Skip to main content
SpringerLink
Log in

Fenugreek seed extract and its phytocompounds- trigonelline and diosgenin arbitrate their hepatoprotective effects through attenuation of endoplasmic reticulum stress and oxidative stress in type 2 diabetic rats

  • Original Paper
  • Published:
European Food Research and Technology Aims and scope Submit manuscript

Abstract

Fenugreek seed and some of its phytoconstituents are known to possess hypoglycemic and hypolipidemic properties but their mode of action in insulin target tissues remains to be elucidated. As hepatic insulin resistance contributes to the development of type 2 diabetes mellitus (T2DM), the protective effects of fenugreek seed extract (FSE) and two of its phytoconstituents-trigonelline and diosgenin were evaluated in T2DM rats with special focus on changes in endoplasmic reticulum (ER) stress and oxidative stress markers in liver. Trigonelline and diosgenin content in FSE were quantified by HPTLC. T2DM was induced in male Sprague–Dawley rats by feeding high-fat diet and administration of low-dose streptozotocin. T2DM rats exhibited hyperglycemia and significantly reduced serum C-peptide levels. Liver damage in T2DM rats was marked by significantly elevated levels of liver marker enzymes in serum, liver triglycerides (TGs), and reduced liver glycogen and was further confirmed by histological analysis. T2DM rats also displayed twofold–threefold increase in the levels of ER chaperones Bip, protein disulfide isomerase (PDI) as well as ER stress associated proapoptotic markers CHOP, Caspase12 and Caspase3 in liver along with elevated lipid peroxidation (LPO) and reduced antioxidant levels. Promisingly, FSE, trigonelline, and diosgenin were found to exhibit protective effects individually and brought about significant reduction in serum enzymes, liver TGs, LPO, expression of liver ER stress marker proteins, and significant increase in liver glycogen content and antioxidants. Histological analysis also supported their protective effects suggesting that FSE and its phytoconstituents alleviate T2DM associated liver damage by normalizing ER stress and oxidative stress.

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
Fig. 4

Similar content being viewed by others

Abbreviations

Bip:

Binding immunoglobulin protein

CHOP:

C/EBP homologous protein

eIF2a:

Eukaryotic initiation factor 2a

ERO1:

Endoplasmic reticulum oxidoreductin 1

GADD34:

Growth arrest and DNA damage-inducible protein 34

GOD–PAP:

Glucose oxidase - phenol + aminophenazone

GPO–PAP–ESPAS:

Glycerol-3-phosphate oxidase–Peroxidase and aminoantipyrine–N-ethyl-N-sulfopropyl-n-anisidine

GRP78:

Glucose regulated protein 78

JNK:

c-Jun N-terminal kinase

NAFLP:

Nonalcoholic fatty liver

PDI:

Protein disulfide isomerase

UPR:

Unfolded protein response

References

  1. World Health Organization (2011) Diabetes key facts. Geneva, World Health Organization

    Google Scholar 

  2. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) B-cell deficit and increased B-cell apoptosis in humans with type II diabetes. Diabetes 52:102–110

    Article  CAS  Google Scholar 

  3. Khan SE (2003) The relative contributions of insulin resistance and B-cell dysfunction to the pathophysiology of type II diabetes. Diabetotologia 46:3–19

    Article  Google Scholar 

  4. Back SH, Kaufman RJ (2012) Endoplasmic reticulum stress and type 2 diabetes. Annu Rev Biochem 81:767–793

    Article  CAS  Google Scholar 

  5. Anderson JW, Kendall CW, Jenkins DJ (2003) Importance of weight management in type 2 diabetes review with meta-analysis of clinical studies. J Am Cell Nutr 22:331–339

    Article  Google Scholar 

  6. Khan SE, Hull RL, Utzschneider KM (2006) Mechanism linking obesity to insulin resistance and type 2 diabetes. Nature 444:840–846

    Article  Google Scholar 

  7. Poitout V, Robertson RP (2002) Minireview: secondary β-cell failure in type 2 diabetes-a convergence of glucotoxicity and lipotoxicity. Endocrinology 143:339–342

    CAS  Google Scholar 

  8. Prentki M, Nolan CJ (2006) Islets β-cell failure in type 2 diabetes. J Clin Invest 116:1802–1812

    Article  CAS  Google Scholar 

  9. Cnop M, Welsh N, Jonas JC, Jörns A, Lenzen S, Eizirik DL (2005) Mechanism of pancreatic β-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 54(suppl.2):S97–S107

