Phloretamide Prevent Hepatic and Pancreatic Damage in Diabetic Male Rats by Modulating Nrf2 and NF-κB

This study examined the effect of phloretamide, a metabolite of phloretin, on liver damage and steatosis in streptozotocin-induced diabetes mellitus (DM) in rats. Adult male rats were divided into two groups: control (nondiabetic) and STZ-treated rats, each of which was further treated orally with the vehicle phloretamide 100 mg or 200 mg. Treatments were conducted for 12 weeks. Phloretamide, at both doses, significantly attenuated STZ-mediated pancreatic β-cell damage, reduced fasting glucose, and stimulated fasting insulin levels in STZ-treated rats. It also increased the levels of hexokinase, which coincided with a significant reduction in glucose-6 phosphatase (G-6-Pase), and fructose-1,6-bisphosphatase 1 (PBP1) in the livers of these diabetic rats. Concomitantly, both doses of phloretamide reduced hepatic and serum levels of triglycerides (TGs) and cholesterol (CHOL), serum levels of low-density lipoprotein cholesterol (LDL-c), and hepatic ballooning. Furthermore, they reduced levels of lipid peroxidation, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), mRNA, and total and nuclear levels of NF-κB p65, but increased mRNA levels, total and nuclear levels of Nrf2, as well as levels of reduced glutathione (GSH), superoxide dismutase (SOD-1), catalase (CAT), and heme-oxygenase-1 (HO-1) in the livers of diabetic rats. All of these effects were dose-dependent. In conclusion, phloretamide is a novel drug that could ameliorate DM-associated hepatic steatosis via its powerful antioxidant and anti-inflammatory effects. Mechanisms of protection involve improving the β-cell structure and hepatic insulin action, suppressing hepatic NF-κB, and stimulating hepatic Nrf2.