Barcelona [Spain], The fact that fasting glucose levels are elevated in individuals with type 2 diabetes is one of the most puzzling factors. This is due to the fact that in these insulin-resistant individuals, the liver produces glucose, a process that still raises many unanswered issues for scientists.
The most significant developments in our knowledge of this mechanism have now been presented in a review paper that was published in the journal Trends in Endocrinology & Metabolism. In the fight against type 2 diabetes mellitus, which the World Health Organization (WHO) has listed as one of the epidemics of the twenty-first century, it also helps in the discovery of new therapeutic targets.
The UB Institute of Biomedicine (IBUB), the Sant Joan de Deu Research Institute (IRSJD), the Faculty of Pharmacy and Food Sciences at the University of Barcelona, the Biomedical Research Network Center on Diabetes and Associated Metabolic Diseases (CIBERDEM), and Professor Manuel Vázquez-Carrera, leader of the study. Are.Experts Emma Barroso, Javier Jurado-Aguilar, and Javier Palomar (UB-IBUB-IRJSJD-SIEBERDEM) as well as Professor Walter Vahli of the University of Lausanne (Switzerland) are involved in this work.Type 2 diabetes mellitus is an increasingly common A chronic disease that results from increased levels of glucose – the cellular energy fuel – due to a lack of insulin response in the body. It can cause severe organ damage and is estimated to be underdiagnosed in a high percentage of the affected population worldwide.
In patients, the glucose synthesis pathway (gluconeogenesis) in the liver is overactive, a process that can be controlled by drugs such as metformin. "Recently, new factors involved in the control of hepatic gluconeogenesis have been identified.For example, a study from our group showed that growth differentiation factor (GDF15) reduces the levels of proteins involved in hepatic gluconeogenesis", says Professor Manuel Vazquez-Carrera, UB's Department of Pharmacology, Toxicology and Therapeutics. From the Department of Chemistry.
To make progress in the fight against this pathology, it will also be necessary to further study pathways such as TGF-β, which are involved in the progression of metabolic dysfunction-associated fatty liver disease (MASLD), a very prevalent pathology that Often co-exist. With type 2 diabetes mellitus. “TGF-β plays a very relevant role in the progression of liver fibrosis and has become one of the most important factors that may contribute to increased hepatic gluconeogenesis and, therefore, contribute to type 2 diabetes mellitus. Therefore "The involvement of the TGF-β pathway in the regulation of hepatic gluconeogenesis may help to achieve better glycemic control", emphasizes Vazquez-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.
“It will be important to be able to design combination therapies that consider the different factors involved to improve the outlook for type 2 diabetes mellitus,” says Vazquez-Carrera.
“Today there are several molecules – TGF-β, TOX3, TOX4, etc. – that can be considered therapeutic targets for designing future strategies to improve the well-being of patients. Their efficacy and safety will determine their therapeutic success. We One cannot ignore the fact that there is an additional difficulty in controlling the hyperactivation of hepatic gluconeogenesis in type 2 diabetes mellitus: this is an important pathway for providing glucose under fasting conditions, it is finely regulated by many factors. And that makes regulation difficult”, he adds. Interestingly, other factors involved in the control of gluconeogenesis have also been identified in hospitalized COVID-19 patients, including those with high glucose levels. level has been observed.“Hyperglycaemia was highly prevalent in patients hospitalized with COVID-19, which appears to be related to the ability of SARS-CoV-2 to induce the activity of proteins involved in hepatic gluconeogenesis,” the experts say.
The mechanism of action of metformin, the most commonly prescribed drug for the treatment of type 2 diabetes, which reduces hepatic gluconeogenesis, is still not fully understood. It is now known that the drug reduces gluconeogenesis through inhibition of complex IV of the mitochondrial electron transport chain. This is a mechanism independent of the classical effects known so far, through activation of the AMPK protein, 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 the substrates required for hepatic glucose synthesis,” says Vazquez-Carrera.In addition, metformin may also reduce gluconeogenesis through its effects on the intestine, causing changes that ultimately reduce hepatic glucose production in the liver. "Thus, metformin increases glucose uptake and utilization in the intestine, and generates metabolites capable of inhibiting gluconeogenesis when it reaches the liver via the portal vein. Finally, metformin also stimulates the secretion of GLP-1 in the intestine. is a hepatic gluconeogenesis inhibitory peptide that contributes to its anti-diabetic effects", he explained.
