Mechanism of action of a diabetes drug differs between males and females

Most diabetes medications do not attack the cause of the disease. Glitazones are different: they improve insulin sensitivity and can promote the conversion of unhealthy white adipose tissue into fat-burning beige adipocytes. However, due to their side effects, they are hardly used. Scientists from the German Cancer Research Center are investigating how the beneficial effects of glitazones can be used without side effects. They have now taken an important first step in this direction. They have discovered a gene that is crucial for the effect of glitazones in female mice, but not in males.

The number of people with diabetes mellitus is increasing in Germany. It is now estimated that 7 to 8 percent of adults in this country suffer from type 2 diabetes, the most frequent and lifestyle-related form of diabetes mellitus. Every year, 500,000 new cases are diagnosed (German Health Report Diabetes 2018). A large number of drugs are available for the treatment of diabetes, but: “Most drugs for diabetes only combat the symptoms of the disease. They have no effect on the cause of the high blood sugar,” explains Alex Vegiopoulos from the German Cancer Research Center (DKFZ).

Together with his colleagues, Vegiopoulos is investigating the mechanism of action of one class of drugs, which is an exception: Glitazones are able to fundamentally improve the lipid and sugar metabolism and restore the sensitivity of body cells to the hormone insulin.

In healthy people, insulin transfers sugar from the blood into the body cells, where it is used to generate energy. In people with type 2 diabetes, the body cells no longer respond to insulin, the sugar no longer enters the cells and accumulates in the blood instead. The result is the elevated blood sugar level characteristic of diabetes. Glitazones cause the body cells to react to insulin again and the sugar from the blood can enter the body cells.

But there is a catch: Glitazones can have serious side effects and are therefore not suitable for a broad application. Nevertheless, there is great interest among researchers in the mode of action of these drugs: they not only improve the sensitivity of body cells to insulin, but also promote the conversion of white to beige adipose tissue.

This second aspect of glitazone plays an important role in the treatment of type 2 diabetes, which is often caused by obesity. Unlike white adipose tissue, which only serves to store fat, beige adipose tissue burns energy and excess nutrients. Its function is similar to that of brown adipose tissue, which is often called a “slimming agent”.

In mouse studies, DKFZ scientists discovered that glitazone treatment activates the gene Cited4 in the fatty tissue of the animals. It turned out that the effect of glitazone was dependent on the function of this gene.

“However, this only applied to female mice, but not to males,” reports Vegiopoulos. When the scientists switched off Cited4 in male mice, the glitazones continued to function normally in the animals. This is different in female mice: Without the gene, glitazones did not improve the insulin sensitivity of the body cells, which was due to a reduced promotion of the conversion of white to beige adipose tissue.

“In men, the mechanism of action of glitazones may function independently of the gene, whereas in women the gene is absolutely necessary,” concludes Vegiopoulos. “For the development of new diabetes therapies based on the mechanism of action of glitazones, it is important to know that the metabolism of men and women differs.

The results of the DKFZ researchers also show how important it is to research new drugs in both female and male volunteers and patients, not only at an advanced stage of development, but also in early animal studies. So far, new active substances are still mainly being investigated in male animals.

Irem Bayindir-Buchhalter, Gretchen Wolff, Sarah Lerch, Tjeerd Sijmonsma, Maximilian Schuster, Jan Gronych, Adrian T. Billeter, Rohollah Babaei, Damir Krunic, Lars Ketscher, Nadine Spielmann, Martin Hrabe de Angelis, Jorge L Ruas, Beat P Müller- Stich, Mathias Heikenwälder, Peter Lichter, Stephan Herzig, Alexandros Vegiopoulos. Cited4 is a sex-biased mediator of the antidiabetic glitazone response in adipocyte progenitors. EMBO Molecular Medicine, DOI: 10.15252/emmm.201708613

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.