    Article  CAS  Google Scholar 

  10. Hotamisligil GS (2010) Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140:900–917

    Article  CAS  Google Scholar 

  11. Basch E, Ulbricht C, Kuo G, Szapary P, Smith M (2003) Therapeutic applications of fenugreek. Altern Med Rev 8:20–27

    Google Scholar 

  12. Hannan JMA (2003) Effect of soluble dietary fibre fraction of Trigonella foenum graecum on glycemic, insulinemic, lipidemic and platelet aggregation status of type 2 diabetic model rats. J Ethnopharmacol 88(1):73–77

    Article  CAS  Google Scholar 

  13. Yaheya MIM (2009) Clinical evaluation of antidiabetic activity of trigonella seeds and aegle marmelos leaves. World Applied Sciences Journal 7(10):1231–1234

    Google Scholar 

  14. Kassaian N, Azadbakht L, Forghani B, Amini M (2009) Effect of fenugreek seeds on blood glucose and lipid profiles in type 2 diabetic patients. Int J Vitam Nutr Res 79(1):34–39

    Article  CAS  Google Scholar 

  15. Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao P (2005) Combination of high-fat diet and low dose streptozotocin-treated rat: a model for type II diabetes and pharmacological screening. Pharmacol Res 52:313–320

    Article  CAS  Google Scholar 

  16. Mu P, Plummer DT (2001) Introduction to practical biochemistry, 3rd edn. Tata McGraw-Hill, NewDelhi

  17. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    Article  CAS  Google Scholar 

  18. Ellman GL (1973) Tissue sulfhydryl groups. Arch Biochem Biophys 179:588–590

    Google Scholar 

  19. Marklund S, Marklund G (1974) Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 47:69–74

    Article  Google Scholar 

  20. Claiborne A (1985) In: Boca Raton FL (ed) Handbook of methods for oxygen radical research. CRC Press, Florida, pp 283–284

    Google Scholar 

  21. Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hateman DG, Hoekstra WG (1973) Selenium: biochemical role as a component of glutathione peroxidase. Science 179:588–590

    Article  CAS  Google Scholar 

  22. Luna LG (1968) Manual of histological staining methods of the Armed Forces Institute of Pathology. McGraw-Hill, New York

    Google Scholar 

  23. Rizza RA (2010) Pathogenesis of fasting and postprandial hyperglycemia in type 2 diabetes: implications for therapy. Diabetes 59:2697–2707

    Article  CAS  Google Scholar 

  24. Samuel VT, Petersen KF, Shulman GI (2010) Lipid-induced insulin resistance: unravelling the mechanism. Lancet 375:2267–2277

    Article  CAS  Google Scholar 

  25. Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman GI, Magnuson MA, Kahn CR (2000) Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell 6:87–94

    Article  CAS  Google Scholar 

  26. Clark JM, Diehl AM (2002) Hepatic steatosis and type 2 diabetes mellitus. Curr Diabetes Rep 2(3):210–215

    Article  Google Scholar 

  27. Festi D, Colecchia A, Sacco T, Bondi M, Roda E, Marchesini G (2004) Hepatic steatosis in obese patients: clinical aspects and prognostic significance. Obes Rev 5(1):27–42

    Article  CAS  Google Scholar 

  28. Pfaffenbach KT, Gentile CL, Nivala AM, Wang D, Wei Y, Pagliassotti MJ (2010) Linking endoplasmic reticulum stress to cell death in hepatocytes: roles of C/EBP homologous protein and chemical chaperones in palmitate-mediated cell death. Am J Physiol Endocrinol Metab 298(5):E1027–E1035

    Article  CAS  Google Scholar 

  29. McAnuff MA, Harding WW, Omoruyi FO, Jacobs H, Morrison EY, Asemota HN (2005) Hypoglycemic effects of steroidal sapogenins isolated from Jamaican bitter yam, (Dioscorea polygonoides). Food Chemistry and Toxicology 43:1667–1672

    Article  CAS  Google Scholar 

  30. Xue WL, Li XS, Zhang J, Liu YH, Wang ZL, Zhang RJ (2007) Effects of Trigonella foenum-graecum (fenugreek) extract on blood glucose, blood lipid and hemorheological properties in streptozotocin-induced diabetic rats. Asia Pac J Clin Nutr 16(1):422–426

    CAS  Google Scholar 

  31. Yoshinari O, Igarashi K (2010) Anti-diabetic effect of trigonelline and nicotinic acid, on KK-A(y) mice. Curr Med Chem 17(20):2196–2202

    Article  CAS  Google Scholar 

  32. Vijayakumar MV, Singh Sandeep, Chhipa Rishi Raj, Bhat MK (2005) The hypoglycaemic activity of fenugreek seed extract is mediated through the stimulation of an insulin signaling pathway. Br J Pharmacol 146:41–48

