New therapeutic targets to fight type 2 diabetes

One of the aspects that most confuses patients affected by type 2 diabetes mellitus is that they have high fasting glucose levels. This situation is explained because in these insulin-resistant patients, glucose production by the liver is triggered, a process still full of questions for the scientific community. Now, a study reviewing the results of other studies presents an integrative vision of the most notable advances to understand this mechanism and help identify new pharmacological targets in the fight against this ailment, which the World Health Organization (WHO) considers a of the pandemics of the 21st century.

The research was led by Professor Manuel Vázquez-Carrera, from the Faculty of Pharmacy and Food Sciences of the University of Barcelona (UB), the Institute of Biomedicine of the UB (IBUB), the Sant Joan de Déu Research Institute ( IRSJD) and the Network Biomedical Research Center for Diabetes and Associated Metabolic Diseases (CIBERDEM), in Spain. Also noteworthy is the participation of experts Emma Barroso, Javier Jurado-Aguilar and Xavier Palomer (UB, IBUB, IRSJD, CIBERDEM) and Professor Walter Wahli, from the University of Lausanne (Switzerland).

Type 2 diabetes mellitus is an increasingly common chronic disease that generates high levels of circulating glucose—cellular energy fuel—due to a deficient insulin response in the body. It can cause severe effects on different organs of the body and it is estimated that today it is underdiagnosed in a high percentage of the affected population around the world.

In patients, the glucose synthesis pathway in the liver (gluconeogenesis) is hyperactivated, a process that can be controlled through drugs such as metformin. «In recent years, new factors involved in the control of hepatic gluconeogenesis have been identified. For example, a study by our group revealed that growth differentiation factor (GDF15) reduces the levels of proteins involved in hepatic gluconeogenesis,” details Professor Manuel Vázquez-Carrera, from the Department of Pharmacology, Toxicology and Therapeutic Chemistry of the UB.

Manuel Vázquez-Carrera. (Photo: UB)

To advance in the fight against this pathology, we must also deepen the study of pathways such as the TGF-beta factor, which is involved in the progression of fatty liver disease associated with metabolic dysfunction (MASLD), a highly prevalent pathology. which often coexists with type 2 diabetes mellitus. «TGF-beta plays a very relevant role in the progression of liver fibrosis and has become one of the most important factors that can contribute to the increase in hepatic gluconeogenesis and Therefore, studying the participation of the TGF-beta pathway in the regulation of hepatic gluconeogenesis could help achieve better glycemic control,” emphasizes Vázquez-Carrera.

However, acting on a single factor to improve the regulation of gluconeogenesis does not seem to be a sufficient therapeutic strategy to adequately control the disease.

«Today there are several substances —TGF-beta, TOX3, TOX4, etc.— that could be considered therapeutic targets to design future strategies and improve the well-being of patients. Its effectiveness and safety will determine its therapeutic success. We cannot lose the perspective that the control of the overactivation of hepatic gluconeogenesis in type 2 diabetes mellitus has an additional difficulty: it is a key pathway to be able to have glucose in fasting situations, it is finely modulated by numerous factors and this makes regulation difficult,” he adds.

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Interestingly, other factors involved in the control of gluconeogenesis have also been identified in patients hospitalized with COVID-19 who showed high glucose levels. “Hyperglycemia was very prevalent in patients hospitalized with COVID-19, which seems to be related to the ability of SARS-CoV-2 to induce the activity of proteins involved in hepatic gluconeogenesis,” points out the expert.

Metformin: the unknowns of the most prescribed drug

The mechanisms of action of metformin, the most prescribed drug for the treatment of type 2 diabetes that reduces hepatic gluconeogenesis, are still not well understood. It has now been discovered that this drug decreases it by inhibiting complex IV of the mitochondrial electron transport chain. This is a mechanism independent of the classic effects that until now were known through the activation of the AMPK protein, a sensor of the cell’s energy metabolism.

“The inhibition of the activity of mitochondrial complex IV by metformin—not complex I as previously thought—reduces the availability of substrates necessary for hepatic glucose synthesis,” indicates Vázquez-Carrera.

In addition, metformin can also reduce gluconeogenesis through its effects on the intestine, causing changes that ultimately attenuate hepatic glucose production in the liver. «Thus, metformin increases the uptake and use of glucose in the intestine, and generates metabolites capable of inhibiting gluconeogenesis when they reach the liver through the portal vein. Finally, metformin also stimulates the secretion of GLP-1 in the intestine, a peptide inhibitor of hepatic gluconeogenesis that contributes to its antidiabetic effect,” he explains.

The new study is titled “Increased hepatic gluconeogenesis and type 2 diabetes mellitus.” And it has been published in the academic journal Trends in Endocrinology & Metabolism.

The team led by Vázquez-Carrera continues research to decipher the mechanisms by which GDF15 could regulate hepatic gluconeogenesis. «In parallel, we want to design new molecules that increase circulating levels of GDF15. If we have powerful GDF15 inducers, glycemia could be improved in those affected by type 2 diabetes mellitus by reducing hepatic gluconeogenesis, but also by other actions of this cytokine,” concludes the researcher. (Source: UB)