Searching for additional markers of impaired iron metabolism in diabetes mellitus

BACKGROUND: It is known that metabolic disorders in diabetes mellitus have a regulating effect on ferrokinetics, and therefore diabetes mellitus is often accompanied by various disorders of iron metabolism, both anemia and secondary iron overload. The main problem is timely and accurate differential diagnosis between anemia of chronic diseases and iron deficiency anemia. It is necessary to establish reliable laboratory markers of anemia of chronic diseases in order to solve this problem, as well as to understand what metabolic disorders can lead to the occurrence and aggravate the course of this type of anemia.

AIMS: To study the frequency of occurrence of violations of ferrokinetics in patients with diabetes mellitus, as well as to establish clinical and biochemical correlations that are significant in the differential diagnosis of various disorders of iron metabolism: iron deficiency anemia, anemia of chronic diseases and dysmetabolic iron overload syndrome in diabetes mellitus.

MATERIALS AND METHODS: The research design a single-stage observational single-center research. The research was conducted on the basis of the endocrinological clinic of the Federal State Budgetary Educational Institution of Higher Education Siberian State Medical University in Tomsk. The research included 76 patients with type 1 and type 2 diabetes mellitus. We conducted an assessment of all patients as follows: anthropometric data assessment; glycated hemoglobin study; creatinine level study with the calculation of glomerular filtration rate (GFR) using the CKD-EPI formula. We also evaluated the number of erythrocytes, reticulocytes, the hemoglobin concentration, haematocrit level and biochemical parameters of iron metabolism: serum iron and ferritin concentrations; the concentration of hepsidin and non-specific markers of inflammation: erythrocyte sedimentation rate (ESR) and highly sensitive C-reactive protein (CRP).

RESULTS: 20 people (26.3%) of the 76 patients included in the study, had type 1 diabetes mellitus and 56 people (73.3%) had type 2 diabetes mellitus. The parameters of ferrokinetics did not significantly differ in patients with type 1 and type 2 diabetes mellitus, while in the group of patients with 20 patients (26.3%) from the 76 ones included into the research had type 1 diabetes mellitus and 56 (73.3%) from them had type 2 diabetes mellitus. The parameters of ferrokinetics did not significantly differ in patients with type 1 and type 2 diabetes mellitus, while in the group of patients with type 2 diabetes mellitus, the levels of CRP (p=0.034) and blood leukocytes (p=0.020) were significantly higher than in patients with type 1 diabetes mellitus. Both in the main group of patients with impaired carbohydrate metabolism, and in patients with type 2 diabetes mellitus, anemia of chronic diseases prevailed in the structure of the anemia syndrome. After dividing the main group of patients into groups by type of anemia syndrome: absence of anemia, anemia of chronic diseases and iron deficiency anemia, a comparative analysis of the average values of markers of inflammation and the level of hepsidin in these groups was performed. It was found that in patients with anemia of chronic diseases, the level of hepsidin is significantly higher than in patients without anemic syndrome (p=0.033). Paired correlation analysis showed a positive correlation of ESR with microalbuminuria (r=0.515; P<0.0001), creatinine level (r=0.467; P<0.0001) and negative — with GFR (r= -0.436; P<0.0001) and iron in serum (r=-0.276; p=0.017). As the result of ROC analysis the most informative in the diagnosis of anemia of chronic disease were: ferritin — sensitivity 78%, specificity 52% with a diagnostic threshold of 75.5 ng/ml (area under the curve 0,695; p=0.006); ESR — sensitivity 67%, specificity 64% with a diagnostic threshold of 15.5 mm/HR (area under the curve of 0.750 in; p=0.040) and the CRP — sensitivity 67%, specificity 64% with a diagnostic threshold of 5.2 ng/ml (area under the curve 0,646; р<0.0001).

CONCLUSION: Thus, the studied markers of inflammation — ESR and CRP, as well as hepsidin in combination with the classic diagnostic parameter — ferritin, demonstrated high value in the diagnosis of anemia of chronic diseases and can be included in the modified algorithm for differential diagnosis of anemia syndrome in patients with diabetes mellitus.

diabetes mellitus, anemia of chronic diseases, iron deficiency anemia, hepsidin, C-reactive protein, inflammation

1. Fernandez-Real JM, Lopez-Bermejo A, Ricart W. Cross-talk between iron metabolism and diabetes. Diabetes. 2002;51(8):2348–2354. doi: 10.2337/diabetes.51.8.2348.

2. Sam AH, Busbridge M, Amin A, et al. Hepcidin levels in diabetes mellitus and polycystic ovary syndrome. Diabet Med. 2013;30(12):1495−1499. doi: 10.1111/dme.12262.

