Skip to main content

Advertisement

SpringerLink
Log in

Naringenin enhances insulin-stimulated tyrosine phosphorylation and improves the cellular actions of insulin in a dietary model of metabolic syndrome

  • Original Contribution
  • Published:
European Journal of Nutrition Aims and scope Submit manuscript

Abstract

Background

There is a growing interest in identifying putative insulin sensitizers from the herbal sources.

Aim of the study

The present study explores the effects of naringenin, a bioflavonoid, in the high fructose-induced model of insulin resistance.

Methods

Adult male Wistar rats were divided into two groups and were fed either a starch-based control diet or a high fructose diet (60 g/100 g) for 60 days. From the 16th day, rats in each group were divided into two, one of which was administered naringenin (50 mg/kg b.w.) and the other was untreated for the next 45 days. Oral glucose tolerance test (OGTT) was done on day 59. On day 60, the levels of glucose, insulin, triglycerides (TG), free fatty acids (FFA) in blood, and the activities of insulin-inducible and suppressible enzymes in the cytosolic and mitochondrial fractions of liver and skeletal muscle were assayed. The extent of protein tyrosine phosphorylation in response to insulin was determined by assaying protein tyrosine kinase (PTK) and protein tyrosine phosphatase (PTP) in liver. Liver histology with periodic acid-Schiff (PAS) staining was done to detect glycogen.

Results

Fructose administration increased the plasma levels of glucose, insulin, TG, and FFA as compared to control rats. Insulin resistance was indicated by alterations in insulin sensitivity indices. Alterations in enzyme activities and reduced glycogen content were observed in fructose-fed rats. PTP activity was higher, while PTK activity was lower suggesting reduced tyrosine phosphorylation status. Administration of naringenin improved insulin sensitivity and enhanced tyrosine phosphorylation in fructose-fed animals, while it did not affect the parameters in control diet-fed rats.

Conclusions

Naringenin improves insulin signaling and sensitivity and thereby promotes the cellular actions of insulin in this model.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

HOMA:

Homeostatic model assessment

FFA:

Free fatty acids

ISI:

Insulin sensitivity index

NAD+ :

Nicotinamide adenine dinucleotide

NADH:

Nicotinamide adenine dinucleotide reduced

OGTT:

Oral glucose tolerance test

PTP:

Protein tyrosine phosphatase

PTK:

Protein tyrosine kinase

PAS:

Periodic acid-Schiff

QUICKI:

Quantitative insulin sensitivity check index

STZ:

Streptozotocin

TG:

Triglycerides

References

  1. Ali MM, El Kader MA (2004) The influence of naringin on the oxidative state of rats with streptozotocin-induced acute hyperglycaemia. Z Naturforsch C 59:726–733

    CAS  Google Scholar 

  2. Basciano H, Federico L, Adeli K (2005) Fructose, insulin resistance and metabolic dyslipidemia. Nutr Metab 2:5–18

    Article  Google Scholar 

  3. Begum N, Sussman KE, Draznin B (1991) Differential effects of diabetes on adipocyte and liver phosphotyrosine and phosphoserine phosphatase activities. Diabetes 40:1620–1629

    Article  CAS  Google Scholar 

  4. Bezerra RM, Ueno M, Silva MS, Tavares DQ, Carvalho CR, Saad MJ (2000) A high fructose diet affects the early steps of insulin action in muscle and liver of rats. J Nutr 30:1531–1535

    Google Scholar 

  5. Bizeau ME, Thresher JS, Pagliassotti MJ (2001) A high-sucrose diet increases gluconeogenic capacity in isolated periportal and perivenous rat hepatocytes. Am J Physiol Endocrinol Metab 280:E695–E702

    CAS  Google Scholar 

  6. Borradaile NM, de Dreu LE, Huff MW (2003) Inhibition of net HepG2 cell apolipoprotein B secretion by the citrus flavonoid naringenin involves activation of phosphatidylinositol 3-kinase, independent of insulin receptor substrate-1 phosphorylation. Diabetes 52:2554–2561

    Article  CAS  Google Scholar 

  7. Brandstrup N, Kirk JE, Bruni C (1957) The hexokinase and phosphoglucoisomerase activities of aortic and pulmonary artery tissue in individuals of various ages. J Gerontol 12:166–171

    CAS  Google Scholar 

  8. Choi JS, Yokozawa T, Oura H (1991) Improvement of hyperglycemia and hyperlipemia in streptozotocin-diabetic rats by a methanolic extract of Prunus davidiana stems and its main component, prunin. Planta Medica 57:208–211

