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Breakthrough in diabetes treatment: understanding the mechanism of glucose regulation
Last reviewed: 02.07.2025
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One of the most challenging issues for patients with type 2 diabetes is high fasting glucose levels. This is because patients with insulin resistance start producing glucose in the liver, a process that is still not fully understood by the scientific community. Now, a review article published in Trends in Endocrinology & Metabolism presents the most significant advances in understanding this mechanism and identifies new targets for drug development against type 2 diabetes, which the World Health Organization (WHO) calls one of the pandemics of the 21st century.
The study and its participants
The study is led by Professor Manuel Vasquez-Carrera from the Faculty of Pharmacy and Food Sciences of the University of Barcelona, the UB Institute of Biomedicine (IBUB), the Sant Joan de Déu Research Institute (IRSJD) and the Biomedical Research Centre on Diabetes and Associated Metabolic Diseases (CIBERDEM). The study also includes experts Emma Barroso, Javier Jurado-Aguilar and Xavier Palomer (UB-IBUB-IRJSJD-CIBERDEM) and Professor Walter Wahli from the University of Lausanne (Switzerland).
Therapeutic targets in the fight against disease
Type 2 diabetes mellitus is an increasingly common chronic disease in which circulating glucose levels are elevated due to the body's insufficient response to insulin. It can cause severe organ damage and is estimated to remain undiagnosed in a significant percentage of the affected population.
In patients, the liver's glucose synthesis pathway (gluconeogenesis) is overactivated, which can be controlled with drugs such as metformin. "New factors involved in the control of hepatic gluconeogenesis have recently been identified. For example, our study showed that growth and differentiation factor (GDF15) reduces the levels of proteins involved in hepatic gluconeogenesis," says Professor Manuel Vasquez-Carrera.
To advance in the fight against this disease, it is also necessary to study pathways such as TGF-β, which is involved in the progression of metabolic dysfunction associated with fatty liver disease (MASLD), which often coexists with type 2 diabetes. "TGF-β plays an important role in the progression of liver fibrosis and is one of the most significant factors contributing to the increase in hepatic gluconeogenesis and, therefore, type 2 diabetes," emphasizes Vasquez-Carrera.
Metformin: Mysteries of the Most Common Drug
The mechanisms of action of metformin, the most commonly prescribed drug for the treatment of type 2 diabetes, which reduces hepatic gluconeogenesis, are still not fully understood. Recently, it was found that the drug reduces gluconeogenesis through inhibition of complex IV of the mitochondrial electron transport chain, which is a mechanism independent of the classical effects through activation of the protein AMPK.
"Inhibition of mitochondrial complex IV activity by metformin—and not complex I, as previously thought—reduces the availability of substrates needed for glucose synthesis in the liver," notes Vasquez-Carrera.
Next steps
The team led by Vasquez-Carrera is continuing its research work to decipher the mechanisms by which GDF15 can regulate hepatic gluconeogenesis. "In parallel, we want to develop new molecules that increase circulating levels of GDF15. If we have potent inducers of GDF15, we will be able to improve glycemia in people with type 2 diabetes by reducing hepatic gluconeogenesis and other actions of this cytokine," the researcher concludes.