Is diabetes treatable?

Rolf Breinbauer (TU Graz), Robert Zimmermann and Gernot Grabner (both Uni Graz, from left to right) have laid the foundation for drugs against diabetes, fatty liver and cardiac insufficiency with their research. Photo: Uni Graz/Tzivanopoulos.

Graz researchers lay the foundation for medications to treat diabetes, fatty liver disease and heart failure

Many illnesses, such as type 2 diabetes, non-alcoholic fatty liver disease and heart problems are the result of an elevated level of fatty acids in the blood. Five years ago Graz researchers developed a drug treatment which reduces the level of fatty acids in a model organism. Now Robert Zimmermann (University of Graz) and Rolf Breinbauer (Graz University of Technology) are taking this research a step further. In a recently published paper they present a variation of the drug Atglistatin, which can now also be used in humans. This lays the foundation for the development of medications to treat lipid metabolism disorders such as type 2 diabetes, non-alcoholic fatty liver disease and heart failure.

A crucial enzyme

A key role in lipid metabolism is played by the enzyme ATGL (short for adipose triglyceride lipase). This mobilises fatty acids in the blood, which is the cause of many illnesses. “So the objective is to block ATGL in such a way that this suppression does not disrupt other processes in the body,” explains Robert Zimmerman (Uni Graz), describing this ingenious intervention in what is a highly sensitive system. He and Rolf Breinbauer (TU Graz) and their teams spent five years working meticulously to refine an ATGL inhibitor which can be used in humans. The starting point was the agent Atglistatin which they had previously synthesised. Its molecular structure was adjusted until the optimal variation was found. This is called NG-497 and has been shown to deactivate human ATGL. Rolf Breinbauer verifies this: “In the cell culture model we are able to inhibit ATGL completely and have so far not seen any harmful side-effects of this intervention.”

Market-ready research

The research work was part of a programme by Research Studios Austria (RSA-Atglistatin), which was awarded funding of 1.2 million euros from the Austrian Research Promotion Agency (FFG). In the near future the ATGL inhibitors created by this team will be developed further as part of a wings4innovation project, and tested in preclinical studies for their effectiveness and any side-effects. As well as exemplifying the successful collaboration between the University of Graz and Graz University of Technology in the natural sciences, this also demonstrates how university basic research can be of interest to high-tech pharma companies.

The research is part of the Field of Excellence BioHealth at the University of Graz.

Publication: Gernot F. Grabner […] Rolf Breinbauer* und Robert Zimmermann*, Small-Molecule Inhibitors Targeting Lipolysis in Human Adipocytes. Journal of the American Chemical Society. 2022, 144, 14, 6237–6250, https://doi.org/10.1021/jacs.1c10836

Gerhild Leljak

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