    Article  CAS  Google Scholar 

  9. Cornblath M, Randle PJ, Parmeggiani A, Morgan HE (1963) Effects of glucagon and anoxia on lactate production, glycogen content and phosphorylase activity in the perfused isolated rat heart. J Biol Chem 235:1592–1597

    Google Scholar 

  10. Falholt K, Lund B, Falholt W (1973) An easy colorimetric micro method for routine determination of free fatty acids in plasma. Clin Chim Acta 46:105–111

    Article  CAS  Google Scholar 

  11. Foster LB, Dunn RT (1973) Stable reagents for determination of serum triglycerides by a colorimetric Hantzsch condensation method. Clin Chem 19:338–340

    CAS  Google Scholar 

  12. Felgines C, Texier O, Morand C, Manach C, Scalbert A, Régerat F, Rémésy C (2000) Bioavailability of the flavanone naringenin and its glycosides in rats. Am J Physiol Gastrointest Liver Physiol 279:G1148–G1154

    CAS  Google Scholar 

  13. Fuhr U, Klittich K, Staib AH (1993) Inhibitory effect of grapefruit juice and its bitter principal naringenin on CYP1A2 dependent metabolism of caffeine in man. Br J Clin Pharmacol 35:431–436

    CAS  Google Scholar 

  14. Fuhr U (1998) Drug interactions with grapefruit juice. Extent, probable mechanism and clinical relevance. Drug Saf 18:251–272

    Article  CAS  Google Scholar 

  15. Gancedo JM, Gancedo C (1971) Fructose-1, 6-diphosphatase, phosphofructokinase and glucose-6-phosphate dehydrogenase from fermenting and non-fermenting yeasts. Arch Mikrobiol 76:132–138

    Article  CAS  Google Scholar 

  16. Gutt M, Davis CL, Spitzer SB, Llabre MM, Kumar M, Czarnecki EM, Schneiderman N, Skyler JS, Marks JB (2000) Validation of the insulin sensitivity index (ISI0,120): comparison with other measures. Diab Res Clin Pract 47:177–184

    Article  CAS  Google Scholar 

  17. Hannan JM, Ali L, Rokeya B, Khaleque J, Akhter M, Flatt PR, Abdel-Wahab YH (2007) Soluble dietary fibre fraction of Trigonella foenum-graecum (fenugreek) seed improves glucose homeostasis in animal models of type 1 and type 2 diabetes by delaying carbohydrate digestion and absorption, and enhancing insulin action. Br J Nutr 97:514–521

    Article  CAS  Google Scholar 

  18. Huong DT, Takahashi Y, Ide T (2006) Activity and mRNA levels of enzymes involved in hepatic fatty acid oxidation in mice fed citrus flavonoids. Nutrition 22:546–552

    Article  CAS  Google Scholar 

  19. Johnson D, Lordy H (1967) Isolation of liver and kidney mitochondria. Methods Enzymol 10:94–96

    Article  CAS  Google Scholar 

  20. Jung UJ, Lee MK, Jeong KS, Choi MS (2004) The hypoglycemic effect 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 

  21. Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, Quon MJ (2000) Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 85:2402–2410

    Article  CAS  Google Scholar 

  22. King J (1965) The dehydrogenases or oxidoreductases-lactate dehydrogenase. In: Van D (ed) Practical clinical enzymology. Nostrand Company Ltd, London, pp 83–93

    Google Scholar 

  23. Klimes I, Seböková E, Vrána A, Kazdová L (1993) Raised dietary intake of N-3 polyunsaturated fatty acids in high sucrose-induced insulin resistance: animal studies. Ann NY Acad Sci 683:69–81

    Article  CAS  Google Scholar 

  24. Koide H, Oda T (1959) Pathological occurrence of glucose-6-phosphatase in serum in liver diseases. Clin Chim Acta 4:554–561

    Article  CAS  Google Scholar 

  25. Lam TK, Van de Werve G, Giacca A (2003) Free fatty acids increase basal hepatic glucose production and induce hepatic insulin resistance at different sites. Am J Physiol Endocrinol Metab 284:E281–E290

