Estimation the levels of Nuclear Factor Erythroid 2–Related Factor 2 (Nrf-2) in Patients with type II diabetes mellitus

  • Hayder Abdulhussen Taher Postgraduate student, Department of Biochemistry, College of Medicine, University of kerbala, kerbala, Iraq
  • Atheer Hameid Al-Ghanimi Asst Prof. Nanotechnology Ph.D, Biochemistry Department, College of Medicine, University of Kerbala, Karbala, Iraq
  • Hassan Haider Khudhir Ph.D. Department of Clinical Biochemistry University of Kerbala, College of Medicine, Karbala, Iraq
Keywords: Type II Diabetes Mellitus, Nuclear Factor Erythroid 2–Related Factor 2 (Nrf2), Oxidative Stress, Metabolic Dysfunction, Antioxidant Defenses

Abstract

Type II Diabetes Mellitus (T2DM) and its precursor, pre-diabetes, are characterized by chronic oxidative stress and metabolic dysfunction.  Nuclear Factor Erythroid 2–Related Factor 2 (Nrf2), a master regulator of antioxidant defenses, are crucial in cellular protection. This study aimed to estimate the levels of serum Nrf2 in T2DM patients, pre-diabetic individuals, and healthy controls, and to evaluate their diagnostic potential. A case control was conducted. This study involved 88 individuals, including 46 type II diabetes patients,12 prediabetic and 30 volunteers as a control, with inclusion criteria including normal fasting blood sugar and haemoglobin A1c results. Blood samples were collected from both control and patient groups after 12 hours of fasting. Data were collected via a structured questionnaire covering sociodemographics, medical history, and lifestyle, complemented by clinical evaluations by specialist physicians. Serum lipid panel were measured . Elisa system was used for the detection of Nrf2 level. The study groups were well-differentiated by HbA1c and lipid profiles, with DM and pre-DM groups exhibiting typical glycemic and dyslipidemic patterns.  median serum Nrf2 levels were remarkably similar and largely overlapping across all three groups (medians: Healthy 26, Pre-DM 30, DM 29), indicating no significant difference. Nrf2 demonstrated poor diagnostic utility (AUCs < 0.63, p-values > 0.05). Serum Nrf2 levels do not appear to be a reliable prognostic indicator for these conditions. These findings underscore the potential of Nrf2 as a valuable non-invasive screening and monitoring tool in the context of impaired glucose metabolism.

References

D. D. Huang, G. Shi, Y. Jiang, C. Yao, and C. Zhu, “A review on the potential of resveratrol in prevention and therapy of diabetes and diabetic complications,” Biomedicine & Pharmacotherapy, vol. 125, p. 109767, May 2020, doi: 10.1016/j.biopha.2019.109767.

R. A. Oram et al., “A type 1 diabetes genetic risk score can aid discrimination between type 1 and type 2 diabetes in young adults,” Diabetes Care, vol. 39, no. 3, pp. 337–344, Mar. 2016, doi: 10.2337/dc15-1111.

F. Samimi, M. Baazm, E. Eftekhar, and F. J. Mashayekh, “Effect of coenzyme Q10 supplementation on liver total oxidant/antioxidant status in streptozotocin-induced diabetic rats,” Journal of Arak University of Medical Sciences, vol. 22, no. 4, pp. 28–39, Sep. 2019, doi: 10.32598/JAMS.22.4.30.

American Diabetes Association, “4. Lifestyle management: standards of medical care in diabetes—2018,” Diabetes Care, vol. 41, no. Suppl. 1, pp. S38–S50, Jan. 2018, doi: 10.2337/dc18-S004.

I. Bellezza, I. Giambanco, A. Minelli, and R. Donato, “Nrf2-Keap1 signaling in oxidative and reductive stress,” Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, vol. 1865, no. 5, pp. 721–733, May 2018, doi: 10.1016/j.bbamcr.2018.02.010.

A. Uruno, Y. Yagishita, and M. Yamamoto, “The Keap1–Nrf2 system and diabetes mellitus,” Archives of Biochemistry and Biophysics, vol. 566, pp. 76–84, Jan. 2015, doi: 10.1016/j.abb.2014.12.012.

