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Journal of Physiology and Biochemistry

, Volume 68, Issue 3, pp 421–431 | Cite as

Effect of Rebaudioside A, a diterpenoid on glucose homeostasis in STZ-induced diabetic rats

  • Ramalingam SaravananEmail author
  • Kaliyappan Vengatash babu
  • Vinayagam Ramachandran
Original Paper

Abstract

Rebaudioside A (Reb A), a major constituent of Stevia rebaudiana, was recently proposed as an insulinotropic agent. The aim of this investigation was to evaluate the antihyperglycemic effect of Reb A on the activities of hepatic enzymes of carbohydrate metabolism in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced in adult male Albino Wistar rats, weighing 180–200 g, by a single intraperitoneal injection at a dose of STZ (40 mg/kg body weight). Diabetic rats showed significant (P < 0.05) increase in the levels of plasma glucose and glycosylated hemoglobin and significant (P < 0.05) decrease in the levels of plasma insulin and hemoglobin. Activities of gluconeogenic enzymes such as glucose-6-phosphatase and fructose-1,6-bisphosphatase were significantly (P < 0.05) increased while hexokinase and glucose-6-phosphate dehydrogenase were significantly (P < 0.05) decreased in the liver along with glycogen. Oral treatment with Reb A to diabetic rats significantly (P < 0.05) decreased blood glucose and reversed these hepatic carbohydrate metabolizing enzymes in a significant manner. Histopathology changes of pancreas confirmed the protective effects of Reb A in diabetic rats. Thus, the results show that Reb A possesses an antihyperglycemic activity and provide evidence for its traditional usage in the control of diabetes.