The most significant developments in our knowledge of this mechanism have now been presented in a review paper that was published in the journal Trends in Endocrinology & Metabolism. In the fight against type 2 diabetes mellitus, which the World Health Organization (WHO) has listed as one of the epidemics of the twenty-first century, it also helps in the discovery of new therapeutic targets.
The UB Institute of Biomedicine (IBUB), the Sant Joan de Deu Research Institute (IRSJD), the Faculty of Pharmacy and Food Sciences at the University of Barcelona, the Biomedical Research Network Center on Diabetes and Associated Metabolic Diseases (CIBERDEM), and Professor Manuel Vázquez-Carrera, leader of the study. Are.Experts Emma Barroso, Javier Jurado-Aguilar, and Javier Palomar (UB-IBUB-IRJSJD-SIEBERDEM) as well as Professor Walter Vahli of the University of Lausanne (Switzerland) are involved in this work.Type 2 diabetes mellitus is an increasingly common A chronic disease that results from increased levels of glucose – the cellular energy fuel – due to a lack of insulin response in the body. It can cause severe organ damage and is estimated to be underdiagnosed in a high percentage of the affected population worldwide.
In patients, the glucose synthesis pathway (gluconeogenesis) in the liver is overactive, a process that can be controlled by drugs such as metformin. "Recently, new factors involved in the control of hepatic gluconeogenesis have been identified.For example, a study from our group showed that growth differentiation factor (GDF15) reduces the levels of proteins involved in hepatic gluconeogenesis", says Professor Manuel Vazquez-Carrera, UB's Department of Pharmacology, Toxicology and Therapeutics. From the Department of Chemistry.
To make progress in the fight against this pathology, it will also be necessary to further study pathways such as TGF-β, which are involved in the progression of metabolic dysfunction-associated fatty liver disease (MASLD), a very prevalent pathology that Often co-exist. With type 2 diabetes mellitus. “TGF-β plays a very relevant role in the progression of liver fibrosis and has become one of the most important factors that may contribute to increased hepatic gluconeogenesis and, therefore, contribute to type 2 diabetes mellitus. Therefore "The involvement of the TGF-β pathway in the regulation of hepatic gluconeogenesis may help to achieve better glycemic control", emphasizes Vazquez-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.
“It will be important to be able to design combination therapies that consider the different factors involved to improve the outlook for type 2 diabetes mellitus,” says Vazquez-Carrera.
“Today there are several molecules – TGF-β, TOX3, TOX4, etc. – that can be considered therapeutic targets for designing future strategies to improve the well-being of patients. Their efficacy and safety will determine their therapeutic success. We One cannot ignore the fact that there is an additional difficulty in controlling the hyperactivation of hepatic gluconeogenesis in type 2 diabetes mellitus: this is an important pathway for providing glucose under fasting conditions, it is finely regulated by many factors. And that makes regulation difficult”, he adds. Interestingly, other factors involved in the control of gluconeogenesis have also been identified in hospitalized COVID-19 patients, including those with high glucose levels. level has been observed.“Hyperglycaemia was highly prevalent in patients hospitalized with COVID-19, which appears to be related to the ability of SARS-CoV-2 to induce the activity of proteins involved in hepatic gluconeogenesis,” the experts say.
The mechanism of action of metformin, the most commonly prescribed drug for the treatment of type 2 diabetes, which reduces hepatic gluconeogenesis, is still not fully understood. It is now known that the drug reduces gluconeogenesis through inhibition of complex IV of the mitochondrial electron transport chain. This is a mechanism independent of the classical effects known so far, through activation of the AMPK protein, 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 the substrates required for hepatic glucose synthesis,” says Vazquez-Carrera.In addition, metformin may also reduce gluconeogenesis through its effects on the intestine, causing changes that ultimately reduce hepatic glucose production in the liver. "Thus, metformin increases glucose uptake and utilization in the intestine, and generates metabolites capable of inhibiting gluconeogenesis when it reaches the liver via the portal vein. Finally, metformin also stimulates the secretion of GLP-1 in the intestine. is a hepatic gluconeogenesis inhibitory peptide that contributes to its anti-diabetic effects", he explained.