A. S. Jiménez-Osorio, A. Picazo, S. González-Reyes, D. Barrera-Oviedo, M. E. Rodríguez-Arellano, and J. Pedraza-Chaverri, “Nrf2 and redox status in prediabetic and diabetic patients,” International Journal of Molecular Sciences, vol. 15, no. 11, pp. 20290–20305, Nov. 2014, doi: 10.3390/ijms151120290.

American Diabetes Association, “2. Classification and diagnosis of diabetes: standards of medical care in diabetes—2022,” Diabetes Care, vol. 45, no. Suppl. 1, pp. S17–S38, 2022, doi: 10.2337/dc22-S002.

G. R. S. Babu, T. Anand, N. Ilaiyaraja, F. Khanum, and N. Gopalan, “Pelargonidin modulates Keap1/Nrf2 pathway gene expression and ameliorates citrinin-induced oxidative stress in HepG2 cells,” Frontiers in Pharmacology, vol. 8, p. 868, Nov. 2017, doi: 10.3389/fphar.2017.00868.

K. Itoh et al., “An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements,” Biochemical and Biophysical Research Communications, vol. 236, no. 2, pp. 313–322, Jul. 1997, doi: 10.1006/bbrc.1997.6943.

T. Nguyen, P. J. Sherratt, and C. B. Pickett, “Regulatory mechanisms controlling gene expression mediated by the antioxidant response element,” Annual Review of Pharmacology and Toxicology, vol. 43, no. 1, pp. 233–260, Apr. 2003, doi: 10.1146/annurev.pharmtox.43.100901.140229.

N. Esteras, A. T. Dinkova-Kostova, and A. Y. Abramov, “Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function,” Biological Chemistry, vol. 397, no. 5, pp. 383–400, May 2016, doi: 10.1515/hsz-2015-0183.

American Diabetes Association, “Standards of medical care in diabetes—2011,” Diabetes Care, vol. 34, no. Suppl. 1, pp. S11–S61, Jan. 2011, doi: 10.2337/dc11-S011.

S. M. Grundy et al., “AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines,” Circulation, vol. 139, no. 25, p. e1082, 2019, doi: 10.1161/CIR.0000000000000625.

J. Halcox and A. Misra, “Type 2 diabetes mellitus, metabolic syndrome, and mixed dyslipidemia: how similar, how different, and how to treat?,” Metabolic Syndrome and Related Disorders, vol. 13, no. 1, pp. 1–21, Feb. 2015, doi: 10.1089/met.2014.0049.

S. I. Sherwani, H. A. Khan, A. Ekhzaimy, A. Masood, and M. K. Sakharkar, “Significance of HbA1c test in diagnosis and prognosis of diabetic patients,” Biomarker Insights, vol. 11, p. BMI-S38440, Jan. 2016, doi: 10.4137/BMI.S38440.

M. R. Taskinen and J. Borén, “New insights into the pathogenesis of diabetic dyslipidaemia,” Current Opinion in Lipidology, vol. 26, no. 4, pp. 254–263, 2015, doi: 10.1016/j.atherosclerosis.2015.01.039.

P. Zimmet, K. G. Alberti, and J. Shaw, “Global and societal implications of the diabetes epidemic,” Nature, vol. 414, no. 6865, pp. 782–787, Dec. 2001, doi: 10.1038/414782a.

B. Olsson et al., “Bovine growth hormone transgenic mice are resistant to diet-induced obesity but develop hyperphagia, dyslipidemia, and diabetes on a high-fat diet,” Endocrinology, vol. 146, no. 2, pp. 920–930, Feb. 2005, doi: 10.1210/en.2004-1232.

G. M. Reaven, “The insulin resistance syndrome: definition and dietary approaches to treatment,” Annual Review of Nutrition, vol. 25, no. 1, pp. 391–406, Jul. 2005, doi: 10.1146/annurev.nutr.24.012003.132155.

