Natural killer cell-derived exosomal miR-1249-3p attenuates insulin resistance and inflammation in mouse models of type 2 diabetes

Abstract

Natural killer (NK) cells have been suggested to be associated with type 2 diabetes by regulating systemic inflammation. However, the mechanism by which NK cells regulate insulin sensitivity remains unknown. This study shows that NK-derived exosomes from lean mice attenuate obesity-induced insulin resistance and inflammation in mice of type 2 diabetes. Moreover, lean NK-derived exosomes enhance insulin sensitivity and relieve inflammation in adipocytes and hepatocytes. MiR-1249-3p, which is significantly upregulated in lean NK-derived exosomes, can be transferred from NK cells to adipocytes and hepatocytes via exosomes. NK-derived exosomal miR-1249-3p dramatically induces cellular insulin sensitivity and relieves inflammation. Mechanistically, exosomal miR-1249-3p directly targets SKOR1 to regulate the formation of ternary complex SMAD6/MYD88/SMURF1, which mediates glucose homeostasis by suppressing the TLR4/NF-κB signaling pathway. This study reveals an emerging role for NK-derived exosomal miR-1249-3p in remission of insulin resistance, and provides a series of potential therapeutic targets in type 2 diabetes.

Effect of Shuangdan Mingmu Capsule on Diabetic Retinopathy in Rats via Regulation of miRNAs

“…MiR-1249 may inhibit the angiogenesis of human umbilical vein endothelial cells by targeting VEGF-A, 45 which is involved in endothelial cell proliferation and apoptosis. Furthermore, miR-1249-3p has attenuated insulin resistance and inflammation in a mouse model of type 2 diabetes, 46 is involved in the development of diabetes and its complications, 47–49 and can be used as a biomarker for diabetes and a potential target for the treatment of diabetes. Numerous studies have shown that miR-155-5p plays an important role in the progression of diabetes.…”

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“…Therefore, it might be that metabolism-regulating miRNAs play a vital role in the dynamics of metabolic homeostasis. 256 …”

Exosomal non coding RNAs as a novel target for diabetes mellitus and its complications

“…The miR-17-5p-Mfn1/2-NF-ΚB pathway has anti-inflammatory and anti-apoptotic effects in GDM [ 82 ]. miR-1249–3p has reduced IR and inflammation in a mouse model of T2DM [ 83 ]. miRNA-26a promotes regulatory T cells to suppress T1DM [ 84 ].…”