Diosmin Potentiates the Antidiabetic Effects of Linagliptin in Nicotinamide/Streptozotocin-Induced Diabetic Wistar Rats

<b>Background/Objectives:</b> Natural therapeutics for the treatment of diabetes mellitus represent a common challenge for many researchers. Thus, the aim of this study was to evaluate the antihyperglycemic and anti-inflammatory effects and the hepatic antioxidant activities of both diosmin and linagliptin on nicotinamide/streptozotocin-induced diabetes mellitus in rats. <b>Methods:</b> Induction of diabetes mellitus was produced by injecting an intraperitoneal dose of nicotinamide (60 mg/kg) to 16-hour-fasted rats, then after 15 min, an intraperitoneal dose of streptozotocin (60 mg/kg) was injected. The rats with diabetes were orally treated with linagliptin (1 mg/kg), diosmin (10 mg/kg), and both of them every other day for 4 weeks. <b>Results:</b> The elevated hepatic glucose-6-phosphatase and glycogen phosphorylase activities, the lowered concentrations of serum insulin, C-peptide, and hepatic glycogen, and the diminished hepatic antioxidant defense system of nicotinamide/streptozotocin-induced diabetic rats were all potentially improved by the therapies. The treatments also improved the deteriorated adiponectin and resistin mRNA expression in visceral adipose tissue of nicotinamide/streptozotocin-induced diabetic rats. In addition, the treatments induced a recovery of damaged islets of Langerhans and a regeneration of islet cells in association with the enhancement of the formation of insulin granules in β-cells and the improvement of kidney function; the combined effect was the most potent. <b>Conclusions:</b> Diosmin alone or in combination with linagliptin has potent antidiabetic effects, which were managed through their insulinotropic and insulin-improving actions. The diosmin in combination with linagliptin has the most potent antihyperglycemic effects.