3. Jiang F, Sun ZZ, Tang YT, et al. Hepcidin expression and iron parameters change in type 2 diabetic patients. Diabetes Res Clin Pract. 2011;93(1):43−48. doi: 10.1016/j.diabres.2011.03.028.

4. Aregbesola A, Voutilainen S, Virtanen JK, et al. Serum hepcidin concentrations and type 2 diabetes. World J Diabetes. 2015;6(7):978−982. doi: 10.4239/wjd.v6.i7.978.

5. Ganz T. Hepcidin and iron regulation, 10 years later. Blood. 2011;117(17):4425–4433. doi: 10.1182/blood-2011-01-258467.

6. Jiang F, Sun ZZ, Tang YT, et al. Hepcidin expression and iron parameters change in type 2 diabetic patients. Diab Res Clin Pract. 2011;93(1):43−48. doi: 10.1016/j.diabres.2011.03.028.

7. Ganz T, Nemeth E. Hepcidin and iron homeostasis. Biochim Biophys Acta. 2012;1823(9):1434−1443. doi: 10.1016/j.bbamcr.2012.01.014.

8. Румянцев А.Г., Масчан А.А., Чернов В.М., Тарасова И.С. Федеральные клинические рекомендации по диагностике и лечению железодефицитной анемии. — М., 2015. — 43 с. [Rumyantsev AG, Maschan AA, Chernov VM, Tarasova IS. Federal`nye klinicheskie rekomendatsii po diagnostike i lecheniyu zhelezodefitsitnoy anemii. Moscow; 2015. 43 р. (In Russ).]

9. Румянцев А.Г., Масчан А.А. Федеральные клинические рекомендации по диагностике и лечению анемии хронических болезней. — М., 2014. — 9 с. [Rumyantsev AG, Maschan AA. Federal`nye klinicheskie rekomendatsii po diagnostike i lecheniyu anemii khronicheskikh bolezney. Moscow; 2014. 9 р. (In Russ).]

10. Thomas M, Tsalamandris C, MacIsaac R, Jerums G. Anemia in diabetes: an emerging complication of microvascular disease. Curr Diabetes Rev. 2005;1(1):107−126. doi: 10.2174/1573399052952587.

11. Angelousi A, Larger E. Anemia, a common but often unrecognized risk in diabetic patients: a review. Diabetes Metab. 2015;41(1):18−27. doi: 10.1016/j.diabet.2014.06.001.

12. Куфелкина Т.Ю., Валеева Ф.В. Анемия у больных сахарным диабетом 1 типа // Сахарный диабет. — 2010. — №4. — С. 49–53. [Kufelkina TYu, Valeeva FV. Anemia in patients with type 1 diabetes mellitus. Diabetes mellitus. 2010;(4):49–53. (In Russ).]

13. Семакова А.Д., Брыкова Я.И., Силина М.Н., Волынкина А.П. Оценка распространенности анемии у больных с сахарным диабетом // Центральный научный вестник. — 2019. — Т.4. — №7. — С. 7–8. [Semakova AD, Brykova YaI, Silina MN, Volynkina AP. Estimation of the anemia prevalence in patients with diabetes mellitus. Central Scientific Herald. 2019;4(7):7–8. (In Russ).]

14. Мартынов С.А., Шестакова М.В., Шилов Е.М., и др. Распространенность анемии у больных сахарным диабетом 1 и 2 типа с поражением почек // Сахарный диабет. — 2017. — Т.20. — №5. — С. 318–328. [Martynov SA, Shestakova MV, Shilov EM, et al. Prevalence of anemia in patients with type 1 and type 2 diabetes mellitus with chronic renal disease. Diabetes mellitus. 2017;20(5):318–328. (In Russ).] doi: 10.14341/DM9369.

15. Alsayegh F, Waheedi M, Bayoud T, et al. Anemia in diabetes: experience of a single treatment center in Kuwait. Prim Care Diabetes. 2017;11(4):383−388. doi: 10.1016/j.pcd.2017.04.002.

16. Саприна Т.В., Зима А.П., Мусина Н.Н., и др. Патогенетические аспекты нарушения метаболизма гепсидина и феррокинетики при патологии углеводного обмена // Сахарный диабет. — 2018. — Т.21. — №6. — С. 506–512. [Saprina TV, Zima AP, Musina NN, et al. Pathogenetic aspects of hepcidin metabolism and ferrocinetics dysregulation in carbohydrate metabolism disorders. Diabetes mellitus. 2018;21(6):506–512. (In Russ).] doi: 10.14341/DM9378.

17. Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113(9):1271–1276. doi: 10.1172/JCI20945.

18. Simcox JA, Mcclain DA. Iron and diabetes risk. Cell Metab. 2013;17(3):329−341. doi: 10.1016/j.cmet.2013.02.007.