Iron metabolism parameters and inflammatory status in patients with diabetes mellitus and dyslipidemia

Background: Investigating the inflammatory status and iron metabolism in patients with impaired carbohydrate metabolism seems quite relevant, while only few studies are devoted to the relationship between metabolic parameters, including lipid profile, inflammatory status indicators and the state of ferrokinetics in diabetes mellitus types 1 and 2 in a comparative aspect.

Aims: To establish the direction of changes in the inflammatory status and the state of ferrokinetics in patients with type 1 and type 2 diabetes mellitus depending on lipid metabolism disorders.

Materials and methods: The study included 48 patients with type 1 diabetes, 81 patients with type 2 diabetes; 11 people with obesity without impaired carbohydrate metabolism made up the comparison group, 17 healthy volunteers - the control group. Low-grade inflammation was assessed by the levels of high-sensitive C-reactive protein (CRP), tumor necrosisfactor-а (TNF-а), ferritin, and erythrocyte sedimentation rate (ESR). The state of iron metabolism was evaluated by the main hematological parameters (hemoglobin, red blood cell count, hematocrit), serum iron concentrations, transferrin, ferritin and hepcidin concentrations. In all patients lipid metabolism parameters, glycated hemoglobin, and microalbuminuria were measured.

Results: Patients with type 1 and type 2 diabetes mellitus had significantly higher inflammatory markers concentrations-TNF-а, ESR, and CRP - in relation to obese patients without impaired carbohydrate metabolism and those in the control group. The highest production of TNF-а was observed in patients with type 1 diabetes mellitus (15.28 [12.41-24.41] pg/ml), whereas CRP (7.00 [3.00-11.85] ng/ml) and ESR (18.00 [9.00-27.00] mm/h) were higher in patients with type 2 diabetes. In the structure of the examined individuals with diabetes mellitus (regardless of its type), dyslipidemia type IIb in comparison with less atherogenic type IIa dyslipidemia was characterized by a higher production of CRP (6.9 [3.00-12.35] and 3.00 [1.80-8.70] ng/ml, respectively), ESR (20.00 [10.00-30.00] and 15.00 [5.00-24.50] mm/h, respectively) and ferritin (114.80 [48.90-196.45] and 50.90 [19.58-114.10] ng/ml, respectively). Compared to iron deficiency anemia, anemia of chronic diseases in diabetes mellitus patients was more often accompanied by dyslipidemia llb (χ²=2.743; p=0.098) and was characterized by a higher content of atherogenic fractions of cholesterol.

Conclusions: Patients with type 2 diabetes mellitus and a more atherogenic dyslipidemia profile (type IIb) have a phenotype of the local inflammatory mesenchymal reaction of the liver with an increase in acute-phase proteins predominantly of hepatic origin (CRP, ferritin), whereas individuals suffering from type 1 diabetes and less atherogenic lipid profile (type IIa) have a phenotype of an autoimmune, genetically determined inflammatory response. It has been established that anemia of chronic diseases developing in the background of diabetes mellitus is associated with a more atherogenic lipid profile, compared with iron deficiency anemia.

1. Rabinovitch A, Suarez-Pinzon WL. Roles of cytokines in the pathogenesis and therapy of type 1 diabetes. Cell Biochem Biophys. 2007;48(2-3):159-163. doi: https://doi.org/10.1007/s12013-007-0029-2

2. Schneider-Brachert W, Tchikov V, Neumeyer J, et al. Compartmentalization of TNF Receptor 1 Signaling. Immunity. 2004;21(3):415-428. doi: https://doi.org/10.1016/jjmmuni.2004.08.017

3. Uno S, Imagawa A, Okita K, et al. Macrophages and dendritic cells infiltrating islets with or without beta cells produce tumour necrosis factor-а in patients with recentonset type 1 diabetes. Diabetologia. 2007;50(3):596-601. doi: https://doi.org/10.1007/s00125-006-0569-9

4. Klimontov VV, Tyan NV, Fazullina ON, et al. Clinical and metabolic factors associated with chronic low-grade inflammation in type 2 diabetic patients. Diabetes mellitus. 2016;19(4):295-302. doi: https://doi.org/10.14341/DM7928

