Key points:
- Researchers carried out experiments in mice and cell cultures to determine that GDF15 inhibits glucose synthesis in the liver.
- They found that the alterations to liver function were triggered by increased hepatic levels of transforming growth factor-beta 1 and an SMAD3 mediator protein—two main inducers of liver fibrosis.
- The results may improve currently available treatments for diabetes and shift how scientists approach the treatment of metabolic disorders.
Researchers identified a mechanism that can improve the efficiency of currently available treatments for diabetes. The study, published in Metabolism, focuses on the GDF15 protein—a factor expressed at high levels in heart failure, cancer, and fatty liver disease—and opens new ways to approach metabolic diseases.
Researchers carried out their experiments in mice and cell cultures. They found that mice deficient in GDF15 have glucose intolerance and low levels of AMPK protein in their liver, which acts as a sensor of energy metabolism in the cell. Using their models, the team detected increased glucose synthesis in the liver and increased liver fibrosis.
“Our study reveals that GDF15 inhibits glucose synthesis in the liver,” explained study lead Manuel Vázquez-Carrera, professor at the Institute of Biomedicine of the UB. “This pathway plays a decisive role in the generation of hyperglycemia in patients with type 2 diabetes mellitus.”
The researchers determined that the alterations to liver function were triggered by increased hepatic levels of transforming growth factor-beta 1 (TGF-b1) and an SMAD3 mediator protein—two main inducers of liver fibrosis. Treating cells with recombinant CDF15 activated AMPK and decreased levels of active SMAD3 in mouse liver and in primary hepatocyte cultures.
“These results suggest that the modulation of GDF15 levels could be useful to improve the effectiveness of current anti-diabetic treatments,” said Vázquez-Carrera. “Hepatic gluconeogenesis is key is in hyperglycemia in patients with type 2 diabetes mellitus, and serum TGF-b1 levels are also increased in these patients.”
In addition to improving currently available therapies, this study may shift how scientists approach the treatment of metabolic disorders. Mapping the GDF15 pathway has implications for treating fatty liver disease, heart failure, and cancer.