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Glutamine Regulates Skeletal Muscle Immunometabolism in Type 2 Diabetes

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posted on 18.01.2022, 16:51 by Lucile Dollet, Michael Kuefner, Elena Caria, David Rizo-Roca, Logan Pendergrast, Ahmed M. Abdelmoez, Håkan KR Karlsson, Emilie Dalbram, Jonas Treebak, Jun Harada, Erik Näslund, Mikael Rydén, Juleen R. Zierath, Nicolas J. Pillon, Anna Krook
Dysregulation of skeletal muscle metabolism influences whole body insulin sensitivity and glucose homeostasis. We hypothesized that type 2 diabetes-associated alterations in the plasma metabolome directly contribute to skeletal muscle immunometabolism and the subsequent development of insulin resistance. To this end, we analyzed the plasma and skeletal muscle metabolite profile and identified glutamine as a key amino acid that correlated inversely with body mass index (BMI) and HOMA-IR index in men with normal glucose tolerance or type 2 diabetes. Using an in vitro model of human myotubes and an in vivo model of diet-induced obesity and insulin resistance in male mice, we provide evidence that glutamine levels directly influence the inflammatory response of skeletal muscle and regulates the expression of the adaptor protein GRB10, an inhibitor of insulin signaling. Moreover, we demonstrate that a systemic increase of glutamine levels in a mouse model of obesity improves insulin sensitivity and restores glucose homeostasis. We conclude that glutamine supplementation may represent a potential therapeutic strategy to prevent or delay the onset of insulin resistance in obesity by reducing inflammatory markers and promoting skeletal muscle insulin sensitivity.


Diabetesfonden DIA2018-336 DIA2018-357 European Foundation for the Study of Diabetes Insamlingsstiftelsen Diabetes Wellness Network Sverige Knut och Alice Wallenbergs Stiftelse 2018-0094 Novo Nordisk Fonden NNF15SA0018346 NNF18CC0034900 Stockholms Läns Landsting SLL20170159 Vetenskapsrådet 2009-1068 2015-00165 2018-02389