Barcelona [Spain], Having high fasting glucose levels is one of the most puzzling characteristics of type 2 diabetes mellitus patients. This is because the liver produces glucose in these insulin-resistant people, a mechanism that still raises many unanswered issues for scientists.
A comprehensive summary of the most important developments in understanding this process has now been provided in a review paper that was published in the journal Trends in Endocrinology & Metabolism.
Additionally, it aids the discovery of new therapeutic targets in the fight against type 2 diabetes mellitus, which the World Health Organization (WHO) lists as one of the epidemics of the twenty-first century. The study was led by the Faculty of Pharmacy of the University of Barcelona and Professor Manuel Vazquez-Carrera of the Faculty of Food Sciences, UB Institute of Biomedicine (IBUB), Sant Joan de Deu Research Institute (IRSJD) and the Center for Biomedical Research.Network on Diabetes and Associated Metabolic Diseases (CIBERDEM). Participants in the study include experts Emma Barroso, Javier Jurado-Aguilar and Javier Palomar (UB-IBUB-IRJSJD-SieberDEM) and Professor Walter Vahli of the University of Lausanne (Switzerland).
therapeutic targets to fight disease
Type 2 diabetes mellitus is an increasingly common 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 serious 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 overactivated, a process that is inhibited by drugs such as metformin. Can be controlled by medicines."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. Gives", said Professor Manuel Vazquez-Carrera, from UB's Department of Pharmacology, Toxicology and Medicinal 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, studying the involvement of the TGF-B pathway in the regulation of hepatic gluconeogenesis may help to achieve better glycemic control", emphasized 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 target both types of disease," Vazquez-Carrera said. 2 to consider the various factors involved in improving the outlook for diabetes mellitus."
“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 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 in fasting conditions, which 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, who have seen high glucose levels. “Hyperglycaemia was very 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. Metformin: Most Unknown of prescribed medication
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.Vazquez-Carrera said, "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". It may also reduce gluconeogenesis, 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 upon reaching 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.
A comprehensive summary of the most important developments in understanding this process has now been provided in a review paper that was published in the journal Trends in Endocrinology & Metabolism.
Additionally, it aids the discovery of new therapeutic targets in the fight against type 2 diabetes mellitus, which the World Health Organization (WHO) lists as one of the epidemics of the twenty-first century. The study was led by the Faculty of Pharmacy of the University of Barcelona and Professor Manuel Vazquez-Carrera of the Faculty of Food Sciences, UB Institute of Biomedicine (IBUB), Sant Joan de Deu Research Institute (IRSJD) and the Center for Biomedical Research.Network on Diabetes and Associated Metabolic Diseases (CIBERDEM). Participants in the study include experts Emma Barroso, Javier Jurado-Aguilar and Javier Palomar (UB-IBUB-IRJSJD-SieberDEM) and Professor Walter Vahli of the University of Lausanne (Switzerland).
therapeutic targets to fight disease
Type 2 diabetes mellitus is an increasingly common 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 serious 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 overactivated, a process that is inhibited by drugs such as metformin. Can be controlled by medicines."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. Gives", said Professor Manuel Vazquez-Carrera, from UB's Department of Pharmacology, Toxicology and Medicinal 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, studying the involvement of the TGF-B pathway in the regulation of hepatic gluconeogenesis may help to achieve better glycemic control", emphasized 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 target both types of disease," Vazquez-Carrera said. 2 to consider the various factors involved in improving the outlook for diabetes mellitus."
“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 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 in fasting conditions, which 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, who have seen high glucose levels. “Hyperglycaemia was very 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. Metformin: Most Unknown of prescribed medication
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.Vazquez-Carrera said, "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". It may also reduce gluconeogenesis, 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 upon reaching 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.