DİYABETİK KADINLARDA SERUM HEM OKSİJENAZ-1 (HO-1) ENZİMİNİN GLİSEMİK KONTROL İLE İLİŞKİSİ
Year 2024,
Volume: 57 Issue: 1, 20 - 24, 30.04.2024
Osman Sağlam
,
Neşe Ersöz Gülçelik
,
Tülay Omma
,
Anara Karaca
,
Yalcin Aral
,
Gül Gürsoy
Abstract
Amaç: Diyabetin hızla artan prevalansı, onu önemli bir küresel sağlık sorunu haline getirmiştir. Mevcut tedavi seçenekleri olsa da, tedavide yenilikçi yaklaşımlara ihtiyaç vardır. Hem molekülünün hem oksijenaz-1 ile parçalanması sonucu CO, bilirubin ve Fe/Ferritin ortaya çıkar. Yapılan hayvan deneyleri, hem oksijenaz-1 indüksiyonu sonucu ortaya çıkan ürünlerin inflamasyon, oksidatif stres ve apoptozu hafiflettiği ve hiperglisemiyi azalttığı gösterilmiştir. Bizde, diyabetli kadınlarda glisemik durum üzerine serum hem oksijenaz-1'in etkisinin olup olmadığını incelemeyi amaçladık.
Gereç ve yöntem: Polikliniğe başvuran 63 kadın hasta (31'i diyabetik, 32'si kontrol) çalışmaya dahil edilmiştir. Çalışmaya akut ve kronik böbrek yetmezliği olan hastalar, akut veya kronik karaciğer hastalığı olan hastalar, akut enfeksiyonu olan hastalar, vücut kitle indeksi (VKİ) ≤18 kg/m2 veya ≥35 kg/m2 olan hastalar ve 18 yaşından küçük ve 65 yaşından büyük hastalar dahil edilmemiştir.
Bulgular: Serum ferritin hasta grubunda kontrol grubuna kıyasla anlamlı olarak daha yüksekti (p = 0.028). Serum total bilirubin ve serum hem oksijenaz-1 iki grupta benzerdi (sırasıyla p = 0.260, p = 0.426).
Sonuç: Çalışmamızda diyabet grubundaki serum ferritin düzeyinin kontrol grubuna göre anlamlı ölçüde daha yüksek olması ferritinin diyabet patogenezindeki olası rolünü desteklemektedir. Bununla birlikte, serum total bilirubin düzeyleri ve serum hem oksijenaz-1 düzeylerinde gruplar arasında önemli bir fark gözlenmemiştir. Bu durum, serum ferritin ile glisemik parametreler arasındaki ilişkinin doğrudan hem moleküllerinin hem oksijenaz-1 tarafından parçalanması ile ilişkili olmayabileceğini düşündürmektedir.
References
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Legrand A, Delattre J. Diabetes mellitus, oxidative stress and advanced
glycation endproducts. Ann Pharm Fr. 2004;62(3):147-157.
- 2. Darenskaya MA, Kolesnikova LI, Kolesnikov SI. Oxidative
Stress: Pathogenetic Role in Diabetes Mellitus and Its Complications
and Therapeutic Approaches to Correction. Bull Exp Biol Med.
2021;171(2):179-189. https://doi:10.1007/s10517-021-05191-7
- 3. Tiwari S, Ndisang J. The Heme Oxygenase System and
Type-1 Diabetes. Curr Pharm Des. 2014;20(9):1328-1337. https://do
i:10.2174/13816128113199990552
- 4. Saeedi P, Petersohn I, Salpea P, et al. Global and regional
diabetes prevalence estimates for 2019 and projections for 2030
and 2045: Results from the International Diabetes Federation Diabetes
Atlas, 9th edition. Diabetes Res Clin Pract. 2019;157:107843.
https://doi:10.1016/j.diabres.2019.107843
- 5. Shah N, Abdalla MA, Deshmukh H, Sathyapalan T. Therapeutics
for type-2 diabetes mellitus: a glance at the recent inclusions
and novel agents under development for use in clinical practice.
