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Grapefruit juice improves glucose intolerance in streptozotocin-induced diabetes by suppressing hepatic gluconeogenesis



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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  1. Florida department of citrus: history of dieting, Florida, Department of Citrus, Lakeland FL, 2003

  2. Bailey DG, Spence JD, Edgar B, Bayliff CD, Arnold JM (1989) Ethanol enhances the hemodynamic effects of felodipine. Clin Invest Med 12:357–362

    CAS  Google Scholar 

  3. 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

    Article  CAS  Google Scholar 

  4. 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

    Article  Google Scholar 

  5. 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

    Article  CAS  Google Scholar 

  6. 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

    Article  CAS  Google Scholar 

  7. 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

    Article  CAS  Google Scholar 

  8. 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

    Article  CAS  Google Scholar 

  9. 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

    Article  CAS  Google Scholar 

  10. 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

    Article  CAS  Google Scholar 

  11. 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

    CAS  Google Scholar 

  12. Seifter S, Dayton S et al (1950) The estimation of glycogen with anthrone reagent. Arch Biochem Biophys 25:191–200

    CAS  Google Scholar 

  13. 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

    Article  CAS  Google Scholar 

  14. 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

    Google Scholar 

  15. 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

    Article  CAS  Google Scholar 

  16. 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

    CAS  Google Scholar 

  17. Bentle LA, Lardy HA (1976) Interaction of anions and divalent metal ions with phosphoenolpyruvate carboxykinase. J Biol Chem 251:2916–2921

    CAS  Google Scholar 

  18. 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

    Article  CAS  Google Scholar 

  19. 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

    Article  CAS  Google Scholar 

  20. 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

    Article  CAS  Google Scholar 

  21. 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

    CAS  Google Scholar 

  22. 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

    Article  CAS  Google Scholar 

  23. 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

    Article  CAS  Google Scholar 

  24. 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

    Article  CAS  Google Scholar 

  25. 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

    CAS  Google Scholar 

  26. Xulu S, Owira PMO (2012) Naringin ameliorates atherogenic dyslipidemia but not hyperglycemia in rats with type 1 diabetes. J Cardiovasc Pharmacol 59:133–141

    Article  CAS  Google Scholar 

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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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Correspondence to Peter M. O. Owira.

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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).

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  • Grapefruit juice
  • Diabetes
  • Insulin
  • Gluconeogenesis