Hypoglycemic effects of grapefruit juice (GFJ) are widely recognized, but the mechanism(s) by which GFJ lowers blood glucose levels have not previously been investigated.
Wistar rats [250–300 g body weight (BW)] were divided into eight groups (n = 7). Group 1 animals were orally treated with 3.0 ml/kg BW of distilled water for 60 days, while groups 3, 4, 5, 6 were similarly treated with 3.0 ml/kg BW of GFJ. Groups 4 and 7 as well as 2, 5, 6 and 8 were given 45.0 and 60.0 mg/kg BW intraperitoneal injections streptozotocin, respectively, while groups 2 and 6 animals were additionally injected with insulin (4.0 units/kg, S.C., b.d), respectively. Fasting blood glucose (FBG) and glucose tolerance tests were done. Hepatic glycogen content and glucokinase, glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) activities were measured in homogenized liver tissues.
Diabetic rats, groups 2 and 4–8 exhibited significantly reduced weight gain but increased polydipsia compared to controls. FBG was significantly increased in diabetic rats compared to controls but were significantly improved in GFJ-treated—compared to non-treated—diabetic rats. Similarly, diabetic rats showed significant glucose intolerance compared to controls which was improved by GFJ treatment. GFJ treatment did not improve fasting plasma insulin in diabetic rats. GFJ treatment significantly elevated glucokinase activity and hepatic glycogen concentrations but suppressed the activities of G6Pase and PEPCK, respectively, in diabetic animals.
These findings show that GFJ is not insulinotropic but improves glucose intolerance in diabetic rats by suppressing hepatic gluconeogenesis.
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Florida department of citrus: history of dieting, Florida, Department of Citrus, Lakeland FL, 2003
Bailey DG, Spence JD, Edgar B, Bayliff CD, Arnold JM (1989) Ethanol enhances the hemodynamic effects of felodipine. Clin Invest Med 12:357–362
Lundahl J, Regårdh CG, Edgar B, Johnsson G (1997) Effects of grapefruit juice ingestion-pharmacokinetics and haemodynamics of intravenously administered felodipine in healthy men. Eur J Clin Pharmacol 52:139–145
Saito Hirata-Koizumi M, Matsumoto M et al (2005) Undesirable effects of citrus juice on pharmacokinetics of drugs: focus on recent studies. Drug Saf 28:677–694
Christensen H, Asberg A, Holmboe AB, Berg KJ (2002) Co-administration of grapefruit juice increases systemic exposure of diltiazem in healthy volunteers. Eur J Clin Pharmacol 58:515–520
Zaidenstein Dishi V, Gips M et al (1998) The effect of grapefruit juice on pharmacokinetics of orally administered verapamil. Eur J Clin Pharm 54:337–340
Kupferschmidt HH, Fattinger KE, Ha HR et al (1998) Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man. Br J Clin Pharmacol 45:355–359
Gorinstein S, Leontowiwicz TH, Leontowicz M et al (2005) Red Star Ruby (Sunrise) and blood quantities of Jaffa grapefruits and their influence on plasma lipid levels and plasma antioxidant activity in rats fed with cholesterol-containing and cholesterol-free diets. Life Sci 77:2384–2397
Gorinstein S, Caspi A, Libman I et al (2006) Red grapefruit positively influences serum triglycerides level in patients suffering from coronary atherosclerosis: studies in vitro and in humans. J Agric Food Chem 54:1887–1892
Fujioka Greenway F, Sheard J et al (2006) The effects of grapefruit juice on weight and insulin resistance: relationship to metabolic syndrome. J Med Food 9:49–54
Owira PMO, Ojewole JAO (2009) Grapefruit juice improves glycemic control but also exacerbates metformin-induced lactic acidosis in non-diabetic rats. Methods Find Exp Clin Pharmacol 31:563–570
Seifter S, Dayton S et al (1950) The estimation of glycogen with anthrone reagent. Arch Biochem Biophys 25:191–200
Davidson AL, Arion WJ (1987) Factors underlying significant underestimations of glucokinase activity in crude liver extracts: Physiological implications of higher cellular activity. Arch Biochem Biophys 253:156–167
Barzila N, Roseseti L (1993) Role of glucokinase and glucose-6-phosphate in the acute and chronic regulation of hepatic glucose fluxes by insulin. J Biol Chem 268:25019–25025
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilising the principle of protein-dye binding. Anal Biochem 72:248–254
Lange AJ, Arion WJ, Burchell A et al (1986) Aluminum ions are required for stabilization and inhibition of hepatic microsomal glucose-6-phosphatase by sodium fluoride. J Biol Chem 261:101–107
Bentle LA, Lardy HA (1976) Interaction of anions and divalent metal ions with phosphoenolpyruvate carboxykinase. J Biol Chem 251:2916–2921
Stiffin RM, Sullivan SM, Carlson GM et al (2008) Differential inhibition of cytosolic PEPCK by substrate analogues. Kinetic and structural characterization of inhibitor recognition. Biochemistry 47:2099–2109
Sundaram B, Singhal K, Sandhir R (2011) Ameliorating effect of chromium administration on hepatic glucose metabolism in streptozotocin-induced experimental diabetes. BioFactors 38:59–68
Postic C, Shiota M, Niswender KD, Jetton TL et al (1999) Dual roles for glucokinase in glucose homeostasis as determined by rat liver and β cell-specific gene knock-outs using Cre recombinase. J Biol Chem 274:305–315
Herling AW, Burger HJ, Schwab D et al (1998) Pharmacodynamic profile of a novel inhibitor of the hepatic glucose-6-phosphatase system. Am J Physiol 274:G1087–G1093
Kim YD, Park KG, Lee YS et al (2008) Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase—dependent regulation of the orphan nuclear receptor SHP. Diabetes 57:306–314
Jung UJ, Lee MK, Park YB et al (2006) Effects of citrus flavonoids on lipid metabolism and glucose-regulating enzymes mRNA levels in type-2 diabetic mice. Int J Biochem Cell Biol 38:1134–1145
Purushotham A, Tian M, Belury MA (2008) The citrus fruit flavonoid naringenin suppresses hepatic glucose production from Fao hepatoma cells. Mol Nutr Food Res 53(2):300–307
Jung UJ, Lee MK, Jeong KS et al (2004) Hypoglycemic effects of hesperidin and naringin are partly mediated by hepatic glucose-regulating enzymes in C57BL/KsJ-db/db mice. J Nutr 134:2499–2503
Xulu S, Owira PMO (2012) Naringin ameliorates atherogenic dyslipidemia but not hyperglycemia in rats with type 1 diabetes. J Cardiovasc Pharmacol 59:133–141
The study was supported by a grant from the Medical Research Council of South African, and there is no conflict of interest to declare. The authors also wish to thank the Biomedical Resource Unit of the University of KwaZulu-Natal for helping with in vivo animal work as well as the final year BPharm students; Dludlu S, Govender K, Mahomed R, Moola W, Ngcobo L, Prem R, Ramasir S for helping with experimental work.
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Hayanga, J.A., Ngubane, S.P., Murunga, A.N. et al. Grapefruit juice improves glucose intolerance in streptozotocin-induced diabetes by suppressing hepatic gluconeogenesis. Eur J Nutr 55, 631–638 (2016). https://doi.org/10.1007/s00394-015-0883-4