Keywords

Rebaudioside A Streptozotocin Carbohydrate metabolism Insulin Diabetes mellitus 

Abbreviations

ATP

Adenosine triphosphate

DNA

Deoxyribonucleic acid

GLUT-2

Glucose transporter-2

Hb

Hemoglobin

HbA1c

Glycosylated hemoglobin

NAD

Nicotinamide adenine dinucleotide

NADPH

Nicotinamide adenine dinucleotide phosphate

Reb A

Rebaudioside A

STZ

Streptozotocin

References

  1. 1.
    Abdel-Rahi S, EI-Saadany S, Abo-Eytta AM, Wasif MM (1992) The effect of sammo administration on some fundamental enzymes of pentose phosphate pathway and energy metabolites of alloxanised rats. Nahrung 36:8–14CrossRefGoogle Scholar
  2. 2.
    Abudula R, Matchkov VV, Jeppesen PB, Nilsson H, Aalkjaer C, Hermansen K (2008) Rebaudioside A directly stimulates insulin secretion from pancreatic beta cells: a glucose dependent action via inhibition of ATP-sensitive K+ channals. Diabetes Obes Metab 11:74–85Google Scholar
  3. 3.
    Adisakwattana S, Roengsamran S, Hsu WH, Yibchok-Anun S (2005) Mechanisms of antihyperglycemic effect of p-methoxycinnamic acid in normal and STZ-induced diabetic rats. Life Sci 78:406–412PubMedCrossRefGoogle Scholar
  4. 4.
    American Diabetes Association (2010) Diagnosis and classification of diabetes mellitus. Diabetes Care 33:S62–S69CrossRefGoogle Scholar
  5. 5.
    Andrikopoulos S, Rosella G, Gaskin A, Thorburn A, Kaczmarczyk S, Zajac JD, Proietto J (1993) Impaired regulation of hepatic fructose-1,6-bisphosphatase in the New Zealand obese mouse model of NIDDM. Diabetes 42:1731–1736PubMedCrossRefGoogle Scholar
  6. 6.
    Aybar MJ, Sanchez Riera AN, Grau A, Sanchez SS (2001) Hypoglycemic effect of the water extract of Smallantus sonchifolius (yacon) leaves in normal and diabetic rats. J Ethnopharmacol 74:125–132PubMedCrossRefGoogle Scholar
  7. 7.
    Bailey CJ (2000) Potential new treatments for type 2 diabetes. Trends Pharmacol Sci 2:259–265CrossRefGoogle Scholar
  8. 8.
    Balamurugan R, Duraipandiyan V, Ignacimuthu S (2011) Antidiabetic activity of γ-sitosterol isolated from lippianodiflora L, in streptozotocin induced diabetic rats. Eur J Pharmacol 667:410–418PubMedCrossRefGoogle Scholar
  9. 9.
    Bisse E, Abragam EC (1985) New less temperature sensitive, microchromato graphic method for the separation and quantitation of glycosylated haemoglobin using a non cyanide buffer system. J Chromatogr 344:81–91PubMedCrossRefGoogle Scholar
  10. 10.
    Bollen M, Keppens S, Stalmans W (1998) Specific features of glycogen metabolism in the liver. Biochem J 336:19–31PubMedGoogle Scholar
  11. 11.
    Bolzan AD, Bianchi MS (2003) Genotoxicity of streptozotocin. Mutat Res 512:121–134Google Scholar
  12. 12.
    Brandstrup N, Kirk JE, Bruni C (1957) Determination of hexokinase in tissues. J Gerontol 12:166–171PubMedGoogle Scholar
  13. 13.
    Chan P, Xu DY, Liu JC, Chan YJ, Tomlinson B, Huang WP, Cheng JT (1998) The effect of stevioside on blood pressure and plasma catecholamines in spontaneously hypertensive rats. Life Sci 63:1679–1684PubMedCrossRefGoogle Scholar
  14. 14.
    Chen R, Meseck M, McEvoy RC, Woo SLC (2000) Glucose-stimulated and self-limiting insulin production by glucose 6-phosphatase promoter driven insulin expression in hepatoma cells. Gene Ther 7:1802–1809PubMedCrossRefGoogle Scholar
  15. 15.
    Chou JY, Matern D, Mansfield BC, Chen YT (2002) Type I glycogen storage diseases: disorders of the glucose-6-phosphatase complex. Curr Mol Med 2:121–143PubMedCrossRefGoogle Scholar
  16. 16.
    Cussimanio BL, Booth AA, Todd P, Hudson BG, Khali-fah RG (2003) Unusual susceptibility of heme proteins to damage by glucose during non-enzymatic glycation. Biophys Chem 105:743–755PubMedCrossRefGoogle Scholar
  17. 17.
    Ellis HA, Kirkman HN (1961) A colorimetric method for assay of erythrocyte glucose-6-phosphate dehydrogenase. Proc Soc Exp Biol Med 106:607–609Google Scholar
  18. 18.
    Fiske CH, Subbarow J (1925) The colorimetric determination of phosphorus. J Biol Chem 66:375–400Google Scholar
  19. 19.
    Gabbay KH (1976) Glycosylated haemoglobin and diabetic control. N Engl J Med 295:443–444PubMedCrossRefGoogle Scholar