Ther Adv Endocrinol Metab. 2021;12:20420188211042145. https://
doi:10.1177/20420188211042145
- 6. Yoshida T, Kikuchi G. Reaction of the microsomal heme
oxygenase with cobaltic protoporphyrin IX, an extremely poor substrate.
Journal of Biological Chemistry. 1978;253(23):8479-8482. https://
doi:10.1016/s0021-9258(17)34316-8
- 7. Campbell NK, Fitzgerald HK, Dunne A. Regulation of inflammation
by the antioxidant haem oxygenase 1. Nat Rev Immunol.
2021;21(7):411-425. https://doi:10.1038/s41577-020-00491-x
- 8. Chen QY, Wang GG, Li W, Jiang YX, Lu XH, Zhou PP.
Heme oxygenase-1 promotes delayed wound healing in diabetic
rats. J Diabetes Res. 2016;2016:9726503. https://
doi:10.1155/2016/9726503
- 9. Abraham NG, Drummond GS, Lutton JD, Kappas A. The
biological significance and physiological role of heme oxygenase.
Cellular Physiology and Biochemistry. 1996;6(3):129-168. https://
doi:10.1159/000154819
- 10. Kikuchi G, Yoshida T, Noguchi M. Heme oxygenase
and heme degradation. Biochem Biophys Res Commun.
2005;338(1):558-567. https://doi:10.1016/j.bbrc.2005.08.020
- 11. Milani M, Pesce A, Nardini M, et al. Structural bases for
heme binding and diatomic ligand recognition in truncated hemoglobins.
J Inorg Biochem. 2005;99(1):97-109. https://doi:10.1016/j.
jinorgbio.2004.10.035
- 12. Vile GF, Basu-Modak S, Waltner C, Tyrrell RM. Heme oxygenase
1 mediates an adaptive response to oxidative stress in human
skin fibroblasts. Proc Natl Acad Sci U S A. 1994;91(7):2607-
2610. https://doi:10.1073/pnas.91.7.2607
- 13. Nocentini A, Bonardi A, Pratesi S, Gratteri P, Dani C, Supuran
CT. Pharmaceutical strategies for preventing toxicity and
promoting antioxidant and anti-inflammatory actions of bilirubin. J
Enzyme Inhib Med Chem. 2022;37(1):487-501. https://doi:10.108
0/14756366.2021.2020773
- 14. Mishra M, Ndisang J. A Critical and Comprehensive Insight
on Heme Oxygenase and Related Products Including Carbon
Monoxide, Bilirubin, Biliverdin and Ferritin in Type-1 and Type-2 Diabetes.
Curr Pharm Des. 2014;20(9):1370-1391. https://doi:10.217
4/13816128113199990559
- 15. Andrews M, Leiva E, Arredondo-Olguín M. Short repeats
in the heme oxygenase 1 gene promoter is associated with increased
levels of inflammation, ferritin and higher risk of type-2 diabetes
mellitus. Journal of Trace Elements in Medicine and Biology.
2016;37:25-30. https://doi:10.1016/j.jtemb.2016.06.001
- 16. Bao W, Song F, Li X, et al. Association between heme
oxygenase-1 gene promoter polymorphisms and type 2 diabetes
mellitus: A HuGE review and meta-analysis. Am J Epidemiol.
2010;172(6):631-636. https://doi:10.1093/aje/kwq162
- 17. Chen YH, Chau LY, Chen JW, Lin SJ. Serum bilirubin and
ferritin levels link heme oxygenase-1 gene promoter polymorphism
and susceptibility to coronary artery disease in diabetic patients.
Diabetes Care. 2008;31(8):1615-1620. https://doi:10.2337/dc07-
2126
- 18. Lee EY, Lee YH, Kim SH, et al. Association between
heme oxygenase-1 promoter polymorphisms and the development
of albuminuria in type 2 diabetes: A case-control study. Medicine
(United States). 2015;94(43):e1825. https://doi:10.1097/
MD.0000000000001825
- 19. Wu R, Zhu Z, Zhou D. VEGF, apelin and HO-1 in diabetic
patients with retinopathy: A correlation analysis. BMC Ophthalmol.
