Online_Appendix_Dollet_et_al_Glutamine_Regulates_Skeletal_Muscle_Immunometabolism_in_Type_2_Diabetes.pdf (917.39 kB)
Download fileGlutamine Regulates Skeletal Muscle Immunometabolism in Type 2 Diabetes
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posted on 2022-01-18, 16:51 authored 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 KrookDysregulation 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.