    CAS  Google Scholar 

  26. Le KA, Tappy L (2006) Metabolic effects of fructose. Curr Opin Clin Nutr Metab Care 9:469–475

    Article  CAS  Google Scholar 

  27. Lee CH, Jeong TS, Choi YK, Hyun BW, Oh GT, Kim EH, Kim JR, Han JI, Bok SH (2001) Anti-atherogenic effect of citrus flavonoids, naringin and naringenin, associated with hepatic ACAT and aortic VAM-1 and MCP-1 in high cholesterol-fed rabbits. Biochem Biophys Res Commun 284:681–688

    Article  CAS  Google Scholar 

  28. Lee MH, Yoon S, Moon JO (2004) The flavonoid naringenin inhibits dimethylnitrosamine-induced liver damage in rats. Biol Pharm Bull 27:72–76

    Article  CAS  Google Scholar 

  29. Li RW, Theriault AG, Au K, Douglas TD, Casaschi A, Kurowska EM, Mukherjee R (2006) Citrus polymethoxylated flavones improve lipid and glucose homeostasis and modulate adipocytokines in fructose-induced insulin resistant hamsters. Life Sci 20:365–373

    Article  Google Scholar 

  30. Lim SL, Soh KP, Kuppusamy UR (2008) Effects of naringenin on lipogenesis, lipolysis and glucose uptake in rat adipocyte primary culture: a natural antidiabetic agent. Internet J Altern Med 5:1–10

    Google Scholar 

  31. Liu IM, Tzeng TF, Liou SS, Lan TW (2007) Myricetin, a naturally occurring flavonol, ameliorates insulin resistance induced by a high-fructose diet in rats. Life Sci 81:1479–1488

    Article  CAS  Google Scholar 

  32. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  Google Scholar 

  33. Madden JA, Bird MI, Man Y, Raven T, Myles DD (1991) Two non-radioactive assays for phosphotyrosine phosphatases with activity toward the insulin receptor. Anal Biochem 199:210–215

    Article  CAS  Google Scholar 

  34. Martinez FJ, Rizza RA, Romero JC (1994) High-fructose feeding elicits insulin resistance, hyperinsulinism, and hypertension in normal mongrel dogs. Hypertension 23:456–463

    CAS  Google Scholar 

  35. Mathews DR, Hosker JP, Rudenkl AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419

    Article  Google Scholar 

  36. Matsumura H, Miyachi S (1980) Cycling assay for nicotinamide adenine dinucleotides. Methods Enzymol 69:465–470

    Article  CAS  Google Scholar 

  37. Meyerovitch J, Rothenberg P, Shechter Y, Bonner-Weir S, Kahn CR (1991) Vanadate normalizes hyperglycemia in two mouse models of non-insulin-dependent diabetes mellitus. J Clin Invest 87:1286–1294

    Article  CAS  Google Scholar 

  38. Morales MA, Jabaggy AJ, Terenzyl HP (1973) Mutations affecting accumulation of glycogen. Neurospora News lett 20:24–25

    Google Scholar 

  39. Obrosova I, Oates P, Nakano T, Petrash JM (1996) Glycolytic pathway, redox state of NAD-couples and energy metabolism in lens in rats with short-term streptozotocin diabetes (Abstract). Diabetes 45(suppl 2):195A

    Google Scholar 

  40. Ortiz-Andrade RR, Sánchez-Salgado JC, Navarrete-Vázquez G, Webster SP, Binnie M, García-Jiménez S, León-Rivera I, Cigarroa-Vázquez P, Villalobos-Molina R, Estrada-Soto S (2008) Antidiabetic and toxicological evaluations of naringenin in normoglycaemic and NIDDM rat models and its implications on extra-pancreatic glucose regulation. Diabetes Obes Metab 10:1097–1104

    Article  CAS  Google Scholar 

  41. Pittas AG, Joseph NA, Greenberg AS (2004) Adipocytokines and insulin resistance. J Clin Endocrinol Metab 89:447–452

    Article  CAS  Google Scholar 

  42. Rijksen G, Van Oirschot BA, Staal GE (1991) Nonradioactive assays of protein-tyrosine kinase activity using anti-phosphotyrosine antibodies. Methods Enzymol 200:98–107

    Article  CAS  Google Scholar 

  43. Rutledge AC, Adeli K (2007) Fructose and the metabolic syndrome: pathophysiology and molecular mechanisms. Nutr Rev 65:S13–S23

    Article  Google Scholar 

  44. Saija A, Scalese M, Lanza M, Marzullo D, Bonina F, Castelli F (1995) Flavonoids as antioxidant agents: importance of their interaction with biomembranes. Free Radic Biol Med 19:481–486

