Infusion of MSCs into high-fat diet/streptozotocin-induced T2D diabetic rats ameliorated hyperglycemia, reduced insulin resistance in peripheral tissue, and promoted β-cell function when delivered at the early phase (7 days after diabetes induction) but not at the later phase (21 days after diabetes induction).The MSCs promoted the recovery of streptozotocin-induced liver and pancreas damage.MSC infusion increased GLUT4 expression and increased insulin receptor substrate 1 (IRS1) and Akt phosphorylation in skeletal muscle, adipose, and liver tissues. Here, IRS1 is linked to diabetes mellitus.