Abstract
Metabolic and insulin-resistant diseases, such as type 2 diabetes mellitus (T2DM), have become major health issues worldwide. The prevalence of insulin resistance in the general population ranges from 15.5% to 44.6%. Shockingly, the global T2DM population is anticipated to double by 2050 compared with 2021. Prior studies indicate that oxidative stress and inflammation are instrumental in causing insulin resistance and instigating metabolic diseases. Numerous methods and drugs have been designed to combat insulin resistance, including metformin, thiazolidinediones (TZDs), sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP1RA), and dipeptidyl peptidase 4 inhibitors (DPP4i). Bilirubin is an antioxidant with fat-burning actions by binding to the PPARα nuclear receptor transcription factor, improving insulin sensitivity, reducing inflammation, and reversing metabolic dysfunction. Potential treatment with antioxidants like bilirubin and increasing the enzyme that produces it, heme oxygenase (HMOX), has also gained attention. This review discusses the relationships between bilirubin, HMOX, and insulin sensitivity, how T2DM medications affect HMOX levels and activity, and potentially using bilirubin nanoparticles to treat insulin resistance. We explore the sex differences between these treatments in the HMOX system and how bilirubin levels are affected. We discuss the emerging concept that bilirubin bioconversion to urobilin may have a role in metabolic diseases. This comprehensive review summarizes our understanding of bilirubin functioning as a hormone, discusses the HMOX isoforms and their beneficial mechanisms, analyzes the sex differences that might cause a dichotomy in responses, and examines the potential use of HMOX and bilirubin nanoparticle therapies in treating metabolic diseases.
Document Type
Article
Publication Date
1-2025
Digital Object Identifier (DOI)
https://doi.org/10.1042/CS20242825
Funding Information
This work was supported by the National Institutes of Health (NIH) R01DK121797 (T.D.H.J.), R01DA058933 (T.D.H.J.), F31HL170972 (Z.A.K.), F31HL175979 (E.A.B.), R01DK126884 (D.E.S.), P01HL05197-11 (D.E.S.), and the National Institute of General Medical Sciences P20GM104357-02 (D.E.S.), and a fellowship awards from the America Heart Association for 25PRE1374495 (G.J.M.) and 23POST1020493 (O.O.B.) The contents are solely the authors' responsibility and do not necessarily represent the official views of the NIH.
Repository Citation
Lee, Wang-Hsin; Kipp, Zachary A.; Pauss, Sally; Martinez, Genesee J.; Bates, Evelyn A.; Badmus, Olufunto O.; Stec, David E.; and Hinds, Terry D. Jr., "Heme oxygenase, biliverdin reductase, and bilirubin pathways regulate oxidative stress and insulin resistance: a focus on diabetes and therapeutics" (2025). Markey Cancer Center Faculty Publications. 406.
https://uknowledge.uky.edu/markey_facpub/406
Notes/Citation Information
© 2025 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).