@article{52457794973e4c8ba8b6f13f2995e34d,
title = "Liver alanine catabolism promotes skeletal muscle atrophy and hyperglycaemia in type 2 diabetes",
abstract = "Both obesity and sarcopenia are frequently associated in ageing, and together may promote the progression of related conditions such as diabetes and frailty. However, little is known about the pathophysiological mechanisms underpinning this association. Here we show that systemic alanine metabolism is linked to glycaemic control. We find that expression of alanine aminotransferases is increased in the liver in mice with obesity and diabetes, as well as in humans with type 2 diabetes. Hepatocyte-selective silencing of both alanine aminotransferase enzymes in mice with obesity and diabetes retards hyperglycaemia and reverses skeletal muscle atrophy through restoration of skeletal muscle protein synthesis. Mechanistically, liver alanine catabolism driven by chronic glucocorticoid and glucagon signalling promotes hyperglycaemia and skeletal muscle wasting. We further provide evidence for amino acid–induced metabolic cross-talk between the liver and skeletal muscle in ex vivo experiments. Taken together, we reveal a metabolic inter-tissue cross-talk that links skeletal muscle atrophy and hyperglycaemia in type 2 diabetes.",
author = "Okun, {J{\"u}rgen G.} and Rusu, {Patricia M.} and Chan, {Andrea Y.} and Yuqin Wu and Yap, {Yann W.} and Thomas Sharkie and Jonas Schumacher and Schmidt, {Kathrin V.} and Roberts-Thomson, {Katherine M.} and Russell, {Ryan D.} and Annika Zota and Susanne Hille and Andreas Jungmann and Ludovico Maggi and Young Lee and Matthias Bl{\"u}her and Stephan Herzig and Keske, {Michelle A.} and Mathias Heikenwalder and M{\"u}ller, {Oliver J.} and Rose, {Adam J.}",
note = "Funding Information: The authors thank J. Fuhrmeister, A. Maida and T. Gantert (A170, DKFZ), L. Figur (A171, DKFZ), as well as J. Hetzer and D. Heide (F180, DKFZ) for experimental support. J.S. was supported by a fellowship from the Helmholtz International Graduate School for Cancer Research. M.H. was supported by an ERC Consolidator grant (HepatoMetaboPath), SFBTR 209 (Liver Cancer) and SFBTR179. This project has received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation programme under grant agreement no. 667273. This work was funded by the Helmholtz Future Topic {\textquoteleft}Aging and metabolic reprogramming{\textquoteright} (to S.H.). This work was was also funded by a project grant from the EFSD/Lilly European Diabetes Research Programme, as well as a Medical Research Grant from the Sir Edward Dunlop Medical Research Foundation (to A.J.R.). Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2021",
month = mar,
doi = "10.1038/s42255-021-00369-9",
language = "English (US)",
volume = "3",
pages = "394--409",
journal = "Nature Metabolism",
issn = "2522-5812",
publisher = "Springer Berlin",
number = "3",
}