Rhoifolin Improves Glycometabolic Control in Streptozotocin-Induced Diabetic Rats by Up-Regulating the Expression of Insulin Signaling Proteins and Down-Regulating the MAPK/JNK Pathway.

Background and Aim:Rhoifolin is a bioactive flavonoid that possesses strong antioxidant and anti-inflammatory activities. The current investigation aimed to examine the anti-diabetic potential of rhoifolin in streptozotocin-induced diabetic rats. Dose-dependent (10 and 20 mg/kg) anti-hyperglycemic, anti-hyperlipidemic, anti-inflammatory, and antioxidant effects of rhoifolin were evaluated by measuring fasting blood glucose, serum glucose, serum insulin, HOMA-IR, lipidemic status, inflammatory cytokines, and hepatic antioxidant markers. To identify the underlying mechanism behind the anti-diabetic activity of rhoifolin, qRT-PCR was carried out using rat pancreatic and hepatic tissues. Results: The results have shown that rhoifolin produced antioxidant effects, as exhibited by DPPH and ABTS⁺ assays, respectively. Rhoifolin showed potent alpha-amylase and alpha-glucosidase inhibitory activities. Rhoifolin enhanced the serum insulin level, significantly decreased the serum glucose, HOMA-IR, and cytokine levels, and improved the lipid profile. Rhoifolin also showed a substantial decline in insulin resistance in the treated rats. Rhoifolin significantly raised catalase and superoxide dismutase levels in hepatic tissues while potentially decreasing the malondialdehyde levels. Moreover, rhoifolin significantly down-regulated the MAPK-8, TRAF-6, and TRAF-4 expressions and up-regulated the PDX-1, SIRT-1, INS-1, and GLUT-4 expressions in treated groups. Conclusions: Our results indicate that rhoifolin exhibits a hypoglycemic effect, which appears to be associated with its regulatory impact on metabolic inflammation and oxidative stress markers. This was accompanied by a lower HOMA-IR index, highlighting its potential role in promoting glucose homeostasis and mitigating insulin resistance. According to preliminary results, rhoifolin could further be tested to introduce it as another viable treatment option for diabetes.