The results of the present study highlighted that hUC-MSCs pretreated with melatonin infusion were superior to either regimen of hUC-MSCs alone in ameliorating HFD- and STZ-induced T2DM in a mouse model through the downregulation of hyperglycemia insulin resistance, glucose tolerance, and oxidative stress, as well as the upregulation of serum insulin secretion and anti-inflammatory and antiapoptotic effects. The gene discussed is INS; the disease is type 2 diabetes mellitus.