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Background: Adipose tissue inflammation is considered as one of the major mechanisms underlying the pathogenesis of insulin resistance and complications in diabetes. Here, we aimed to study the effects of adipose-derived stromal cells on diabetes-induced insulin resistance and M1 cytokine expression., Methods: Stromal vascular fractions (SVFs) purified from the inguinal adipose tissue of diabetic mice were treated with plasma from either nondiabetic (Lepr +/+ ) or diabetic (Lepr db/db ) mice and injected into the inguinal white adipose tissue of Lepr db/db mice., Results: We found that diabetic plasma treatment induced, whereas nondiabetic plasma suppressed TNF-α, IL-1β, and dipeptidyl peptidase 4 (DPP4) mRNA expression in SVFs in vitro. Importantly, the injection of nondiabetic plasma-treated SVFs significantly decreased TNF-α, IL-6, IL-1β, CCL2, and IL-33 and induced IL-10 mRNA expression in adipose tissue of Lepr db/db mice in vivo. Furthermore, we observed that nondiabetic plasma-treated SVFs increased mRNA expression of Foxp3 in adipose tissue macrophages and Foxp3 in adipose CD4 + T cells, decreased CD11b + CD11c + cells in adipose tissue, and suppressed mRNA expression of ICAM-1, FCM3, IL-6, IL-1β, iNOS, TNF-α, and DPP4 as well as protein expression of DPP4 and phosphorylated JNK and NF-κB in the liver of Lepr db/db mice. Moreover, we found that nondiabetic plasma-treated SVFs increased Akt activation following insulin administration and attenuated glucose intolerance in Lepr db/db mice., Conclusions: Our results demonstrate that nondiabetic plasma inhibits M1 but increases M2 cytokine expression in adipose tissue of diabetic mice. Most importantly, our findings reveal that nondiabetic plasma-treated SVFs are capable of mitigating diabetes-induced plasma DPP4 activity, liver inflammation, and insulin resistance and that may be mediated through suppressing M1 cytokines but increasing IL-10 and Tregs in adipose tissue. Altogether, our findings suggest that adipose stromal cell-based therapy could potentially be developed as an efficient therapeutic strategy for the treatment of diabetes., (© 2022. The Author(s).)