5. Wang Z, Shen X-H, Feng W-M, Ye G, Qiu W, Li B. Analysis of Inflammatory Mediators in Prediabetes and Newly Diagnosed Type 2 Diabetes Patients. J Diabetes Res. 2016;2016(4):1-10. doi: https://doi.org/10.1155/2016/7965317

6. Yamamoto Y, Yamamoto H. RAGE-Mediated Inflammation, Type 2 Diabetes, and Diabetic Vascular Complication. Front Endocrinol (Lausanne). 2013;4(4):1-10. doi: https://doi.org/10.3389/fendo.2013.00105

7. Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract. 2014;105(2):141-150. doi: https://doi.org/10.1016/j.diabres.2014.04.006

8. Dandona P, Aljada A, Chaudhuri A, Bandyopadhyay A. The Potential Influence of Inflammation and Insulin Resistance on the Pathogenesis and Treatment of Atherosclerosis-Related Complications in Type 2 Diabetes. J Clin Endocrinol Metab. 2003;88(6):2422-2429. doi: https://doi.org/10.1210/jc.2003-030178

9. Donath MY, Gross DJ, Cerasi E, Kaiser N. Hyperglycemia-induced beta-cell apoptosis in pancreatic islets of Psammomys obesus during development of diabetes. Diabetes. 1999;48(4):738-744. doi: https://doi.org/10.2337/diabetes.48.4738

10. Kluppelholz B, Thorand B, Koenig W, et al. Association of subclinical inflammation with deterioration of glycaemia before the diagnosis of type 2 diabetes: the KORA S4/F4 study. Diabetologia. 2015;58(10):2269-2277. doi: https://doi.org/10.1007/s00125-015-3679-4

11. Ammirati E, Moroni F, Norata GD, Magnoni M, Camici PG. Markers of Inflammation Associated with Plaque Progression and Instability in Patients with Carotid Atherosclerosis. Mediators Inflamm. 2015;2015(10):1-15. doi: https://doi.org/10.1155/2015/718329

12. Soeki T, Sata M. Inflammatory Biomarkers and Atherosclerosis. Int Heart J. 2016;57(2):134-139. doi: https://doi.org/10.1536/ihj.15-346

13. Hameed I, Masoodi SR, Mir SA, et al. Type 2 diabetes mellitus: From a metabolic disorder to an inflammatory condition. World J Diabetes. 2015;6(4):598. doi: https://doi.org/10.4239/wjd.v6.i4.598

14. Ganz T. Anemia of Inflammation. N Engl J Med. 2019;381(12):1148-1157. doi: https://doi.org/10.1056/NEJMra1804281

15. Kufelkina TY, Valeeva FV. Anemia in patients with type 1 diabetes mellitus. Diabetes mellitus. 2010;13(4):49-53. (In Russ.) doi: https://doi.org/10.14341/2072-0351-6057

16. Semakova AD., Brykova YI., Silina MN., Volynkina AP, Estimation of the anemia prevalence in patients with diabetes mellitus. Central' nyj naucnyj vestnik. 2019;7(72):7-8. (in Russ.).

17. Martynov SA, Shestakova M V., 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: https://doi.org/10.14341/DM9369

18. Rumyantsev AG, Maschan AA, Chernov VM, Tarasova IS; FGBU «FNKC DGOI imeni Dmitriya Rogacheva» Minzdrava Rossii; Obschestvennaia organistsia Natsional'noe obschestvo detskih gematologov, onkologov. Federal'nye klinicheskie rekomendatsii po diagnostike I lecheniiu zhelezodeficitnoi anemii. - 2015. (in Russ.)

19. Rumyantsev AG, Maschan AA, Chernov VM, Tarasova IS; FGBU «FNKC DGOI imeni Dmitriya Rogacheva» Minzdrava Rossii; Obschestvennaia organistsia Natsional'noe obschestvo detskih gematologov, onkologov. Federal'nye klinicheskie rekomendatsii po diagnostike I lecheniiu zhelezodeficitnoi anemii. - 2014. (in Russ.)

