New insights into insulin action: Dynamic signaling network offers therapeutic approaches for type 2 diabetes

Researchers from the German Diabetes Center (DDZ) and the Heinrich Heine University Dusseldorf (HHU) have studied the temporal pattern of insulin action on protein kinases in human muscle cells in detail for the first time. Their findings have now been published in the journal Nature Communications and reveal previously unknown mechanisms that could be used to treat type 2 diabetes.

Insulin is a vital hormone that controls numerous processes in the body-from blood glucose (“blood sugar”) regulation to cell growth. Impaired insulin action is a major factor in the development of type 2 diabetes, which in turn increases the risk of cardiovascular diseases, such as a heart attack or stroke. But how does insulin influence so many different processes in the cell? This question has now been examined by scientists from the DDZ together with researchers from the Max Planck Institute for Molecular Genetics in Berlin and the University of Oslo.

Insulin Regulates a Dynamic Network

Based on mass spectrometric analysis methods (phosphoproteomics), the researchers tracked changes in more than 13,000 phosphorylation sites in muscle cells over time. This involves small chemical modifications to proteins that act like molecular on and off switches and are induced by particular enzymes called protein kinases. The stimulation of muscles with insulin has major consequences for the coordination of molecular processes within the cell. The scientists discovered that a total of 159 different protein kinases-around a third of all members of this enzyme family-were activated after just a few minutes, which in turn regulates the activity of hundreds of other enzymes involved in energy metabolism and cell formation. The analysis has now shown for the first time that insulin triggers a complex network of signals that spread through the cells in a wavelike manner. Similar to radio transmissions, both the signal strength and the frequency of the waves play a role. The researchers found that the precise temporal pattern of the waves, i.e., the activation of protein kinases, is responsible for the targeted effect in the cell.

Certain signals are generated by the overlap of multiple waves, such as in the so-called mTOR signaling pathway-a key regulator of cell division and cell growth. Using mathematical models, the researchers demonstrated that this dynamic network of several hundred proteins is regulated by only around 30 enzymes (protein kinases and phosphatases). This finding could provide the basis for the development of new therapeutic approaches to improve the treatment of type 2 diabetes: Active substances that specifically activate or inhibit these key enzymes could enhance insulin action.

New Findings on Gene Regulation

In addition, it was shown that insulin influences the function of the so-called spliceosome complex, a key regulatory element of gene regulation. This suggests that the hormone insulin performs many more functions in the human body than was previously suspected. “Our research demonstrates that insulin not only controls blood glucose regulation, but orchestrates a dynamic network of protein modifications that coordinate the response of the cells to insulin in a precise and synchronized manner,” explains Prof. Dr. Hadi Al-Hasani, director of the Institute of Clinical Biochemistry and Pathobiochemistry at the DDZ and lead scientist of the study.

“The study provides important findings on the mechanisms of insulin action and could make a decisive contribution to the development of new and more targeted therapies for people with insulin resistance and diabetes mellitus,” adds Prof. Dr. Michael Roden, scientific director and spokesman of the board of the DDZ and director of the Clinic for Endocrinology and Diabetology at the University Hospital Düsseldorf (UKD).

The researchers hope that, in the long term, these findings will not only lead to an improved understanding of the development of type 2 diabetes but also deliver new treatment approaches.

Reference:

Turewicz, M., Skagen, C., Hartwig, S. et al. Temporal phosphoproteomics reveals circuitry of phased propagation in insulin signaling. Nat Commun 16, 1570 (2025). https://doi.org/10.1038/s41467-025-56335-6