2020;20(1):1-6. https://doi:10.1186/s12886-020-01593-9
- 20. Hong J, Kim YH. Fatty Liver/Adipose Tissue Dual-Targeting
Nanoparticles with Heme Oxygenase-1 Inducer for Amelioration
of Obesity, Obesity-Induced Type 2 Diabetes, and Steatohepatitis.
Advanced Science. 2022;9(33):2203286. https://
doi:10.1002/advs.202203286
- 21. Fan J, Xu G, Jiang T, Qin Y. Pharmacologic induction of
heme oxygenase-1 plays a protective role in diabetic retinopathy in
rats. Invest Ophthalmol Vis Sci. 2012;53(10):6541-6556. https://
doi:10.1167/iovs.11-9241
- 22. Negi G, Nakkina V, Kamble P, Sharma SS. Heme oxygenase-
1, a novel target for the treatment of diabetic complications:
Focus on diabetic peripheral neuropathy. Pharmacol Res.
2015;102:158-167. https://doi:10.1016/j.phrs.2015.09.014
- 23. Li M, Kim DH, Tsenovoy PL, et al. Treatment of obese
diabetic mice with a heme oxygenase inducer reduces visceral
and subcutaneous adiposity, increases adiponectin levels,
and improves insulin sensitivity and glucose tolerance. Diabetes.
2008;57(6):1526-1535. https://doi:10.2337/db07-1764
- 24. Castilho ÁF, Aveleira CA, Leal EC, et al. Heme oxygenase-
1 protects retinal endothelial cells against high glucose-
and oxidative/nitrosative stress-induced toxicity. PLoS One.
2012;7(8):e42428. https://doi:10.1371/journal.pone.0042428
- 25. Thorand B, Löwel H, Schneider A, et al. C-reactive protein
as a predictor for incident diabetes mellitus among middle-aged
men: Results from the MONICA Augsburg Cohort Study, 1984-
1998. Arch Intern Med. 2003;163(1):93-99. https://doi:10.1001/
archinte.163.1.93
- 26. Soinio M, Marniemi J, Laakso M, Lehto S, R̈onnemaa
T. High-sensitivity C-reactive protein and coronary heart disease
mortality in patients with type 2 diabetes: A 7-year follow-up
study. Diabetes Care. 2006;29(2):329-333. https://doi:10.2337/
diacare.29.02.06.dc05-1700
- 27. Liu Q, Jiang CY, Chen BX, Zhao W, Meng D. The association
between high-sensitivity C-reactive protein concentration and
diabetic nephropathy: A meta-analysis. Eur Rev Med Pharmacol
Sci. 2015;19(23):4558-4568.
- 28. Hayashino Y, Mashitani T, Tsujii S, Ishii H. Serum high-
sensitivity C-reactive protein levels are associated with high
risk of development, not progression, of diabetic nephropathy
among Japanese type 2 diabetic patients: A prospective cohort
study (Diabetes Distress and Care Registry at Tenri [DDCRT7]). Diabetes
Care. 2014;37(11):2947-2952. https://doi:10.2337/dc14-
1357
- 29. Ma H, Lin H, Hu Y, et al. Serum ferritin levels are associated
with insulin resistance in Chinese men and post-menopausal women:
The Shanghai Changfeng study. British Journal of Nutrition.
2018;120(8):863-871. https://doi:10.1017/S0007114518002167
- 30. Chen L, Li Y, Zhang F, Zhang S, Zhou X, Ji L. Association
of serum ferritin levels with metabolic syndrome and insulin
resistance in a Chinese population. J Diabetes Complications.
2017;31(2):364-368. https://doi:10.1016/j.jdiacomp.2016.06.018
- 31. Forouhi NG, Harding AH, Allison M, et al. Elevated serum
ferritin levels predict new-onset type 2 diabetes: Results from the
EPIC-Norfolk prospective study. Diabetologia. 2007;50(5):949-
956. https://doi:10.1007/s00125-007-0604-5
- 32. Arredondo M, Fuentes M, Jorquera D, et al. Cross-talk
between body iron stores and diabetes: Iron stores are associated
with activity and microsatellite polymorphism of the heme oxygenase
and type 2 diabetes. Biol Trace Elem Res. 2011;143(2):625-
636. https://doi:10.1007/s12011-010-8895-7
- 33. Wei Y, Liu C, Lai F, et al. Associations between serum total
bilirubin, obesity and type 2 diabetes. Diabetol Metab Syndr.
