Ameliorative activity of standardized Coccoloba uvifera leaves extract against streptozotocin-induced diabetic rats via activation of IRS-1/PI3K/AKT/GLUT2 pathway in liver

Background Coccoloba uvifera L. (Family: Polygonaceae) known as sea grape is natively distributed in middle and south America. The aqueous leaf extract showed inhibitory activities against alpha-glucosidase and alpha-amylase in previous reports. Moreover, the hydroalcoholic leaves extract ameliorated hyperglycemia in the oral glucose tolerance test. Despite these promising results, the extracts used in these studies were not standardized, nor was their mechanism of action elucidated. The current study aims to standardize the ethanolic C. uvifera leaves extract (CU) using markers, and assess its ameliorative activity against diabetes and its hepatoprotective activity against diabetic complications. Results Standardized leaves' ethanolic extract contained 0.09 +/- 0.00057 and 0.23 +/- 0.0011 mg/g gallic acid and rutin, respectively, as estimated by HPLC. Administration of CU (100, 200 and 400 mg/kg) for 6 weeks ameliorated DM manifestations in STZ-induced diabetic rats in a dose-dependent manner. The ethanolic extract reduced fasting blood glucose, increased serum insulin and reduced elevated liver enzymes. CU counteracted oxidative stress, promoted glucose metabolizing enzymes and reduced gluconeogenesis enzymes. The underlying mechanism involved increased expression of IR, IRS-1, IRS-2 and GLUT2 in liver tissue through activation of PI3K/AKT signaling. The histopathological study demonstrated reduced inflammation and hepatocyte degeneration. Conclusion CU could be used as a promising antidiabetic drug with hepatoprotective activity in diabetes hepatic complications. The standardized CU ethanolic extract should be further assessed clinically alone or in combination with other antidiabetic remedies.