A novel compound that protects bone cells may benefit diabetic patients

Individuals with diabetes face an elevated risk of fractures. A promising new compound that not only enhances insulin sensitivity, but also safeguards bones, could be the answer. The experimental compound known as MSDC-0602K, initially developed for the treatment of type 2 diabetes and fatty liver disease, is being tested by the Institute of Physiology of the Czech Academy of Sciences (CAS), the Institute of Organic Chemistry and Biochemistry of the CAS, and CarDia, the National Institute for Metabolic and Cardiovascular Disease Research. The study was published in Metabolism.

MSDC-0602K is an experimental compound from a new generation of antidiabetic drugs called thiazolidinediones (TZDs), developed by the Metabolic Solutions Development Company in the USA. According to the study’s lead author, Ondřej Kuda from the Institute of Physiology of the CAS, the idea to test this compound arose somewhat by chance.

Kuda and his colleague, Milan Vrábel from the Institute of Organic Chemistry and Biochemistry of the CAS, were seeking a way to label metabolites within cells at various structural levels, such as the nucleus, cytoplasm, or mitochondria. For this purpose, they employed click chemistry and various inhibitors, i.e., substances that prevent the movement of compounds within cells.

The difference lies in creativity
The impetus to use MSDC-0602K arose from an encounter with Michaela Tencerová from the Institute of Physiology of the CAS, who was working with the new compound as part of a mouse experiment related to osteoporosis. Together, the researchers discovered that MSDC-0602K prevents certain substances from entering the mitochondria, thereby acting as an inhibitor. “We decided to explore it as an intriguing potential therapeutic agent that we could characterize using our new labeling methods. We primarily employ the principle of click chemistry, labeling molecules within living cells at specific locations. This allows us to determine their quantities and potential functions in those locations,” Kuda explains.

The older generation of TZDs functions altogether differently from the second generation represented by the MSDC compound. They promote the formation and growth of fat cells. Researchers found an interesting difference between two molecules from this family – pioglitazone and rosiglitazone. The former is considered metabolically lazy. “Simply put, it creates fats that either get stored in adipose tissue, where they should be, or in bones, where they shouldn’t be, leading to increased bone fragility,” Kuda adds.

Rosiglitazone is metabolically more “creative.” It produces the same amount of adipose tissue and fat cells but does so differently. It combines various precursors, amino acid residues, and sugars to construct triglycerides. This creative process consumes more energy, resulting in a more active metabolism.

The second generation of TZDs has a significantly reduced ability to promote fat formation.

People with diabetes are at greater risk of bone marrow loss and fractures than healthy individuals.

Fat or bone?
How does the new MSDC-0602K compound affect bone and adipose tissue, then? “The target cell is essentially a bone stem cell that has yet to decide its future role. Depending on its location, it can become a fat cell or, if it’s located in bone, a bone cell,” the researcher continues. The administered compound nudges the undecided cell in a particular direction.

While older-generation TZDs directed these bone stem cells toward becoming fat cells, second-generation TZDs favor their development into osteoblasts, which subsequently strengthen bones and reduce their fragility. Utilizing different metabolic pathways and fates thus supports the formation of new bone cells while simultaneously suppressing fat formation in the bone marrow.

The described study provides important insights into the mechanisms of action of various TZDs and paves the way for developing safer and more effective drugs against type 2 diabetes. However, further clinical studies are needed to confirm this promising potential. “The compound primarily targets type 2 diabetes and fatty liver. It is currently in the third phase of clinical trials and could be approved within about a year. We have essentially discovered its positive side effect – it doesn’t harm bones; on the contrary, it benefits them,” Kuda concludes.

Written and prepared by: Markéta Wernerová, drawing on the CAS press release, External Relations Division, CAO of the CAS
Translated by: Tereza Novická, External Relations Division, CAO of the CAS
Photo: Shutterstock

 The text is released for use under the Creative Commons license.

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