5,7- Dimethoxycoumarin Enhances Insulin Release and Stimulates Extrapancreatic Secretion of Amylin.

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 aimed to investigate the 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 10mg/kg, 20mg/kg 5,7-dimethoxycoumarin, 4) methanol fraction containing 10mg/kg, 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 5,7-dimethoxycoumarin had comparable plasma glucose control with glimepiride, with indirect insulin secretion effect unlike direct acting glimepiride; the methanol fraction was less effective. Both ethyl acetate and methanol fractions of 5,7- dimethoxycoumarin induced extrapancreatic amylin synthesis and secretion. Conclusion 5,7-dimethoxycoumarin will find special applications in the management of obesity, and 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. There is need to focus on natural compounds that stimulate extrapancreatic amylin release.