Hepatic Biomarkers in Diabetes as Modulated by Dietary Phytochemicals

  • Arpita BasuEmail author
  • Paramita BasuEmail author
  • Timothy J. LyonsEmail author
Reference work entry
Part of the Biomarkers in Disease: Methods, Discoveries and Applications book series (BDMDA)


Both type 2 diabetes (T2D) and features of the metabolic syndrome are associated with hepatic insulin resistance, which may gradually progress to nonalcoholic fatty liver disease (NAFLD) and fibrosis. Biomarkers, including those related to glycemia, serum lipid profiles, lipid oxidation, inflammation, and levels of enzymes reflecting hepatocellular damage (e.g., aminotransferases), may reflect liver function in diabetes. New epidemiological data suggest that noninvasive imaging techniques, such as computed tomography (CT) scans, may provide better predictive biomarkers for NAFLD than circulating liver enzymes. Phytochemicals or plant-derived bioactive compounds present in foods, beverages, and herbal supplements have been shown to modulate biomarkers of liver function in clinical trials and mechanistic studies. Mediterranean diet and dietary phytochemicals, such as polyphenols derived from green tea, berries, olive oil, and resveratrol, have been shown to lower liver enzymes, liver fat content, and to improve hepatic insulin resistance and related biomarkers of oxidative stress and inflammation, especially in the presence of adiposity and the metabolic syndrome. Herbs, such as silymarin and those used in traditional Chinese medicine (for example, hawthorn fruit extract), have also been shown to lower hepatic enzymes and markers of oxidative stress and to increase hepatic antioxidant status in patients with NAFLD. Other emerging biomarkers, such as cytokines and microRNAs, are also being evaluated for efficacy in monitoring and predicting liver dysfunction. Thus, selected phytochemicals, especially those occurring naturally in berries and grapes, tea, olives, nuts, and legumes, when used in the context of a low-calorie diet may have a role in treating liver dysfunction. The use of herbal supplements to modulate hepatic biomarkers requires further evaluation of safety and efficacy.


Nonalcoholic fatty liver disease Hepatic insulin resistance Aminotransferase Mediterranean diet Resveratrol Green tea Silymarin 

