<p>Previous studies have shown that FGF-21 can ameliorate hyperglycemia and improve the level of oxidative stress in vivo in diabetic mice. The hypoglycemic effect is safe and lasting, but it takes a longer time to exert its effect. Insulin treatment of canine diabetes takes effect quickly; however, its action time is short, and it is prone to cause hypoglycemia. In the present study, we investigated the synergistic effect of cFGF-21 combined with insulin in the treatment of canine diabetes. In the short and long-term treatment of diabetic dogs, cFGF-21 combined with insulin showed an obvious synergistic effect, and its hypoglycemic effect was significantly better than that of cFGF-21 or insulin injection alone. The combination, exhibited the advantage of the fast onset of insulin and the long-term hypoglycemic effect of cFGF-21. Additionally, cFGF-21 combined with insulin effectively relieved the oxidative stress in diabetic dogs. Studies of the synergistic mechanism showed that cFGF-21 combined with insulin could effectively inhibit liver gluconeogenesis and the synthesis of long-chain fatty acids and promote the phosphorylation of the common factor AKT in the pathway to better regulate hyperglycemia in diabetic dogs. In conclusion, cFGF-21 combined with insulin is a promising candidate for canine diabetes therapeutics.</p>