M. J. Chapman et al., “Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management,” European Heart Journal, vol. 32, no. 11, pp. 1345–1361, Jun. 2011, doi: 10.1093/eurheartj/ehr112.

R. M. Krauss, “Atherogenic lipoprotein phenotype and diet-gene interactions,” The Journal of Nutrition, vol. 131, no. 2, pp. 340S–343S, Feb. 2001, doi: 10.1093/jn/131.2.340S.

A. D. Sniderman, A. C. St-Pierre, B. Cantin, G. R. Dagenais, J. P. Després, and B. Lamarche, “Concordance/discordance between plasma apolipoprotein B levels and the cholesterol indexes of atherosclerotic risk,” The American Journal of Cardiology, vol. 91, no. 10, pp. 1173–1177, May 2003, doi: 10.1016/S0002-9149(03)00262-5.

Emerging Risk Factors Collaboration, “Diabetes mellitus, fasting glucose, and risk of cause-specific death,” New England Journal of Medicine, vol. 364, no. 9, pp. 829–841, Mar. 2011, doi: 10.1056/NEJMoa1008862.

D. S. Pratt and M. M. Kaplan, “Evaluation of abnormal liver-enzyme results in asymptomatic patients,” New England Journal of Medicine, vol. 342, no. 17, pp. 1266–1271, Apr. 2000, doi: 10.1056/NEJM200004273421707.

G. Targher, C. D. Byrne, and H. Tilg, “NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications,” Gut, vol. 69, no. 9, pp. 1691–1705, Sep. 2020, doi: 10.1136/gutjnl-2020-320622.

N. Chalasani 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, vol. 55, no. 6, pp. 2005–2023, Jun. 2012, doi: 10.1002/hep.25762.

Q. Ma, “Role of Nrf2 in oxidative stress and toxicity,” Annual Review of Pharmacology and Toxicology, vol. 53, no. 1, pp. 401–426, Jan. 2013, doi: 10.1146/annurev-pharmtox-011112-140320.

T. Nguyen, P. Nioi, and C. B. Pickett, “The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress,” Journal of Biological Chemistry, vol. 284, no. 20, pp. 13291–13295, May 2009, doi: 10.1074/jbc.R800011200.

S. M. Shin, J. H. Yang, and S. H. Ki, “Role of the Nrf2‐ARE pathway in liver diseases,” Oxidative Medicine and Cellular Longevity, vol. 2013, p. 763257, 2013, doi: 10.1155/2013/763257.

C. T. Chu, A. Uruno, F. Katsuoka, and M. Yamamoto, “Role of NRF2 in pathogenesis of Alzheimer’s disease,” Antioxidants, vol. 13, no. 12, p. 1529, Dec. 2024, doi: 10.3390/antiox13121529.

M. Guerrero-Hue et al., “Protective role of Nrf2 in renal disease,” Antioxidants, vol. 10, no. 1, p. 39, Dec. 2020, doi: 10.3390/antiox10010039.

A. Uruno and H. Motohashi, “The Keap1–Nrf2 system as an in vivo sensor for electrophiles,” Nitric Oxide, vol. 25, no. 2, pp. 153–160, Aug. 2011, doi: 10.1016/j.niox.2011.02.007.

D. Kim, B. You, E. K. Jo, S. K. Han, M. I. Simon, and S. J. Lee, “NADPH oxidase 2-derived reactive oxygen species in spinal cord microglia contribute to peripheral nerve injury-induced neuropathic pain,” Proceedings of the National Academy of Sciences, vol. 107, no. 33, pp. 14851–14856, Aug. 2010, doi: 10.1073/pnas.1009926107.

Published
2025-08-15
How to Cite
Taher, H. A., Al-Ghanimi, A. H., & Khudhir, H. H. (2025). Estimation the levels of Nuclear Factor Erythroid 2–Related Factor 2 (Nrf-2) in Patients with type II diabetes mellitus. Central Asian Journal of Medical and Natural Science, 6(4), 1863-1875. https://doi.org/10.17605/cajmns.v6i4.2905
Section
Articles