2021;13(1):1-7. https://doi:10.1186/s13098-021-00762-0
- 34. Oda E. Cross-Sectional and Longitudinal Associations
between Serum Bilirubin and Prediabetes in a Health Screening
Population. Can J Diabetes. 2016;40(3):270-275. https://doi:
10.1016/j.jcjd.2016.01.001
- 35. Wang J, Li Y, Han X, et al. Serum bilirubin levels and
risk of type 2 diabetes: Results from two independent cohorts in
middle-aged and elderly Chinese. Sci Rep. 2017;7:41338. https://
doi:10.1038/srep41338
- 36. Choi SW, Lee YH, Kweon SS, et al. Association between
total bilirubin and hemoglobin A1c in Korean type 2 diabetic
24
patients. J Korean Med Sci. 2012;27(10):1196. https://doi:10.3346/
jkms.2012.27.10.1196
- 37. Kawamoto R, Ninomiya D, Senzaki K, Kumagi
T. Mildly elevated serum total bilirubin is negatively associated
with hemoglobin A1c independently of confounding
factors among community-dwelling middle-aged and
elderly persons. J Circ Biomark. 2017;6:1849454417726609. https://
doi:10.1177/1849454417726609
- 38. Huang SS, Chan WL, Leu HB, Huang PH, Lin SJ, Chen JW.
Serum bilirubin levels predict future development of metabolic syndrome
in healthy middle-aged nonsmoking men. American Journal
of Medicine. 2015;128(10):1138-e35. https://doi:10.1016/j.amjmed.
2015.04.019
- 39. Jo J, Yun JE, Lee H, Kimm H, Jee SH. Total, direct, and indirect
serum bilirubin concentrations and metabolic syndrome among
the Korean population. Endocrine. 2011;39(2):182-189. https://
doi:10.1007/s12020-010-9417-2
- 40. Oda E, Aizawa Y. Total bilirubin is inversely associated with
metabolic syndrome but not a risk factor for metabolic syndrome in
Japanese men and women. Acta Diabetol. 2013;50(3):417-422. https://
doi:10.1007/s00592-012-0447-5
- 41. Wu Y, Li M, Xu M, et al. Low serum total bilirubin concentrations
are associated with increased prevalence of metabolic syndrome
in Chinese. J Diabetes. 2011;3(3):217-224. https://doi:10.1111/
j.1753-0407.2011.00138.x
ASSOCIATION OF SERUM HEME OXYGENASE-1 (HO-1) ENZYME WITH GLYCEMIC CONTROL IN DIABETIC WOMEN
Year 2024,
Volume: 57 Issue: 1, 20 - 24, 30.04.2024
Osman Sağlam
,
Neşe Ersöz Gülçelik
,
Tülay Omma
,
Anara Karaca
,
Yalcin Aral
,
Gül Gürsoy
Abstract
Aim: The rapidly increasing prevalence of diabetes has made it a significant global health issue. While there are existing treatment options, there is a need for innovative approaches to treatment. The heme molecule broken down by heme oxygenase-1 produces CO, bilirubin, and Fe/ferritin. Animal experiments have shown that products resulting from heme oxygenase-1 induction attenuate inflammation, oxidative stress and apoptosis and reduce hyperglycemia. We aimed to investigate whether serum heme oxygenase-1 has an effect on glycemic status in women with diabetes.
Material and methods: Sixty-three female patients (31 diabetic and 32 control) who applied to the outpatient clinic were included in the study. The study excluded patients with acute and chronic renal failure, patients with acute or chronic liver disease, patients with acute infection, patients with a body mass index (BMI) of ≤18 kg/m2 or ≥35 kg/m2, and patients younger than 18 years and older than 65 years.
Results: Serum ferritin was significantly higher in the patient group compared to the control group (p = 0.028). Serum total bilirubin and serum heme oxygenase-1 were similar in the two groups (p = 0.260, p = 0.426, respectively).
