Grapefruit Peel-derived 5,7- Dimethoxycoumarin Enhances Insulin Release and Stimulates Extrapancreatic Secretion of Amylin in Wistar Rats.

Objective: Coumarins are known to have antidiabetic properties. They are also known to have direct effects on the cardiovascular system. However, their insulin and amylin-releasing effects have not been thoroughly studied. This study investigated the effect of 5,7-dimethoxycoumarin (Citropten) fractions in grapefruit peel on insulin and amylin secretions in normal male Wistar rats.

Methods: Methanol extract from 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 the 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, 1 ml of sterile water 2) positive control, 0.2 mg/kg glimepiride, 3) ethyl acetate fraction containing 20 mg/kg 5,7-dimethoxycoumarin, 4) methanol fraction containing 20 mg/kg 5,7-dimethoxycoumarin, 5a) 1 ml 0.6% hydrogen peroxide and 20 mg/kg 5,7-dimethoxycoumarin; 5b) 1 ml 6% hydrogen peroxide and 20 mg/kg 5,7-dimethoxycoumarin; and 5c) 1000 mg/kg Vitamin C and 20 mg/kg 5,7-dimethoxycoumarin.

Results: Results showed that ethyl acetate fraction containing 20 mg/kg 5,7-dimethoxycoumarin had comparable plasma glucose control as obtained with glimepiride, with indirect insulin secretion effect unlike direct-acting glimepiride; the methanol fraction was less effective. An oral Glucose Tolerance Test confirmed the antidiabetic efficacy of 5,7-dimethoxycoumarin. 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 for people with diabetes having 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 a need to focus on natural compounds that stimulate extrapancreatic amylin release, especially in patients with type 1 diabetes who are insulin dependent.