Insulin modulates MMP-2 and 9 activities through the control of oxidative stress in the heart of diabetic rats Running title: Insulin modulates MMPs via oxidative stress control

This study aimed to evaluate the effects of insulin therapy on oxidative stress markers, matrix metalloproteinases (MMPs) 2 and 9 activities and cardiac remodeling in alloxan-induced diabetic rats. Forty-two male Wistar rats were randomly allocated into three groups (n≤ of 14 animals), for 30 days: control (CON; saline, IP); diabetes mellitus (DM; alloxan 60 mg/kg, IP); and insulin-treated diabetic (DINS; NPH insulin 4 U, twice daily, IP). After the treatment, the animals were anesthetized and euthanized, plasma and heart were collected for biochemical, histological and enzymatic analysis. Compared to DM, the DINS exhibited improved body and heart masses, as well as reduced food intake. Insulin significantly decreased glycemia, triglycerides and total cholesterol. The antioxidant defenses were enhanced (increased catalase activity and concentrations of reduced glutathione), while the oxidative damage was reduced (decreased protein carbonyls and thiobarbituric acid reactive substances concentrations). Histological analysis revealed a reduction in the inflammatory nuclei and collagen deposition. MMP-2 and MMP-9 activities were lower in the DINS compared to the DM. The insulin treatment attenuated oxidative stress, modulated MMP activity and collagen accumulation in the heart of diabetic rats. These findings support the potential role of insulin in mitigating diabetes-induced cardiac remodeling through redox balance.