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Beta cells play an indispensable role in regulating blood sugar levels in our bodies by producing insulin. In patients with type 2 diabetes, prolonged exposure to excess glucose and fats in the blood gradually damages these cells.

As a result, insulin production declines, making it increasingly difficult for the body to regulate blood sugar levels. Over time, patients may require insulin injections or other medications to compensate.

The recently completed study aimed to develop a method to protect beta cells from this type of damage. Specially designed ‘glue molecules’ are intended to prevent the hyperactivity of a key protein involved in glucose processing.

Eindhoven's contribution to the research

On behalf of ºÚÁϸ£ÀûÍø, PhD candidates and were responsible for designing and testing the molecules. Associate Professor Christian Ottmann was involved as lead researcher. ºÚÁϸ£ÀûÍø has also filed a patent for the developed glue molecule.

The University of Duisburg-Essen provided the chemical synthesis of these molecules. In New York, research then focused on cell biological experiments to test their efficacy. In the follow-up project, ºÚÁϸ£ÀûÍø will produce and optimize the molecules, while Mount Sinai conducts the necessary animal experiments using material produced in Eindhoven.

Key protein

The research focused on ChREBP, a protein that plays an essential role in glucose processing within beta cells. Under normal conditions, this protein helps regulate blood sugar levels by promoting insulin production. However, prolonged exposure to high sugar and fatty acid levels can cause it to become hyperactive. This leads to the destruction of beta cells and the development of type 2 diabetes.

To prevent or slow down this process, the scientists developed special 'molecular glues' that keep the protein trapped in the cell’s cytoplasm. This prevents it from entering the nucleus, where it could trigger harmful effects.

In laboratory tests on human beta cells, these glue molecules significantly reduced the damage caused by this process.

Research into medication

Proteins like ChREBP, which contribute to the development and progression of diabetes, have so far proven resistant to drug intervention. The research team is now working on refining these molecules and testing them in preclinical conditions. This will help determine whether the approach is suitable for further clinical development and, ultimately, for patient treatment.

An important part of the next phase is assessing the stability of the compound, says PhD candidate Marloes Pennings. For example, does the molecule remain intact in the body so that it continues to function as intended?

The ideal method of administration is also a key consideration. If this treatment eventually reaches the market as a medication, professor and promotor Luc Brunsveld would prefer it to come in the form of a pill. That would be far less invasive than carrying an insulin pump, for example. Further research needs to determine whether this is feasible.

This image shows how a synthesized molecule, or molecular glue (blue), binds to a protein (white) and its binding protein partner ChREBP (red).

The various panels show chemical structures of attempts to optimize such a molecule and the binding strength achieved.

The graph shows how well the 'blue' molecule binds to the protein complex at different concentrations.