The hepatokine fetuin-A disrupts functional maturation of pancreatic beta cells – published online 25/03/2021

Felicia Gerst, Elisabeth Kemter, Estela Lorza-Gil, Gabriele Kaiser, Ann-Kathrin Fritz, Rita Nano, Lorenzo Piemonti, Marie Gauder, Andreas Dahl, Silvio Nadalin, Alfred Königsrainer, Falko Fend, Andreas L. Birkenfeld, Robert Wagner, Martin Heni, Norbert Stefan, Eckhard Wolf, Hans-Ulrich Häring, Susanne Ullrich

There is accumulating evidence that beta cells acquire a neonatal-like phenotype in type 2 diabetes, i.e. increased basal secretion and reduced glucose responsiveness. The loss of functional maturity occurs early during disease development and hepatic steatosis could be a driver of this process. Fetuin-A is a fetal glycoprotein that is downregulated post-partum, but the secretion of which is increased by hepatocytes of the fatty liver. This glycoprotein is also a marker of insulin resistance and a risk factor for type 2 diabetes. In this issue, Gerst et al (https://doi.org/10.1007/s00125-021-05435-1) report that fetuin-A restrains functional maturity of both neonatal and adult beta cells. They show that fetuin-A impairs TGFβ receptor (TGFBR)–SMAD2/3 signalling, thereby curtailing expression of genes governing beta cell identity. It is also shown to reduce adaptive proliferation via downregulation of forkhead box M1 (FOXM1) targets. By doing so, fetuin-A impairs glucose responsiveness and decreases beta cells mass. Indeed, the authors found a negative correlation between plasma fetuin-A level and beta cell area in individuals without diabetes. The authors conclude that their findings suggest that therapies effectively counteracting hepatic steatosis may also prevent beta cell failure and the onset of type 2 diabetes.

All News