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A study led by the University of Barcelona and the Center de Recerca Biomèdica en Xarxa de Diabetes i Malalties Metabòliques Associades (CIBERDEM) reveals that a new mechanism could improve the efficiency of available treatments against diabetes. The study, carried out with mice and cell cultures, may open new ways to address metabolic diseases that are a global health problem.
The study, published in the journal Metabolism, focuses on the GDF15 protein, a factor that is expressed at high levels in many diseases, such as heart failure, cancer or fatty liver. Obese patients also have high levels of this protein, but its functioning is altered and affected people can develop resistance to GDF15 (that is, a reduction in the effectiveness of its activity).
The research was directed by Professor Manuel Vázquez-Carrera, from the Faculty of Pharmacy and Food Sciences of the UB, the Institute of Biomedicine of the UB (IBUB), the Sant Joan de Déu Research Institute (IRSJD) and the CIBERDEM. . The participation of its researchers Patricia Rada and Ángela M. Valverde (CIBERDEM-CSIC-UAM) and Professor Walter Wahli, from the University of Lausanne (Switzerland), among other experts, stands out.
New alternatives to reduce glucose synthesis in the liver
“Our study reveals that the GDF15 factor inhibits glucose synthesis in the liver. This pathway has a decisive role in the generation of hyperglycemia (high blood glucose concentrations) in patients affected by type 2 diabetes mellitus,” explains Professor Manuel Vázquez-Carrera.
“The action of the protein would also help reduce the presence of liver fibrosis, a disorder that is associated with greater mortality in patients with fatty liver disease,” the researcher points out.
The work reveals that mice that are deficient in GDF15 have glucose intolerance and that in the liver they have low levels of the AMPK protein, a sensor of the cell’s energy metabolism that protects against type 2 diabetes mellitus.
Furthermore, in these study models, greater glucose synthesis was detected in the liver (hepatic gluconeogenesis) and also fibrosis in this organ.
Everything indicates that all the alterations described were triggered by an increase in hepatic levels of the factor TGF-B1 and a mediator protein SMAD3, which are the main inducers of liver fibrosis. Thus, treatment with recombinant GDF15 was able to activate AMPK and decreased levels of active SMAD3 in the liver of mice and in primary cultures of hepatocytes.
“In conclusion, the results indicate that the GDF15 factor activates the AMPK protein and inhibits hepatic gluconeogenesis and fibrosis by reducing the TGF-B1/SMAD3 pathway.”
“These results suggest that the modulation of GDF15 levels could be useful to improve the effectiveness of current antidiabetic treatments, since hepatic gluconeogenesis is key in hyperglycemia in patients with type 2 diabetes mellitus, and serum levels of TGF -B1 are also increased in these patients,” concludes the researcher.
