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Okun, J.G.* ; Rusu, P.M.* ; Chan, A.Y.* ; Yap, Y.W.* ; Sharkie, T.* ; Schumacher, J.* ; Schmidt, K.V.* ; Zota, A. ; Hille, S.* ; Jungmann, A.* ; Maggi. L.* ; Lee, Y.* ; Blüher, M. ; Herzig, S. ; Heikenwalder, M.* ; Müller, O.* ; Rose, A.J.*

Liver alanine catabolism promotes skeletal muscle atrophy and hyperglycaemia in type 2 diabetes.

Nat. Metab. 3, 394–409 (2021)
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.

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 uncover dysregulated systemic alanine metabolism and hyper-expression of the alanine transaminases (ALT) in the liver of obese/diabetic mice and humans. Hepatocyte-selective silencing of both ALT enzymes revealed a clear role in systemic alanine clearance which related to glycemic control. In obese/diabetic mice, not only did silencing both ALT enzymes retard hyperglycemia, but also reversed skeletal muscle atrophy. This was due to a rescue of depressed skeletal muscle protein synthesis, with a liver-skeletal muscle amino acid metabolic crosstalk exemplified by ex vivo experiments. Mechanistically, chronic liver glucocorticoid and glucagon signaling driven liver alanine catabolism promoted hyperglycemia and skeletal muscle wasting. Taken together, here we reveal an endocrine-hepato-muscular metabolic cycle linking hyperglycemia and skeletal muscle atrophy in type 2 diabetes.

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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
ISSN (print) / ISBN 2522-5812
e-ISSN 2522-5812
Zeitschrift Nature metabolism
Quellenangaben Band: 3, Heft: , Seiten: 394–409 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Cancer (IDC)
Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Förderungen Helmholtz Future Topic AMPro
Helmholtz International Graduate School for Cancer Research
Lilly European Diabetes Research Programme
Horizon 2020 Framework Programme
EC | European Research Council (ERC)
Faculty of Medicine, Nursing and Health Sciences, Monash University
Sir Edward Dunlop Medical Research Foundation
European Foundation for the Study of Diabetes (EFSD)
Sir Edward 'Weary' Dunlop Medical Research Foundation