Disorders of glucose metabolism in various tissues, including skeletal muscle tissue and adipose tissue are features of diabetes. The aim of the present study was to evaluate the long-term effect of moderate-intensity continuous exercise on the expression of irisin and sirtuin-1 genes in the skeletal muscle of streptozotocin-nicotinamide-diabetic rats. Thirty-six 8-week-old males were randomly divided into three groups: healthy control (n = 12), diabetic (n = 12), and moderate-persistent diabetes (n = 12). Diabetic groups developed diabetes by intraperitoneal injection of nicotinamide and STZ solution at a doses of 95 and 55 mg/kg. The diabetic-moderate-intensity continuous exercise group performed their training protocol by running on a treadmill for 12 weeks, 5 sessions per week. Forty-eight hours after the last training session, the subjects were anesthetized and their horseshoe muscle tissue was removed and the expression of the genes Irisin and Sirtuin-1 was measured. 12 weeks of moderate-intensity continuous exercise in diabetic mice resulted in a significant increase in the expression of the genes Irisin and Sirtuin-1 (p <0.05). Performing 12 weeks of continuous exercise with moderate intensity in diabetic rats increased the expression of Irisin and sirtuin-1. Thus, changes in the expression of irisin and serotonin-1 may improve the symptoms of metabolic syndrome and can be a compensatory mechanism for reducing oxidative stress in diabetics.