    Article  CAS  Google Scholar 

  45. Schiller KR, Mauro LJ (2005) Tyrosine phosphatases as regulators of skeletal development and metabolism. J Cell Biochem 96:262–277

    Article  CAS  Google Scholar 

  46. Shang M, Cai S, Han J, Li J, Zhao Y, Zheng J, Namba T, Kadota S, Tezuka Y, Fan W (1998) Studies on flavonoids from fenugreek (Trigonella foenum graecum L). Zhongguo Zhong Yao Za Zhi 23:614–616

    CAS  Google Scholar 

  47. Shim YJ, Doo HK, Ahn SY, Kim YS, Seong JK, Park IS, Min BH (2003) Inhibitory effect of aqueous extract from the gall of Rhus chinensis on alpha-glucosidase activity and postprandial blood glucose. J Ethnopharmacol 85:283–287

    Article  Google Scholar 

  48. Slater EC, Bonner WD (1952) Effect of fluoride on succinate oxidase system. J Biochem 52:185–196

    CAS  Google Scholar 

  49. So FV, Guthrie N, Chambers AF, Moussa M, Carroll KK (1996) Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices. Nutr Cancer 26:167–181

    Article  CAS  Google Scholar 

  50. Southgate DA (1995) Digestion and metabolism of sugars. Am J Clin Nutr 62:203S–211S

    CAS  Google Scholar 

  51. Suga A, Hirano T, Kageyama H, Osaka T, Namba Y, Tsuji M, Miura M, Adachi M, Inoue S (2000) Effects of fructose and glucose on plasma leptin, insulin, and insulin resistance in lean and VMH-lesioned obese rats. Am J Physiol Endocrinol Metab 278:E677–E683

    CAS  Google Scholar 

  52. Sugimoto K, Suzuki J, Nakagawa K, Hayashi S, Enomoto T, Fujita T, Yamaji R, Inui H, Nakano Y (2005) Eucalyptus leaf extract inhibits intestinal fructose absorption, and suppresses adiposity due to dietary sucrose in rats. Br J Nutr 93:957–963

    Article  CAS  Google Scholar 

  53. Tesch GH, Allen TJ (2007) Rodent models of streptozotocin-induced diabetic nephropathy. Nephrology (Carlton) 12:261–266

    Article  Google Scholar 

  54. Thresher JS, Podolin DA, Wei Y, Mazzeo RS, Pagliassotti MJ (2000) Comparison of the effects of sucrose and fructose on insulin action and glucose tolerance. Am J Physiol Regul Integr Comp Physiol 279:R1334–R1340

    CAS  Google Scholar 

  55. Ueno M, Bezerra RMN, Silva MS, Tavares DQ, Carvalho CR, Saad MJA (2000) A high-fructose diet induced changes in pp185 phosphorylation in muscle and liver of rats. Braz J Med Biol Res 33:1421–1427

    Article  CAS  Google Scholar 

  56. Valentine WN, Tanaka KR (1966) Pyruvate kinase: clinical aspects. Methods Enzymol 9:468–473

    Article  CAS  Google Scholar 

  57. White MF, Kahn CR (1994) The insulin signaling system. J Biol Chem 269:1–4

    CAS  Google Scholar 

  58. Wu LY, Juan CC, Hwang LS, Hsu YP, Ho PH, Ho LT (2004) Green tea supplementation ameliorates insulin resistance and increases glucose transporter IV content in a fructose-fed rat model. Eur J Nutr 43:116–124

    Article  CAS  Google Scholar 

  59. Zavaroni I, Sander S, Scott S, Reaven GM (1980) Effect of fructose feeding on insulin secretion and insulin action in the rat. Metabolism 29:970–973

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Dr. R. Sundarapandiyan, Lecturer, Department of Pathology, Government Medical College, Theni, Tamil Nadu, India for his help in histopathological studies and the Indian Council of Medical Research, New Delhi, India, for providing financial support.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalai Nagar, 608002, Tamil Nadu, India

    Sriramajayam Kannappan & Carani Venkatraman Anuradha

Authors
  1. Sriramajayam Kannappan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carani Venkatraman Anuradha
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carani Venkatraman Anuradha.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kannappan, S., Anuradha, C.V. Naringenin enhances insulin-stimulated tyrosine phosphorylation and improves the cellular actions of insulin in a dietary model of metabolic syndrome. Eur J Nutr 49, 101–109 (2010). https://doi.org/10.1007/s00394-009-0054-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00394-009-0054-6

Keywords

Search

Navigation