List of Abbreviations


Alanine aminotransferase


Aspartate aminotransferase


Body mass index


Cystathionine β-synthase


Coronary heart disease




C-reactive protein


Cystathionine γ-lyase


Computed tomography


Cardiovascular disease


Gamma-glutamyl transferase


Hydrogen sulfide

HMG CoA reductase

Hydroxymethylglutaryl-coenzyme A reductase


Homeostatic model assessment of insulin resistance


Hepatic steatosis


Interleukin-2 receptor


Interleukin 8

Med diet

Mediterranean diet


Nonalcoholic fatty liver disease


Nonalcoholic steatohepatitis


Otsuka Long-Evans Tokushima Fatty


Prostaglandin E2


Polyunsaturated fatty acids


Randomized controlled trial


Sterol regulatory element-binding protein-1c


Sterol regulatory element-binding protein-2


Type 2 diabetes


Traditional Chinese medicine


Transforming growth factor alpha


Tissue-polypeptide-specific antigen


Very low density lipoprotein


  1. Abenavoli L, Greco M, Nazionale I, et al. Effects of Mediterranean diet supplemented with silybin-vitamin E-phospholipid complex in overweight patients with non-alcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol. 2015;9:519–27.CrossRefPubMedGoogle Scholar
  2. Aller R, Izaola O, Gómez S, et al. Effect of silymarin plus vitamin E in patients with non-alcoholic fatty liver disease. A randomized clinical pilot study. Eur Rev Med Pharmacol Sci. 2015;19:3118–24.PubMedGoogle Scholar
  3. Andersen CJ, Fernandez ML. Dietary strategies to reduce metabolic syndrome. Rev Endocr Metab Disord. 2013;14:241–54.CrossRefPubMedGoogle Scholar
  4. Bedogni G, Bellentani S, Miglioli L, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006;6:33.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bhatt HB, Smith RJ. Fatty liver disease in diabetes mellitus. Hepatobiliary Surg Nutr. 2015;4:101–8.PubMedPubMedCentralGoogle Scholar
  6. Blanco-Rojo R, Alcala-Diaz JF, Wopereis S, et al. The insulin resistance phenotype (muscle or liver) interacts with the type of diet to determine changes in disposition index after 2 years of intervention: the CORDIOPREV-DIAB randomised clinical trial. Diabetologia. 2016; 59:67–76.Google Scholar
  7. Bugianesi E, Gastaldelli A, Vanni E, et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia. 2005;48:634–42.CrossRefPubMedGoogle Scholar
  8. Castera L, Vilgrain V, Angulo P. Noninvasive evaluation of NAFLD. Nat Rev Gastroenterol Hepatol. 2013;10:666–75.CrossRefPubMedGoogle Scholar
  9. Chachay VS, Macdonald GA, Martin JH, et al. Resveratrol does not benefit patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2014;12:2092–103.e1–6.CrossRefGoogle Scholar
  10. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55:2005–23.CrossRefPubMedGoogle Scholar
  11. Chang HC, Huang CN, Yeh DM, et al. Oat prevents obesity and abdominal fat distribution, and improves liver function in humans. Plant Foods Hum Nutr. 2013;68:18–23.CrossRefPubMedGoogle Scholar
  12. Chang HC, Peng CH, Yeh DM, Kao ES, Wang CJ. Hibiscus sabdariffa extract inhibits obesity and fat accumulation, and improves liver steatosis in humans. Food Funct. 2014;5:734–9.CrossRefPubMedGoogle Scholar
  13. Chen S, Zhao X, Ran L, et al. Resveratrol improves insulin resistance, glucose and lipid metabolism in patients with non-alcoholic fatty liver disease: a randomized controlled trial. Dig Liver Dis. 2015;47:226–32.CrossRefPubMedGoogle Scholar
  14. Choi SH, Ginsberg HN. Increased very low density lipoprotein (VLDL) secretion, hepatic steatosis, and insulin resistance. Trends Endocrinol Metab. 2011;22:353–63.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Chung MY, Park HJ, Manautou JE, Koo SI, Bruno RS. Green tea extract protects against nonalcoholic steatohepatitis in ob/ob mice by decreasing oxidative and nitrative stress responses induced by proinflammatory enzymes. J Nutr Biochem. 2012;23:361–7.CrossRefPubMedGoogle Scholar
  16. Chung MY, Mah E, Masterjohn C, et al. Green tea lowers hepatic COX-2 and prostaglandin E2 in rats with dietary fat-induced nonalcoholic steatohepatitis. J Med Food. 2015;18:648–55.CrossRefPubMedGoogle Scholar
  17. de Oliveira PR, da Costa CA, de Bem GF. Euterpe oleracea Mart.-derived polyphenols protect mice from diet-induced obesity and fatty liver by regulating hepatic lipogenesis and cholesterol excretion. PLoS One. 2015;10:e0143721.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Deng YQ, Zhao H, Ma AL, China HepB Related Fibrosis Assessment Research Group, et al. Selected cytokines serve as potential biomarkers for predicting liver inflammation and fibrosis in chronic hepatitis B patients with normal to mildly elevated aminotransferases. Medicine (Baltimore). 2015;94:e2003.CrossRefGoogle Scholar