Conclusion: In our study, serum ferritin were significantly higher in the diabetes group than controls, supporting a possible role for ferritin in diabetes pathogenesis. Nevertheless, no considerable differences were observed in serum total bilirubin and serum heme oxygenase-1 between the groups. This suggests that the relationship between serum ferritin and glycemic parameters may not be directly associated with the breakdown of heme molecules by heme oxygenase-1.
References
- 1. Bonnefont-Rousselot D, Beaudeux JL, Thérond P, Peynet J,
Legrand A, Delattre J. Diabetes mellitus, oxidative stress and advanced
glycation endproducts. Ann Pharm Fr. 2004;62(3):147-157.
- 2. Darenskaya MA, Kolesnikova LI, Kolesnikov SI. Oxidative
Stress: Pathogenetic Role in Diabetes Mellitus and Its Complications
and Therapeutic Approaches to Correction. Bull Exp Biol Med.
2021;171(2):179-189. https://doi:10.1007/s10517-021-05191-7
- 3. Tiwari S, Ndisang J. The Heme Oxygenase System and
Type-1 Diabetes. Curr Pharm Des. 2014;20(9):1328-1337. https://do
i:10.2174/13816128113199990552
- 4. Saeedi P, Petersohn I, Salpea P, et al. Global and regional
diabetes prevalence estimates for 2019 and projections for 2030
and 2045: Results from the International Diabetes Federation Diabetes
Atlas, 9th edition. Diabetes Res Clin Pract. 2019;157:107843.
https://doi:10.1016/j.diabres.2019.107843
- 5. Shah N, Abdalla MA, Deshmukh H, Sathyapalan T. Therapeutics
for type-2 diabetes mellitus: a glance at the recent inclusions
and novel agents under development for use in clinical practice.
Ther Adv Endocrinol Metab. 2021;12:20420188211042145. https://
doi:10.1177/20420188211042145
- 6. Yoshida T, Kikuchi G. Reaction of the microsomal heme
oxygenase with cobaltic protoporphyrin IX, an extremely poor substrate.
Journal of Biological Chemistry. 1978;253(23):8479-8482. https://
doi:10.1016/s0021-9258(17)34316-8
- 7. Campbell NK, Fitzgerald HK, Dunne A. Regulation of inflammation
by the antioxidant haem oxygenase 1. Nat Rev Immunol.
2021;21(7):411-425. https://doi:10.1038/s41577-020-00491-x
- 8. Chen QY, Wang GG, Li W, Jiang YX, Lu XH, Zhou PP.
Heme oxygenase-1 promotes delayed wound healing in diabetic
rats. J Diabetes Res. 2016;2016:9726503. https://
doi:10.1155/2016/9726503
- 9. Abraham NG, Drummond GS, Lutton JD, Kappas A. The
biological significance and physiological role of heme oxygenase.
Cellular Physiology and Biochemistry. 1996;6(3):129-168. https://
doi:10.1159/000154819
- 10. Kikuchi G, Yoshida T, Noguchi M. Heme oxygenase
and heme degradation. Biochem Biophys Res Commun.
2005;338(1):558-567. https://doi:10.1016/j.bbrc.2005.08.020
- 11. Milani M, Pesce A, Nardini M, et al. Structural bases for
heme binding and diatomic ligand recognition in truncated hemoglobins.
J Inorg Biochem. 2005;99(1):97-109. https://doi:10.1016/j.
jinorgbio.2004.10.035
- 12. Vile GF, Basu-Modak S, Waltner C, Tyrrell RM. Heme oxygenase
1 mediates an adaptive response to oxidative stress in human
skin fibroblasts. Proc Natl Acad Sci U S A. 1994;91(7):2607-
2610. https://doi:10.1073/pnas.91.7.2607
- 13. Nocentini A, Bonardi A, Pratesi S, Gratteri P, Dani C, Supuran
CT. Pharmaceutical strategies for preventing toxicity and
promoting antioxidant and anti-inflammatory actions of bilirubin. J
Enzyme Inhib Med Chem. 2022;37(1):487-501. https://doi:10.108
0/14756366.2021.2020773
- 14. Mishra M, Ndisang J. A Critical and Comprehensive Insight
on Heme Oxygenase and Related Products Including Carbon
Monoxide, Bilirubin, Biliverdin and Ferritin in Type-1 and Type-2 Diabetes.
