the liver is triggered, a process that is still full of questions for the scientific community. Now, a review article presents a comprehensive overview of the most important advances in understanding this mechanism.The liver activation process still raises many questions for the scientific community. A recent article in the journal Trends in Endocrinology & Metabolism provides a comprehensive overview of the recent advances in understanding this process. It also helps to identify new targets for drugs in the fight against type 2 diabetes mellitus, which the World Health Organization (WHO) considers a major global health issue. The study is conducted by Professor Manuel Vázquez-Carrera, from the Faculty of Pharmacy and Food Sciences at the University of Barcelona.The UB Institute of Biomedicine (IBUB), the Sant Joan de Déu Research Institute (IRSJD) and the Centre for Biomedical Research Network on Diabetes and Associated Metabolic Diseases (CIBERDEM) collaborated on a study with 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 to combat the disease
Type 2 diabetes mellitus is a common chronic disease that leads to high levels of circulating glucose, due to a deficient insulin response, which is the cellular energy fuel.Once in the body, non-alcoholic fatty liver disease can cause severe damage to the organs and is often not diagnosed in a large portion of the global population. In patients, the liver’s glucose synthesis pathway, known as gluconeogenesis, becomes overactive, but this process can be managed with medications like metformin. New factors that play a role in controlling hepatic gluconeogenesis have been discovered, such as growth differentiation factor (GDF15), which has been found to reduce the levels of proteins involved in this process, according to Professor Manuel Vázquez-Carrera from the UB’s Department of Pharmacology, Toxicology, and Therapeutic Chemistry.The fight against metabolic dysfunction-associated fatty liver disease (MASLD) and type 2 diabetes mellitus requires further research into pathways such as TGF-β, according to experts in hepatology and therapeutic chemistry. TGF-β is known to play a significant role in the progression of liver fibrosis, which can lead to increased hepatic gluconeogenesis and the development of type 2 diabetes mellitus. Therefore, studying the involvement of the TGF-β pathway in regulating hepatic function is crucial for making progress in treating these conditions.Vázquez-Carrera emphasizes the potential benefits of gluconeogenesis for improving glycaemic control. However, addressing a single factor to regulate gluconeogenesis may not be enough to effectively manage the disease. Vázquez-Carrera suggests that combination therapies should be designed to consider various factors involved in type 2 diabetes mellitus. He also mentions several molecules, such as TGF-β, TOX3, and TOX4, as potential therapeutic targets for future strategies.In order to improve the well-being of patients, the effectiveness and safety of treatments are crucial for their success. It’s important to consider that managing the excessive activation of hepatic gluconeogenesis in type 2 diabetes mellitus presents an added challenge, as it is a critical process for providing glucose during fasting and is regulated by numerous factors, making it difficult to control,” he explains.
Interestingly, other factors involved in regulating gluconeogenesis have also been found in COVID-19 patients with high glucose levels. “Hyperglycemia was common in hospitalized patients with COVID-19, highlighting the significance of finding effective ways to manage this aspect of the disease.”
“It has been observed that liver dysfunction is highly prevalent in patients hospitalised with COVID-19, which appears to be linked to the ability of SARS-CoV-2 to stimulate the activity of proteins involved in hepatic gluconeogenesis,” the specialist explains.
Metformin: the mysteries of the most commonly prescribed medication
The ways in which metformin, the most frequently prescribed medication for treating type 2 diabetes, reduces hepatic gluconeogenesis are not completely understood. It has recently been revealed that the medication decreases gluconeogenesis by inhibiting complex IV of the mitochondrial electron transport chain. This is a mechanism separate from the traditional effects that have been known until now.Through the activation of the AMPK protein, which is a sensor of the cell’s energy metabolism. “Inhibition of mitochondrial complex IV activity by metformin – not complex I as previously thought – reduces the availability of substrates required for hepatic glucose synthesis,” says Vázquez-Carrera. Additionally, metformin can also reduce gluconeogenesis through its effects on the gut. This leads to changes that ultimately decrease hepatic glucose production in the liver. Therefore, metformin increases glucose uptake and utilization in the gut, and generates metabolites capable of inhibiting gluconeogenesis when they reach the liver via the portal.The vein. metformin also stimulates the secretion of GLP-1 in the intestine, a hepatic gluconeogenesis inhibitory peptide that contributes to its anti-diabetic effect,” he explains.
Currently, the team led by Vázquez-Carrera is continuing its research to understand how GDF15 may regulate hepatic gluconeogenesis. “At the same time, we want to create new molecules that can increase GDF15 levels in the bloodstream. By developing powerful GDF15 inducers, we could improve blood sugar levels in people with type 2 diabetes by reducing hepatic gluconeogenesis, as well as through other actions of this cytokine,” the researcher concludes.