  19. Ding D, Li H, Liu P, et al. FibroScan, aspartate aminotransferase and alanine aminotransferase ratio (AAR), aspartate aminotransferase to platelet ratio index (APRI), fibrosis index based on the 4 factor (FIB-4), and their combinations in the assessment of liver fibrosis in patients with hepatitis B. Int J Clin Exp Med. 2015;8:20876–82.PubMedPubMedCentralGoogle Scholar
  20. Esposito K, Kastorini CM, Panagiotakos DB, Giugliano D. Mediterranean diet and metabolic syndrome: an updated systematic review. Rev Endocr Metab Disord. 2013;14:255–63.CrossRefPubMedGoogle Scholar
  21. Faghihzadeh F, Adibi P, Rafiei R, Hekmatdoost A. Resveratrol supplementation improves inflammatory biomarkers in patients with nonalcoholic fatty liver disease. Nutr Res. 2014;34:837–43.CrossRefPubMedGoogle Scholar
  22. Faghihzadeh F, Hekmatdoost A, Adibi P. Resveratrol and liver: a systematic review. J Res Med Sci. 2015a;20:797–810.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Faghihzadeh F, Adibi P, Hekmatdoost A. The effects of resveratrol supplementation on cardiovascular risk factors in patients with non-alcoholic fatty liver disease: a randomised, double-blind, placebo-controlled study. Br J Nutr. 2015b;114:796–803.CrossRefPubMedGoogle Scholar
  24. Fukuda T, Hamaguchi M, Kojima T, et al. The impact of non-alcoholic fatty liver disease on incident type 2 diabetes mellitus in non-overweight individuals. Liver Int. 2016;36:275–83.CrossRefPubMedGoogle Scholar
  25. Guo H, Zhong R, Liu Y, et al. Effects of bayberry juice on inflammatory and apoptotic markers in young adults with features of non-alcoholic fatty liver disease. Nutrition. 2014;30:198–203.CrossRefPubMedGoogle Scholar
  26. Hajiaghamohammadi AA, Ziaee A, Oveisi S, Masroor H. Effects of metformin, pioglitazone, and silymarin treatment on non-alcoholic Fatty liver disease: a randomized controlled pilot study. Hepat Mon. 2012;12:e6099.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Hayes CN, Chayama K. MicroRNAs as biomarkers for liver disease and hepatocellular carcinoma. Int J Mol Sci. 2016;17:280.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Higuera-de la Tijera F, Servín-Caamaño AI. Pathophysiological mechanisms involved in non-alcoholic steatohepatitis and novel potential therapeutic targets. World J Hepatol. 2015;7:1297–301.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Kani AH, Alavian SM, Esmaillzadeh A, Adibi P, Azadbakht L. Effects of a novel therapeutic diet on liver enzymes and coagulating factors in patients with non-alcoholic fatty liver disease: a parallel randomized trial. Nutrition. 2014;30:814–21.CrossRefPubMedGoogle Scholar
  30. Lepore SM, Morittu VM, Celano M, et al. Oral administration of Oleuropein and its semisynthetic peracetylated derivative prevents hepatic steatosis, hyperinsulinemia, and weight gain in mice fed with high fat cafeteria diet. Int J Endocrinol. 2015;2015:431453.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Liu K, Zhou R, Wang B, et al. Effect of green tea on glucose control and insulin sensitivity: a meta-analysis of 17 randomized controlled trials. Am J Clin Nutr. 2013;98:340–8.CrossRefPubMedGoogle Scholar
  32. Liu Y, Yu J, Oaks Z, et al. Liver injury correlates with biomarkers of autoimmunity and disease activity and represents an organ system involvement in patients with systemic lupus erythematosus. Clin Immunol. 2015;160:319–27.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Lomonaco R, Bril F, Portillo-Sanchez P, et al. Metabolic impact of nonalcoholic steatohepatitis in obese patients with type 2 diabetes. Diabetes Care. 2016;39:632; pii: dc151876. [Epub ahead of print].CrossRefPubMedGoogle Scholar
  34. Loomba R, Abraham M, Unalp A, Nonalcoholic Steatohepatitis Clinical Research Network, et al. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology. 2012;56:943–51.CrossRefPubMedPubMedCentralGoogle Scholar
  35. López-Miranda J, Pérez-Jiménez F, Ros E, et al. Olive oil and health: summary of the II international conference on olive oil and health consensus report, Jaén and Córdoba (Spain) 2008. Nutr Metab Cardiovasc Dis. 2010;20:284–94.CrossRefPubMedGoogle Scholar
  36. McGill MR, Du K, Weemhoff JL, Jaeschke H. Critical review of resveratrol in xenobiotic-induced hepatotoxicity. Food Chem Toxicol. 2015;86:309–18.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Nigam P, Bhatt S, Misra A, et al. Effect of a 6-month intervention with cooking oils containing a high concentration of monounsaturated fatty acids (olive and canola oils) compared with control oil in male Asian Indians with nonalcoholic fatty liver disease. Diabetes Technol Ther. 2014;16:255–61.CrossRefPubMedGoogle Scholar
  38. Park HJ, Lee JY, Chung MY, et al. Green tea extract suppresses NFkB activation and inflammatory responses in diet-induced obese rats with nonalcoholic steatohepatitis. J Nutr. 2012;142:57–63.CrossRefPubMedGoogle Scholar
