New therapeutic targets to combat type 2 diabetes

One of the most confusing aspects for people with type 2 diabetes is high fasting blood glucose levels, because in those with insulin resistance, this triggers the liver to produce glucose, a process that still leaves many questions for the scientific community.

Now, the review article published in this journal Trends in Endocrinology and Metabolism We provide a comprehensive overview of the most important advances in understanding this mechanism, which will also help identify new drug targets in the fight against type 2 diabetes, which the World Health Organization (WHO) considers to be one of the pandemics of the 21st century.

The study is led by Professor Manuel Vásquez Carrera from the Department of Pharmacy and Food Sciences at the University of Barcelona, ​​the UB Biomedical Institute (IBUB), the Sant Joan de Déu Research Institute (IRSJD) and the Centre for Biomedical Research Network on Diabetes and Related Metabolic Diseases (CIBERDEM).

Participants of the study included experts Emma Barroso, Javier Jurado Aguilar and Xavier Palomel (UB-IBUB-IRJSJD-CIBERDEM) and Professor Walter Wahle from the University of Lausanne (Switzerland).

Therapeutic targets to fight disease

Type 2 diabetes is an increasingly common chronic disease in which an inadequate insulin response in the body leads to high circulating levels of glucose, the energy source for cells. It can lead to severe organ damage and is estimated to be underdiagnosed in a significant proportion of the affected population worldwide.

In patients with this condition, the glucose synthesis pathway in the liver (gluconeogenesis) is overactive, a process that can be controlled with drugs such as metformin.

“Recently, new factors involved in the control of hepatic gluconeogenesis have been identified. For example, studies from our group have revealed that growth differentiation factor 15 (GDF15) reduces the levels of proteins involved in hepatic gluconeogenesis,” says Professor Manuel Vásquez-Carrera from the UB's Department of Pharmacology, Toxicology and Therapeutic Chemistry.

Making progress in fighting this condition will also require further study of pathways such as TGF-β that are involved in the progression of metabolic dysfunction-associated fatty liver disease (MASLD), a very common condition that often coexists with type 2 diabetes.

“TGF-β plays a very important role in the progression of liver fibrosis and is one of the most important factors contributing to increased hepatic gluconeogenesis and therefore to type 2 diabetes. Therefore, studying the involvement of the TGF-β pathway in the regulation of hepatic gluconeogenesis may help to improve glycemic control,” says Vásquez-Carrera.

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

“To improve our approach to type 2 diabetes, it is important to be able to design combination therapies that take into account different factors,” says Vásquez-Carrera.

“Currently, there are several molecules, such as TGF-β, TOX3 and TOX4, that could be considered therapeutic targets for designing future strategies to improve patients' health. Their efficacy and safety will determine the success of treatment. We must not lose sight of the fact that controlling the overactivation of hepatic gluconeogenesis in type 2 diabetes is even more challenging. It is a key pathway for making glucose available during fasting and is difficult to control, as it is finely regulated by a large number of factors.”

Interestingly, other factors involved in the control of gluconeogenesis have also been identified in patients hospitalized with COVID-19 who showed hyperglycemia: “The high prevalence of hyperglycemia in patients hospitalized with COVID-19 seems to be linked to the ability of SARS-CoV-2 to induce the activity of proteins involved in hepatic gluconeogenesis,” the experts point out.

Metformin: What you didn't know about the most prescribed drug

Metformin, which inhibits hepatic gluconeogenesis, is the most commonly prescribed drug for the treatment of type 2 diabetes, but its mechanism of action has not yet been fully elucidated.

The drug was found to reduce gluconeogenesis by inhibiting complex IV of the mitochondrial electron transport chain, a mechanism independent of its classical effects previously known through activation of the AMPK protein, a sensor of cellular energy metabolism.

“Inhibition of mitochondrial complex IV activity (rather than complex I as previously thought) by metformin reduces the availability of substrates needed for glucose synthesis in the liver,” says Vásquez-Carrera.

Additionally, metformin may act on the intestine to reduce gluconeogenesis and ultimately produce changes in the liver that attenuate hepatic glucose production.

“Thus, metformin increases glucose absorption and utilisation in the intestine and produces metabolites that inhibit gluconeogenesis when they reach the liver via the portal vein. Finally, metformin also stimulates the secretion of GLP-1 in the intestine, which is a hepatic gluconeogenesis-inhibiting peptide and contributes to its antidiabetic effects,” he explains.

For now, Vásquez-Carrera and his team are continuing their work to uncover the mechanisms by which GDF15 controls hepatic gluconeogenesis.

“In parallel, we hope to design new molecules that increase circulating GDF15 levels. A potent inducer of GDF15 might improve blood glucose levels in patients with type 2 diabetes, not only by reducing hepatic gluconeogenesis but also through other actions of this cytokine,” the researchers conclude.