Curr Pharm Des. 2014;20(9):1370-1391. https://doi:10.217
4/13816128113199990559
- 15. Andrews M, Leiva E, Arredondo-Olguín M. Short repeats
in the heme oxygenase 1 gene promoter is associated with increased
levels of inflammation, ferritin and higher risk of type-2 diabetes
mellitus. Journal of Trace Elements in Medicine and Biology.
2016;37:25-30. https://doi:10.1016/j.jtemb.2016.06.001
- 16. Bao W, Song F, Li X, et al. Association between heme
oxygenase-1 gene promoter polymorphisms and type 2 diabetes
mellitus: A HuGE review and meta-analysis. Am J Epidemiol.
2010;172(6):631-636. https://doi:10.1093/aje/kwq162
- 17. Chen YH, Chau LY, Chen JW, Lin SJ. Serum bilirubin and
ferritin levels link heme oxygenase-1 gene promoter polymorphism
and susceptibility to coronary artery disease in diabetic patients.
Diabetes Care. 2008;31(8):1615-1620. https://doi:10.2337/dc07-
2126
- 18. Lee EY, Lee YH, Kim SH, et al. Association between
heme oxygenase-1 promoter polymorphisms and the development
of albuminuria in type 2 diabetes: A case-control study. Medicine
(United States). 2015;94(43):e1825. https://doi:10.1097/
MD.0000000000001825
- 19. Wu R, Zhu Z, Zhou D. VEGF, apelin and HO-1 in diabetic
patients with retinopathy: A correlation analysis. BMC Ophthalmol.
2020;20(1):1-6. https://doi:10.1186/s12886-020-01593-9
- 20. Hong J, Kim YH. Fatty Liver/Adipose Tissue Dual-Targeting
Nanoparticles with Heme Oxygenase-1 Inducer for Amelioration
of Obesity, Obesity-Induced Type 2 Diabetes, and Steatohepatitis.
Advanced Science. 2022;9(33):2203286. https://
doi:10.1002/advs.202203286
- 21. Fan J, Xu G, Jiang T, Qin Y. Pharmacologic induction of
heme oxygenase-1 plays a protective role in diabetic retinopathy in
rats. Invest Ophthalmol Vis Sci. 2012;53(10):6541-6556. https://
doi:10.1167/iovs.11-9241
- 22. Negi G, Nakkina V, Kamble P, Sharma SS. Heme oxygenase-
1, a novel target for the treatment of diabetic complications:
Focus on diabetic peripheral neuropathy. Pharmacol Res.
2015;102:158-167. https://doi:10.1016/j.phrs.2015.09.014
- 23. Li M, Kim DH, Tsenovoy PL, et al. Treatment of obese
diabetic mice with a heme oxygenase inducer reduces visceral
and subcutaneous adiposity, increases adiponectin levels,
and improves insulin sensitivity and glucose tolerance. Diabetes.
2008;57(6):1526-1535. https://doi:10.2337/db07-1764
- 24. Castilho ÁF, Aveleira CA, Leal EC, et al. Heme oxygenase-
1 protects retinal endothelial cells against high glucose-
and oxidative/nitrosative stress-induced toxicity. PLoS One.
2012;7(8):e42428. https://doi:10.1371/journal.pone.0042428
- 25. Thorand B, Löwel H, Schneider A, et al. C-reactive protein
as a predictor for incident diabetes mellitus among middle-aged
men: Results from the MONICA Augsburg Cohort Study, 1984-
1998. Arch Intern Med. 2003;163(1):93-99. https://doi:10.1001/
archinte.163.1.93
- 26. Soinio M, Marniemi J, Laakso M, Lehto S, R̈onnemaa
T. High-sensitivity C-reactive protein and coronary heart disease
mortality in patients with type 2 diabetes: A 7-year follow-up
study. Diabetes Care. 2006;29(2):329-333. https://doi:10.2337/
diacare.29.02.06.dc05-1700
- 27. Liu Q, Jiang CY, Chen BX, Zhao W, Meng D. The association
between high-sensitivity C-reactive protein concentration and
diabetic nephropathy: A meta-analysis. Eur Rev Med Pharmacol
Sci. 2015;19(23):4558-4568.