  20. 20.
    Gancedo JM, Gancedo C (1971) Fructose-1, 6-diphosphatase, phosphofructokinase and glucose-6-phosphate dehydrogenase from fermenting and non fermenting yeasts. Arch Microbiol 76:132–138Google Scholar
  21. 21.
    Gardana C, Simonetti P, Canzi E, Zanchi R, Pietta P (2003) Metabolism of stevioside and rebaudioside A from Stevia rebaudiana extracts by human microflora. J Agric Food Chem 5:6618–6622CrossRefGoogle Scholar
  22. 22.
    Gayathri M, Kannabiran K (2008) Antidiabetic and ameliorative potential of Ficus bengalensis bark extract in streptozotocin induced diabetic rats. Int J Clin Biochem 23:394–400CrossRefGoogle Scholar
  23. 23.
    Geuns JMC (2004) Review: safety of stevioside used as a sweetener. In: Geuns JMC, Buyse J (eds) Proceedings of the first symposium safety of stevioside. Euprint Ed, Leuven, pp 85–127Google Scholar
  24. 24.
    Ghosh R, Mukherjee B, Chatterjee MA (1994) Effect of selenium on streptozotocin-induced diabetic mice. Diabetes Res 25:165–171PubMedGoogle Scholar
  25. 25.
    Gomes A, Vedasiromoni JR, Das M, Sharma RM, Ganguly DK (1995) Antihyperglycemic effect of black tea (Camellia sinensis) in rat. J Ethnopharmacol 45:223–226PubMedCrossRefGoogle Scholar
  26. 26.
    Grover JK, Vats V, Rathi SS (2000) Antihyperglycemic effect of Eugenia jambolana and Tinospora cordifolia in experimental diabetes and their effects on keymetabolic enzymes involved in carbohydrate metabolism. J Ethnopharmacol 73:461–470PubMedCrossRefGoogle Scholar
  27. 27.
    Gupta BL, Nehal M, Baquer NZ (1997) Effect of experimental diabetes on the activities of hexokinase, glucose-6-phosphate dehydrogenase and catecholamines in rat erythrocytes of different ages. Indian J Exp Biol 35:792–795PubMedGoogle Scholar
  28. 28.
    Hii CST, Howell SL (1985) Effect of flavonodis in insulin secretion and Ca2+ handling in rats islets of Langerhans. J Endocrinol 107:1–8PubMedCrossRefGoogle Scholar
  29. 29.
    IDF (2009) Diabetes Atlas 4th Edition, International Diabetes Federation. President of International Diabetes Federation calls for concerted action to stop diabetes epidemic. Montreal CanadaGoogle Scholar
  30. 30.
    IDF (2011) Diabetes Atlas News, 5th Edition of the Diabetes Atlas released on World Diabetes DayGoogle Scholar
  31. 31.
    JECFA (2005) Steviol glycosides. In: 63rd Meeting of the Joint FAO/WHO Expert Committee on Food Additives, Geneva, Switzerland. World Health Organization (WHO), Geneva, Switzerland, WHO Technical Report Series 928:34–39Google Scholar
  32. 32.
    Kasetti RB, Rajasekhar MD, Konteti VK, Fatima SS, Kumar EGT, Swapa S, Ramesh B, Rao CA (2010) Antihyperglycemic and antihyperlipidemic activities of methanol:water (4:1) fraction isolated from aqueous extract of Syzygium alternifolium seeds in streptozotocin induced diabetic rats. Food Chem Toxicol 48:1078–1084PubMedCrossRefGoogle Scholar
  33. 33.
    Koide H, Oda T (1959) Pathological occurrence of glucose-6-phosphatase in liver disease. Clin Chim Acta 74:554–561Google Scholar
  34. 34.
    Kondeti VK, Badri KR, Maddirala DR, Mekala Thur SK, Fatima SS, Kasetti RB, Rao CA (2010) Effect of Pterocarpus santalinus bark, on blood glucose, serum lipids, plasma insulin and hepatic carbohydrate metabolic enzymes in streptozotocin-induced diabetic rats. Food Chem Toxicol 48:1281–1287PubMedCrossRefGoogle Scholar
  35. 35.
    Lowry OH, Rosenbrough NJ, Farr AI, Randall RJ (1951) Protein measurement with folin-phenol reagent. J Biol Chem 193:265PubMedGoogle Scholar
  36. 36.
    Lyons TJ, Silvestri G, Dunn JA, Dyer DG, Baynes JW (1991) Role of glycation in modification of lens crystallins in diabetic and nondiabetic senile cataracts. Diabetes 40:1010–1015PubMedCrossRefGoogle Scholar
  37. 37.
    Mandarino LJ, Wrihgt KS, Verit LS, Nicolus J, Bell JM, Kolterman OG, Beck-Nielson H (1987) Effects of insulin infusion on human skeletal muscle pyruvate dehydrogenase, osphofructo kinase, and glycogen synthase. Evidence for their role in oxidative and nonoxidative glucose metabolism. J Clin Invest 80:655–663PubMedCrossRefGoogle Scholar
