Forty-three tricyclic matrinic derivatives with a unique scaffold were prepared and evaluated for their stimulation effects on glucose consumption in HepG2 cells. The structure-activity relationship was systematically elucidated for the first time. Among them, compound 17a exhibited the most promising potency, and dose-dependently increased glucose consumption in L6 myotubes. It significantly lowered blood glucose, glucosylated haemoglobin and AGE level, and improved glucose tolerance and insulin resistance in KK-Ay mice as well. More importantly, 17a effectively ameliorated diabetic nephropathy (DN), as indicated by the improvement of renal function and pathological changes, and decrease of urinary protein. Furthermore, 17a could induce glycolysis but suppressed aerobic oxidation of glucose, in a similar mechanism to Metform. Our results indicated that in addition to hyperglycemia, 17a may be developed to treat diabetic complication such as DN.