20. Fredrickson DS, Lees RS. Editorial. Circulation. 1965;31(3):321-327. doi: https://doi.org/10.1161/01.CIR.31.3321

21. Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol. 2016;12(1):49-62. doi: https://doi.org/10.1038/nrrheum.2015.169

22. Aggarwal BB. Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol. 2003;3(9):745-756. doi: https://doi.org/10.1038/nri1184

23. Hotamisligil GS. Molecular mechanisms of insulin resistance and the role of the adipocyte. Int J Obes. 2000. doi: https://doi.org/10.1038/sj.ijo.0801497

24. Hauner H, Petruschke T, Russ M, Rohrig K, Eckel J. Effects of tumour necrosis factor alpha (TNFa) on glucose transport and lipid metabolism of newly-differentiated human fat cells in cell culture. Diabetologia. 1995;38(7):764-771. doi: https://doi.org/10.1007/s001250050350

25. Zhang HH, Halbleib M, Ahmad F, et al. Tumor Necrosis Factor-Stimulates Lipolysis in Differentiated Human Adipocytes Through Activation of Extracellular Signal-Related Kinase and Elevation of Intracellular cAMP. Diabetes. 2002;51(10):2929-2935. doi: https://doi.org/10.2337/diabetes.51.10.2929

26. Gotsman I, Stabholz A, Planer D, et al. Serum cytokine tumor necrosis factor-alpha and interleukin-6 associated with the severity of coronary artery disease: indicators of an active inflammatory burden? Isr Med Assoc J. 2008;10(7):494-498.

27. Ben-Mahmud BM, Chan WH, Abdulahad RM, et al. Clinical validation of a link between TNF-а and the glycosylation enzyme core 2 GlcNAc-T and the relationship of this link to diabetic retinopathy. Diabetologia. 2006;49(9):2185-2191. doi: https://doi.org/10.1007/s00125-006-0332-2

28. Hussain MJ, Peakman M, Gallati H., et al. Elevated serum levels of macrophage-derived cytokines precede and accompany the onset of IDDM. Diabetologia. 1996;39(1):60-69.

29. Prokhorenko TS, Saprina T V., Lazarenko FE, et al. The system of tumor necrosis factor a in the pathogenesis of autoimmune diabetes mellitus. Bulletin ofSiberian Medicine. 2011;10(1):64-69. (in Russ.) doi: https://doi.org/10.20538/1682-0363-2011-1-64-69

30. Schutze S, Tchikov V, Schneider-Brachert W, Regulation ofTNFR1 and CD95 signalling by receptor compartmentalization. Nat Rev Mol Cell Biol. 2008;9(8):655-662. doi: https://doi.org/10.1038/nrm2430

31. Saisho Y. Metformin and Inflammation: Its Potential Beyond Glucose-lowering Effect. Endocrine, Metab Immune Disord Targets. 2015;15(3):196-205. doi: https://doi.org/10.2174/1871530315666150316124019

32. Shaenko ZA, Rasin MS. Efficiency and Safety of Metformine and Pioglitazone in Patients with Coronary Heart Disease and Diabetes Mellitus Type 2. International Journal of Endocrinology. 2015;(2):66-70. (In Russ.)

33. Pizov A V., Pizov NA, Skachkova OA, Pizova N V. Endothelial dysfunction as early predictor of atherosclerosis. Med Alph. 2020;4(35):28-33. (In Russ.) doi: https://doi.org/10.33667/2078-5631-2019-4-35(410)-28-33

34. Koenig W, Lowel H, Baumert J, Meisinger C. C-Reactive Protein Modulates Risk Prediction Based on the Framingham Score. Circulation. 2004;109(11):1349-1353. doi: https://doi.org/10.1161/01.CIR.0000120707.98922.E3

35. Solovyeva AE, Kobalava ZhD. Perspective of antiinflammatory treatment for atherosclerosis. Kliniceskaa farmakologia i terapia. 2014,23(3):28-38. (In Russ.).

36. Paltsev IV, Kalinin AL, Snitsarenko EN. Serum ferritin as a predictor of diabetes mellitus type 2 in patients with chronic hepatitis. Problemyzdorov'a iekologii. 2016;2(48):65-68. (In Russ.).