  38. 38.
    Masiello P, Broca C, Gross M, Roye R, Manteghetti M, Hillaire-Buys D, Novelli M, Ribes G (1998) Experimental NIDDM: development of a new model in adult rats administered streptozotocin and nicotinamide. Diabetes 47:224–229PubMedCrossRefGoogle Scholar
  39. 39.
    Melis MS (1992) Stevioside effect on renal function of normal and hypertensive rats. J Ethnopharmcol 6:213–217CrossRefGoogle Scholar
  40. 40.
    Mohana Priya E, Gothandam KM, Karthikeyan S (2012) antidiabetic activity of Feronia limonia and Artocarpus heterophllus in streptozotocin induced diabetic rats. Am J Food Tech 7:43–49CrossRefGoogle Scholar
  41. 41.
    Morales MA, Jabbay AJ, Tenenzi HP (1975) Mutation affecting accumulation of glycogen. Neurospora News 20:24–25Google Scholar
  42. 42.
    Murray RK, Granner DK, Mayes PA, Rodwell VW (2000) Harper’s biochemistry (25th Ed). Appleton & Lange, Stanford, pp 610–617Google Scholar
  43. 43.
    Nordlie RC, Foster JD, Lange AJ (1999) Regulation of glucose production by the liver. Annu Rev Nutr 19:379–406PubMedCrossRefGoogle Scholar
  44. 44.
    Pari L, Saravanan R (2007) Beneficial effect of succinic acid monoethyl ester on erythrocyte membrane bound enzymes and antioxidant status in streptozotocin-nicotinamide induced type 2 diabetes. Chem Biol Interact 169:15–24PubMedCrossRefGoogle Scholar
  45. 45.
    Pepato MT, Migliorini RH, Goldberg AL, Kettelhut IC (1996) Role of different proteolytic pathways in degradation of muscle protein from streptozotocin-diabetic rats. Am J Physiol 271:E340–E347PubMedGoogle Scholar
  46. 46.
    Rajasekaran S, Kasiappan R, Karuran S, Subramanian S (2006) Benificial effects of Aleo vera leaf gel extract on lipid profile status in rats with streptozotocin diabetes. Clin Exp Pharmacol 33:232–237CrossRefGoogle Scholar
  47. 47.
    Roden M, Bernroider E (2003) Hepatic glucose metabolism in humans—its role in health and disease. Best Pract Res Clin Endocrinol Metab 17:365–383PubMedCrossRefGoogle Scholar
  48. 48.
    Senthil kumar GP, Arulselvan P, Sathiskumar D, Subramanian S (2006) Antidiabetic activity of fruits of Terminalia chebula on streptozotocin induced diabetes in rats. J Health Sci 52:283–291CrossRefGoogle Scholar
  49. 49.
    Shimazu T (1987) Neuronal regulation of hepatic glucose metabolism in mammals. Diabtes Metabol Rev 3:185–206CrossRefGoogle Scholar
  50. 50.
    Soejarto DD, Kinghorn AD, Farnsworth NR (1982) Potential sweetening agents of plant origin. III. Organoleptic evaluation of stevia leaf herbarium samples for sweetness. J Nat Prod 45:590–599PubMedCrossRefGoogle Scholar
  51. 51.
    Stalmans W, Cadefau J, Wera S, Bollen M (1997) New insight into the liver glycogen metabolism by glucose. Biochem Soc Trans 25:19–25PubMedGoogle Scholar
  52. 52.
    Tahrani AA, Piya MK, Kennedy A, Barnett AH (2010) Glycaemic control in type 2 diabetes: targets and new therapies. Pharmacol Ther 125:328–361PubMedCrossRefGoogle Scholar
  53. 53.
    Trinder P (1969) Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Ann Clin Biochem 6:24Google Scholar
  54. 54.
    Ugochukwu NH, Babady NE (2002) Antidiabetic effects of Gongronema latifolium in hepatocyte of rat models of non-insulin dependent diabetes mellitus. Fitoterapia 73:612–618PubMedCrossRefGoogle Scholar
  55. 55.
    Wagle A, Jivraj GL, Garlock SR (1998) Stapleton, Insulin regulation of glucose-6-phosphate dehydrogenase gene expression is rapamycin-sensitive and requires phosphatidylinositol 3-kinase. J Biol Chem 273:14968–14974PubMedCrossRefGoogle Scholar
  56. 56.
    Wiernsperger NF, Bailey CJ (1999) The antihyperglycaemic effect of metformin: therapeutic and cellular mechanisms. Drugs 58:31–39PubMedCrossRefGoogle Scholar

Copyright information

© University of Navarra 2012

Authors and Affiliations

  • Ramalingam Saravanan
    • 1
    Email author
  • Kaliyappan Vengatash babu
    • 1
  • Vinayagam Ramachandran
    • 1
  1. 1.Department of Biochemistry and Biotechnology, Faculty of ScienceAnnamalai UniversityAnnamalainagarIndia

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