    Article  CAS  Google Scholar 

  33. Shitole PP, Badole SL, Bodhankar SL, Mohan V, Bhaskaran S (2009) Anti-hyperglycaemic activity of IND 01 and its interaction with glyburide and pioglitazone in alloxan induced diabetic mice. Int J Diabetes Metab 17:21–26

    CAS  Google Scholar 

  34. Zhou J, Chan L, Zhou S (2012) Trigonelline: a plant alkaloid with therapeutic potential for diabetes and central nervous system disease. Curr Med Chem 19(21):3523–3531

    Article  CAS  Google Scholar 

  35. Eizirik DL, Cardozo AK, Cnop M (2008) The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev 29(1):42–61

    Article  CAS  Google Scholar 

  36. Ji C, Kaplowitz N (2006) ER stress: can the liver cope? J Hepatol 45(2):321–333

    Article  CAS  Google Scholar 

  37. Malhi H, Kaufman RJ (2011) Endoplasmic reticulum stress in liver disease. J Hapatol 54(4):795–809

    Article  CAS  Google Scholar 

  38. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Görgün C, Glimcher LH, Hotamisligil GS (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306:457–461

    Article  Google Scholar 

  39. Yoshiuchi K, Kaneto H, Matsuoka TA, Kohno K, Iwawaki T, Nakatani Y, Yamasaki Y et al (2008) Direct monitoring of in vivo ER stress during the development of insulin resistance with ER stress-activated indicator transgenic mice. Biochem Biophys Res Commun 366:545–555

    Article  CAS  Google Scholar 

  40. Wang D, Wei Y, Pagliassotti MJ (2006) Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. Endocrinology 147:943–951

    Article  CAS  Google Scholar 

  41. Sanges D, Marigo V (2006) Cross-talk between two apoptotic pathways activated by endoplasmic reticulum stress: differential contribution of caspase-12 and AIF. Apoptosis 11:1629–1641

    Article  CAS  Google Scholar 

  42. Cullinan SB, Diehl JA (2006) Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway. Int J Biochem Cell Biol 38:317–332

    Article  CAS  Google Scholar 

  43. Papa FR (2012) Endoplasmic reticulum stress, pancreatic β-cell degeneration and diabetes. Cold Spring Harb Perspect Med 2(9):a007666

    Article  Google Scholar 

  44. Nagy G, Kardon T, Wunderlich L, Szarka A, Kiss A, Schaff Z, Bánhegyi G, Mandl J (2007) Acetaminophen induces ER dependent signaling in mouse liver. Arch Biochem Biophys 459:273–279

    Article  CAS  Google Scholar 

  45. Garg MC, Ojha S, Bansal DD (1996) Antioxidant status of streptozotocin diabetic rats. Indian J Exp Biology 34:264–266

    CAS  Google Scholar 

Download references

Acknowledgments

The financial support provided by University Grants Commission, India, and the equipment support from DST-FIST and DBT-IPLS is gratefully acknowledged. This work is supported by University Grants Commission, India. [MRP F. No. 36-191/2008(SR)].

Conflict of interest

We hereby state that we do not have any conflict of interest in the present work.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Kalapet, Puducherry, India

    Tharaheswari Mayakrishnan, Jayachandra Reddy Nakkala, Syam Praveen Kumar Jeepipalli & Sudha Rani Sadras

  2. Department of Pathology, Rajiv Gandhi College of Veterinary and Animal Sciences, Kurumbapet, Puducherry, India

    Kumar Raja & Varshney Khub Chandra

  3. Herbal and Indian Medicine Research Laboratory, Department of Biochemistry, Sri Ramachandra University, Chennai, India

    Vasanth Kumar Mohan

Authors
  1. Tharaheswari Mayakrishnan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jayachandra Reddy Nakkala
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Syam Praveen Kumar Jeepipalli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kumar Raja
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Varshney Khub Chandra
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vasanth Kumar Mohan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sudha Rani Sadras
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sudha Rani Sadras.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mayakrishnan, T., Nakkala, J.R., Jeepipalli, S.P.K. et al. Fenugreek seed extract and its phytocompounds- trigonelline and diosgenin arbitrate their hepatoprotective effects through attenuation of endoplasmic reticulum stress and oxidative stress in type 2 diabetic rats. Eur Food Res Technol 240, 223–232 (2015). https://doi.org/10.1007/s00217-014-2322-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00217-014-2322-9

Keywords

Search

Navigation