5,7- Dimethoxycoumarin Indirectly Enhances Insulin Release, But Directly Induces the Synthesis and Secretion of Amylin, 3 Times More Than Glimepiride

Abstract Objective Oxidative stress decreases the ability of β-cells to secrete insulin through glucolipotoxicity of the pancreatic islets. Flavonoids modulate insulin and amylin secretion through mainly antioxidant activities. Coumarins isomers of flavonoids have direct effects on the cardiovascular system, not linked to antioxidant activities. This study aim to investigate in vivo the direct effects of 5,7-dimethoxycoumarin (Citropten) fractions present in grapefruit peel on insulin and amylin secretions in normal male Wistar rats. Methods Methanol extract of grapefruit peels was fractionated using vacuum assisted liquid chromatography with n-Hexane, Ethyl acetate and Methanol. Gas Chromatography Mass Spectrometry analysis reported ethyl acetate fraction with highest concentration (85.66%) of 5,7-dimethoxycoumarin. Intraperitoneal Glucose Tolerance Test was performed on 5 sets of 5 rats receiving intraperitoneally: 1) negative control, 1ml of sterile water 2) positive control, 0.2mg/kg glimepiride, 3) ethyl acetate fraction containing 20mg/kg 5,7-dimethoxycoumarin, 4) methanol fraction containing 20mg/kg 5,7-dimethoxycoumarin 5a)1ml H2O2 (0.6%, 6%) plus 20mg/kg 5,7-dimethoxycoumarin, and 5b)1000mg/kg Vitamin C plus 20mg/kg 5,7-dimethoxycoumarin. Results Results showed Ethyl acetate fractions containing 10mg/kg and 20mg/kg dimethoxycoumarin had comparable plasma glucose control with glimepiride. Both ethyl acetate and methanol fractions of 5,7- dimethoxycoumarin had indirect insulin secretion effect, but directly induced amylin synthesis and secretion 3-fold that of glimepiride. Conclusion 5,7-dimethoxycoumarin will find special application in diabetics with chronic complications. Since the overall plasma glucose regulation is achieved through amylin and insulin synergy, attention should be shifted from insulin-based to amylin-based therapy, and also shifted from regulating blood glucose level to regulating its absorption in the GIT.