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

<b>Background and Aim:</b><i>Rhoifolin</i> is a bioactive flavonoid that possesses strong antioxidant and anti-inflammatory activities. The current investigation aimed to examine the anti-diabetic potential of <i>rhoifolin</i> in streptozotocin-induced diabetic rats. Dose-dependent (10 and 20 mg/kg) anti-hyperglycemic, anti-hyperlipidemic, anti-inflammatory, and antioxidant effects of <i>rhoifolin</i> 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 <i>rhoifolin</i>, qRT-PCR was carried out using rat pancreatic and hepatic tissues. <b>Results:</b> The results have shown that <i>rhoifolin</i> produced antioxidant effects, as exhibited by DPPH and ABTS⁺ assays, respectively. <i>Rhoifolin</i> showed potent alpha-amylase and alpha-glucosidase inhibitory activities. <i>Rhoifolin</i> enhanced the serum insulin level, significantly decreased the serum glucose, HOMA-IR, and cytokine levels, and improved the lipid profile. <i>Rhoifolin</i> also showed a substantial decline in insulin resistance in the treated rats. <i>Rhoifolin</i> significantly raised catalase and superoxide dismutase levels in hepatic tissues while potentially decreasing the malondialdehyde levels. Moreover, <i>rhoifolin</i> 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. <b>Conclusions:</b> Our results indicate that <i>rhoifolin</i> 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, <i>rhoifolin</i> could further be tested to introduce it as another viable treatment option for diabetes.