apfcbAPFCB eNewscoAPFCB News Volume 5, Issue 2MultidisciplinaryEnglishJuly-Dec, 2026NNY2026099ArticlesHyperglycemia-Induced Oxidative Stress and Inflammatory Signaling in the Pathogenesis of Type 2 Diabetes MellitusEnglishY5867Dr. RachanaMenonEnglishNDr. DeepakParchwaniEnglishYDr. MehulKaliyaEnglishYDr. RaginiSinghEnglishYDr. SagarDholariyaEnglishYDr. AnitaMotianiEnglishYDr. AmitSonagraEnglishY10.62772/APFCB-News.2026.5205Insulin resistance arises from serine phosphorylation of insulin receptor substrate (IRS) proteins mediated by stress kinases such as c-Jun N-terminal kinase (JNK) and IκB kinase-β (IKKβ), compounded by lipotoxic and cytokine-driven signaling defects. Sustained hyperglycemia diverts glucose flux into four classical pathogenic pathways, the polyol pathway, advanced glycation end-product (AGE) formation, protein kinase C (PKC) activation, and hexosamine biosynthesis, each converging on excess reactive oxygen species (ROS) generation. ROS-mediated activation of NF-κB establishes a selfamplifying loop between oxidative stress and chronic low-grade inflammation, further impairing insulin signaling and accelerating vascular injury. Epigenetic changes underlying “metabolic memory” explain why complications may progress despite subsequent glycemic control. Oxidative stress and inflammation are not peripheral bystanders but central, mechanistically interdependent drivers of T2DM pathogenesis and its complications. Early, intensive metabolic control exploits a therapeutic window before metabolic memory is consolidated, underscoring the need for sensitive biomarkers and targeted antioxidant/anti-inflammatory strategies alongside conventional glycemic management.EnglishType 2 diabetes mellitus; Insulin resistance; Oxidative stress; Reactive oxygen species;Advanced glycation end products; Metabolic memoryhttps://www.apfcb.org/APFCB_News/abstract?id=53References16191. Sun H, Saeedi P, Karuranga S, et al. IDF Diabetes Atlas: global, regional and country -level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022;183:109119.2. Poretsky L. Milestones in the history of diabetes mellitus. World J Diabetes. 2016;7(1):1and;ndash;7.3. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in diabetes prevalence and treatment from 1990 to 2022: a pooled analysis of 1108 population-representative studies with 141 million participants. Lancet. 2024;404(10468):2125and;ndash;2143.4. International Diabetes Federation. IDF global clinical practice recommendations for managing type 2 diabetesand;mdash;2025 [Internet]. Brussels: IDF; 2025 [cited 2026 Jul 9]. Available from: https://idf.org/t2d-cpr-2025 5. Lascar N, Brown J, Pattison H, et al. Type 2 diabetes in young adults: challenges and future possibilities. Lancet Diabetes Endocrinol. 2018;6(1):69and;ndash;80.6. Bommer C, Sagalova V, Heesemann E, et al. Global economic burden of diabetes in adults: projections from 2015 to 2030. Diabetes Care. 2018;41(5):963and;ndash;970.7. Parchwani DN, Murthy SMS, Upadhyah AA, Patel DD. Genetic factors in the etiology of type 2 diabetes: linkage analyses, candidate gene association, and genome-wide association and;ndash; still a long way to go! Natl J Physiol Pharm Pharmacol 2013; 3:57-68.8. Gaede P, Oellgaard J, Carstensen B, et al. Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: 21 years of follow-up on the Steno2 randomised trial. Lancet Diabetes Endocrinol. 2016;4(12):1008and;ndash;1016.9. halmers J, Cooper ME. UKPDS and the legacy effect. N Engl J Med. 2008;359(15):1618and;ndash;1620.10. Yamanouchi D. The roles of incretin hormones GIP and GLP-1 in metabolic and cardiovascular health: a comprehensive review. Int J Mol Sci. 2026;27(1):27.11. Martand;iacute;nez Band;aacute;ez A, Ayala G, Pedroza-Saavedra A, Gonzand;aacute;lez-Sand;aacute;nchez HM, Chihu Amparan L. Phosphorylation codes in IRS-1 and IRS-2 are associated with the activation/inhibition of insulin canonical signaling pathways. Curr Issues Mol Biol. 2024;46(1):41.12. Woo JR, Bae SH, Wales TE, et al. The serine phosphorylations in the IRS-1 PIR domain abrogate IRS-1 and IR interaction. Proc Natl Acad Sci U S A. 2024;121(17):e2401716121.13. Ueki K, Kondo T, Tseng YH, Kahn CR. Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse. Proc Natl Acad Sci U S A. 2004;101(28):10422and;ndash;10427.14. Onyango AN. Excessive gluconeogenesis causes the hepatic insulin resistance paradox and its sequelae. Heliyon. 2022;8(12):e12294. 15.15. Poitout V, Robertson RP. Glucolipotoxicity: fuel excess and and;beta;-cell dysfunction. Endocr Rev. 2008;29(3):351and;ndash;366. 16.16. Sies H. Oxidative stress: concept and some practical aspects. Antioxidants (Basel). 2020;9(9):852. 17.17. Wani ZA, Sharma AK, Muzamil S, et al. Molecular pathways of oxidative stress in diabetes: redox imbalance and insulin pathway dysregulation. Mol Biol Rep. 2026;53:222. 18.18. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414(6865):813and;ndash;820. 19.19. Yamagishi S, Nakamura K, Matsui T, Noda Y, Imaizumi T. Receptor for advanced glycation end products (RAGE): a novel therapeutic target for diabetic vascular complication. Curr Pharm Des. 2008;14(5):487and;ndash;495. 20.20. Parchwani DN, Vachhani U, Dholariya S, Agravatt A, Singh R, Sonagra A. Role of Inflammatory and Oxidative Stress Biomarkers with Albuminuria: A Cross Sectional Analysis in Type 2 Diabetes Mellitus Patients. EJIFCC. 2025 Oct 1;36(3):284-297. 21.21. Ceriello A, Lucisano G, Prattichizzo F, et al. The legacy effect of hyperglycemia and early use of SGLT-2 inhibitors: a cohort study with newly-diagnosed people with type 2 diabetes. Lancet Reg Health Eur. 2023;31:100666. 22.22. Liu T, Zhang L, Joo D, Sun SC. NF-and;kappa;B signaling in inflammation. Signal Transduct Target Ther. 2017;2:17023.