  39. Petta S, Valenti L, Bugianesi E, Special Interest Group on Personalised Hepatology of the Italian Association for the Study of the Liver (AISF), Special Interest Group on Personalised Hepatology of the Italian Association for the Study of the Liver AISF, et al. A “systems medicine” approach to the study of non-alcoholic fatty liver disease. Dig Liver Dis. 2016;48:333–42.CrossRefPubMedGoogle Scholar
  40. Ryan MC, Itsiopoulos C, Thodis T, et al. The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J Hepatol. 2013;59:138–43.CrossRefPubMedGoogle Scholar
  41. Sakata R, Nakamura T, Torimura T, Ueno T, Sata M. Green tea with high-density catechins improves liver function and fat infiltration in non-alcoholic fatty liver disease (NAFLD) patients: a double-blind placebo-controlled study. Int J Mol Med. 2013;32:989–94.PubMedGoogle Scholar
  42. Sarna LK, Sid V, Wang P, Siow YL, House JD, Kamin O. Tyrosol attenuates high fat diet-induced hepatic oxidative stress: potential involvement of cystathionine β-synthase and cystathionine γ-lyase. Lipids. 2015;51:583. [Epub ahead of print].CrossRefPubMedGoogle Scholar
  43. Shah RV, Allison MA, Lima JA, et al. Liver fat, statin use, and incident diabetes: the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis. 2015;242:211–7.CrossRefPubMedPubMedCentralGoogle Scholar
  44. Shi KQ, Fan YC, Liu WY, et al. Traditional Chinese medicines benefit to nonalcoholic fatty liver disease: a systematic review and meta-analysis. Mol Biol Rep. 2012;39:9715–22.CrossRefPubMedGoogle Scholar
  45. Singh SP, Singh A, Misra D, et al. Risk factors associated with non-alcoholic fatty liver disease in Indians: a case–control study. J Clin Exp Hepatol. 2015;5:295–302.CrossRefPubMedPubMedCentralGoogle Scholar
  46. Sofi F, Giangrandi I, Cesari F, et al. Effects of a 1-year dietary intervention with n-3 polyunsaturated fatty acid-enriched olive oil on non-alcoholic fatty liver disease patients: a preliminary study. Int J Food Sci Nutr. 2010;61:792–802.CrossRefPubMedGoogle Scholar
  47. Solhi H, Ghahremani R, Kazemifar AM, Hoseini Yazdi Z. Silymarin in treatment of non-alcoholic steatohepatitis: a randomized clinical trial. Caspian J Intern Med. 2014;5:9–12.PubMedPubMedCentralGoogle Scholar
  48. Sorrentino G, Crispino P, Coppola D, De Stefano G. Efficacy of lifestyle changes in subjects with non-alcoholic liver steatosis and metabolic syndrome may be improved with an antioxidant nutraceutical: a controlled clinical study. Drugs R&D. 2015;15:21–5.CrossRefGoogle Scholar
  49. Stefan N, Häring HU. The metabolically benign and malignant fatty liver. Diabetes. 2011;60:2011–7.CrossRefPubMedPubMedCentralGoogle Scholar
  50. Trovato FM, Catalano D, Martines GF, Pace P, Trovato GM. Mediterranean diet and non-alcoholic fatty liver disease: the need of extended and comprehensive interventions. Clin Nutr. 2015;34:86–8.CrossRefPubMedGoogle Scholar
  51. Valtueña S, Pellegrini N, Franzini L, et al. Food selection based on total antioxidant capacity can modify antioxidant intake, systemic inflammation, and liver function without altering markers of oxidative stress. Am J Clin Nutr. 2008;87:1290–7.PubMedGoogle Scholar
  52. Vargas-Mendoza N, Madrigal-Santillán E, Morales-González A, et al. Hepatoprotective effect of silymarin. World J Hepatol. 2014;6:144–9.CrossRefPubMedPubMedCentralGoogle Scholar
  53. Wild SH, Morling JR, McAllister DA, Scottish and Southampton Diabetes and Liver Disease Group and the Scottish Diabetes Research Network Epidemiology Group, et al. Type 2 diabetes, chronic liver disease and hepatocellular cancer: a national retrospective cohort study using linked routine data. J Hepatol. 2016. doi:10.1016/j.jhep.2016.01.014. pii: S0168-8278(16)00020-9. [Epub ahead of print].Google Scholar
  54. Xu ZR, Li JY, Dong XW, et al. Apple polyphenols decrease atherosclerosis and hepatic steatosis in ApoE−/− mice through the ROS/MAPK/NF-kB pathway. Nutrients. 2015;7:7085–105.CrossRefPubMedPubMedCentralGoogle Scholar
  55. Yamabe N, Kang KS, Hur JM, Yokozawa T. Matcha, a powdered green tea, ameliorates the progression of renal and hepatic damage in type 2 diabetic OLETF rats. J Med Food. 2009;12:714–21.CrossRefPubMedGoogle Scholar
  56. Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of non-alcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence and outcomes. Hepatology. 2015. doi:10.1002/hep.28431. [Epub ahead of print].Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2017

Authors and Affiliations

  1. 1.Department of Nutritional Sciences, 301 Human SciencesOklahoma State UniversityStillwaterUSA
  2. 2.Department of BiologyTexas Woman’s UniversityDentonUSA
  3. 3.Centre for Experimental MedicineQueen’s University of BelfastNorthern IrelandUK

Personalised recommendations