cytokine. After causing obesity and type 2 diabetes in these mice by feeding them a high-fat diet, they observed that the antidiabetic effect produced by metformin in wild-type mice disappeared in GDF15-deficient mice.

Likewise, AMPK activation caused by metformin in liver and muscle in wild-type mice was also absent in mice that did not express GDF15.

To rule out the involvement of central GDF15 receptors in the changes caused by GDF15, cell cultures of hepatocytes and muscle cells were used in which reduced GDF15 expression also attenuated the increased AMPK activity caused by metformin, suggesting that the effects of metformin on AMPK were independent of the central nervous system.

The study is titled “A positive feedback loop between AMPK and GDF15 promotes metformin antidiabetic effects.” And it has been published in the academic journal Pharmacological Research. (Source: UB)