- 28. Hayashino Y, Mashitani T, Tsujii S, Ishii H. Serum high-
sensitivity C-reactive protein levels are associated with high
risk of development, not progression, of diabetic nephropathy
among Japanese type 2 diabetic patients: A prospective cohort
study (Diabetes Distress and Care Registry at Tenri [DDCRT7]). Diabetes
Care. 2014;37(11):2947-2952. https://doi:10.2337/dc14-
1357
- 29. Ma H, Lin H, Hu Y, et al. Serum ferritin levels are associated
with insulin resistance in Chinese men and post-menopausal women:
The Shanghai Changfeng study. British Journal of Nutrition.
2018;120(8):863-871. https://doi:10.1017/S0007114518002167
- 30. Chen L, Li Y, Zhang F, Zhang S, Zhou X, Ji L. Association
of serum ferritin levels with metabolic syndrome and insulin
resistance in a Chinese population. J Diabetes Complications.
2017;31(2):364-368. https://doi:10.1016/j.jdiacomp.2016.06.018
- 31. Forouhi NG, Harding AH, Allison M, et al. Elevated serum
ferritin levels predict new-onset type 2 diabetes: Results from the
EPIC-Norfolk prospective study. Diabetologia. 2007;50(5):949-
956. https://doi:10.1007/s00125-007-0604-5
- 32. Arredondo M, Fuentes M, Jorquera D, et al. Cross-talk
between body iron stores and diabetes: Iron stores are associated
with activity and microsatellite polymorphism of the heme oxygenase
and type 2 diabetes. Biol Trace Elem Res. 2011;143(2):625-
636. https://doi:10.1007/s12011-010-8895-7
- 33. Wei Y, Liu C, Lai F, et al. Associations between serum total
bilirubin, obesity and type 2 diabetes. Diabetol Metab Syndr.
2021;13(1):1-7. https://doi:10.1186/s13098-021-00762-0
- 34. Oda E. Cross-Sectional and Longitudinal Associations
between Serum Bilirubin and Prediabetes in a Health Screening
Population. Can J Diabetes. 2016;40(3):270-275. https://doi:
10.1016/j.jcjd.2016.01.001
- 35. Wang J, Li Y, Han X, et al. Serum bilirubin levels and
risk of type 2 diabetes: Results from two independent cohorts in
middle-aged and elderly Chinese. Sci Rep. 2017;7:41338. https://
doi:10.1038/srep41338
- 36. Choi SW, Lee YH, Kweon SS, et al. Association between
total bilirubin and hemoglobin A1c in Korean type 2 diabetic
24
patients. J Korean Med Sci. 2012;27(10):1196. https://doi:10.3346/
jkms.2012.27.10.1196
- 37. Kawamoto R, Ninomiya D, Senzaki K, Kumagi
T. Mildly elevated serum total bilirubin is negatively associated
with hemoglobin A1c independently of confounding
factors among community-dwelling middle-aged and
elderly persons. J Circ Biomark. 2017;6:1849454417726609. https://
doi:10.1177/1849454417726609
- 38. Huang SS, Chan WL, Leu HB, Huang PH, Lin SJ, Chen JW.
Serum bilirubin levels predict future development of metabolic syndrome
in healthy middle-aged nonsmoking men. American Journal
of Medicine. 2015;128(10):1138-e35. https://doi:10.1016/j.amjmed.
2015.04.019
- 39. Jo J, Yun JE, Lee H, Kimm H, Jee SH. Total, direct, and indirect
serum bilirubin concentrations and metabolic syndrome among
the Korean population. Endocrine. 2011;39(2):182-189. https://
doi:10.1007/s12020-010-9417-2
- 40. Oda E, Aizawa Y. Total bilirubin is inversely associated with
metabolic syndrome but not a risk factor for metabolic syndrome in
Japanese men and women. Acta Diabetol. 2013;50(3):417-422. https://
doi:10.1007/s00592-012-0447-5
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