Preview

Obesity and metabolism

Advanced search

The role of dysmetabolic iron overload syndrome in non-alcoholic fatty liver disease and carbohydrate metabolism disorders induction

https://doi.org/10.14341/omet13013

Abstract

Iron affects the pathogenesis and clinical course of several chronic metabolic diseases such as obesity, atherosclerosis, non-alcoholic fatty liver disease and type 2 diabetes mellitus. High pro-oxidant iron activity is physiologically controlled by mechanisms regulating entry, recycling, and loss of body iron. These mechanisms include the interplay of iron with ferritin, transferrin, hepcidin, insulin, as well as with adipokines and proinflammatory molecules. An imbalance of these regulatory mechanisms results in both systemic and parenchymal siderosis. Iron overload has a toxic effect on the major tissues involved in lipid and glucose metabolism — pancreatic β cells, liver, muscle, and adipose tissue — as well as the organs affected by chronic hyperglycemia — brain, retina and kidneys. Hyperferremia leads to a decrease in insulin secretion, the formation of insulin resistance and increased liver gluconeogenesis. Molecular mechanisms for these effects are diverse. Elucidating them will implicate both for carbohydrate metabolism disorders prevention and for the pathogenesis of other diseases that are, like diabetes mellitus type 2, associated with nutrition, aging and iron. The literature review presents data from world studies on the mutual influence of glucose metabolism and iron overload, and discusses the differences between hereditary and acquired disorders of iron metabolism from the standpoint of their influence on carbohydrate metabolism.

About the Authors

N. N. Musina
Siberian State Medical University
Russian Federation

Nadezhda N. Musina, MD, PhD

2 Moscowski Trakt, 634050 Tomsk

eLibrary SPIN: 3468-8160



Ya. S. Slavkina
Siberian State Medical University
Russian Federation

Yana S. Slavkina, MD

Tomsk

eLibrary SPIN: 2194-2470



D. A. Petrukhina
Siberian State Medical University
Russian Federation

Daria A. Petrukhina, MD

Tomsk



A. P. Zima
Siberian State Medical University
Russian Federation

Anastasiia P. Zima, MD, PhD, Professor

Tomsk

eLibrary SPIN: 5710-4547



T. S. Prokhorenko
Tomsk Regional Blood Center
Russian Federation

Tatiana S. Prokhorenko, MD, PhD

Tomsk

eLibrary SPIN: 1495-4127



T. V. Saprina
Siberian State Medical University
Russian Federation

Tatiana V. Saprina, MD, PhD, Professor

Tomsk

eLibrary SPIN: 2841-2371



References

1. Moirand R, Mortaji AM, Loréal O, et al. A new syndrome of liver iron overload with normal transferrin saturation. Lancet. 1997;349(9045):95-97. doi: https://doi.org/10.1016/S0140-6736(96)06034-5

2. Root HF. Insulin resistance and bronze diabetes. N Engl J Med. 1929;201(5):201-206. doi: https://doi.org/10.1056/NEJM192908012010501

3. Fernández-Real JM, McClain D, Manco M. Mechanisms linking glucose homeostasis and iron metabolism toward the onset and progression of type 2 diabetes. Diabetes Care. 2015;38(11):2169-2176. doi: https://doi.org/10.2337/dc14-3082

4. Deugnier Y, Turlin B, le Quilleuc D, et al. A reappraisal of hepatic siderosis in patients with end-stage cirrhosis: practical implications for the diagnosis of hemochromatosis. Am J Surg Pathol. 1997;21(6):669-675. doi: https://doi.org/10.1097/00000478-199706000-00007

5. Mendler MH, Turlin B, Moirand R, et al. Insulin resistance-associated hepatic iron overload. Gastroenterology. 1999;117(5):1155-1163. doi: https://doi.org/10.1016/s0016-5085(99)70401-4

6. Pietrangelo A. Hemochromatosis: an endocrine liver disease. Hepatology. 2007;46(4):1291-1301. doi: https://doi.org/10.1002/hep.21886

7. Fernández-Real JM, López-Bermejo A, Ricart W. Cross-talk between iron metabolism and diabetes. Diabetes. 2002;51(8):2348-2354. doi: https://doi.org/10.2337/diabetes.51.8.2348

8. Bozzini C, Girelli D, Olivieri O, et al. Prevalence of body iron excess in the metabolic syndrome. Diabetes Care. 2005;28(8):2061-2063. doi: https://doi.org/10.2337/diacare.28.8.2061

9. Riva A, Trombini P, Mariani R, et al. Revaluation of clinical and histological criteria for diagnosis of dysmetabolic iron overload syndrome. World J Gastroenterol. 2008;14(30):4745-4752. doi: https://doi.org/10.3748/wjg.14.4745

10. Root HF. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol. 2010;53(1):3-22. doi: https://doi.org/10.1016/j.jhep.2010.03.001

11. Mechtiev SN, Mechtieva OA. Iron overload syndrome in chronic hepatic diseases: the focus is on non-alcoholic fat hepatic disease. Lechaschi Vrach. 2017;(12):60-67. (In Russ).

12. Nelson JE, Wilson L, Brunt EM, et al. Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease. Hepatology. 2011;53(2):448-457. doi: https://doi.org/10.1002/hep.24038

13. Valenti L, Fracanzani AL, Bugianesi E, et al. HFE genotype, parenchymal iron accumulation, and liver fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology. 2010;138(3):905-912. doi: https://doi.org/10.1053/j.gastro.2009.11.013

14. Zimiao C, Dongdong L, Shuoping C, et al. Correlations between iron status and body composition in patients with type 2 diabetes mellitus. Front Nutr. 2022;9(1):3-22. doi: https://doi.org/10.3389/fnut.2022.911860

15. Huang J, Jones D, Luo B, et al. Iron overload and diabetes risk: a shift from glucose to Fatty Acid oxidation and increased hepatic glucose production in a mouse model of hereditary hemochromatosis. Diabetes. 2011;60(1):80-87. doi: https://doi.org/10.2337/db10-0593

16. Paltsev IV, Kalinin AL, Snitsarenko EN. Serum ferritin as a predictor of diabetes mellitus type 2 in patients with chronic hepatitis. Health and Ecology Issues. 2016;48(2):65-68. (In Russ.).

17. Fernández-Real JM, Manco M. Effects of iron overload on chronic metabolic diseases. Lancet Diabetes Endocrinol. 2014;2(6):513-526. doi: https://doi.org/10.1016/S2213-8587(13)70174-8

18. Bao W, Rong Y, Rong S, Liu L. Dietary iron intake, body iron stores, and the risk of type 2 diabetes: a systematic review and meta-analysis. BMC Med. 2012;10(1):119. doi: https://doi.org/10.1186/1741-7015-10-119

19. Zhao Z, Li S, Liu G, et al. Body iron stores and heme-iron intake in relation to risk of type 2 diabetes: a systematic review and meta-analysis. PLoS One. 2012;7(7):e41641. doi: https://doi.org/10.1371/journal.pone.0041641

20. Kunutsor SK, Apekey TA, Walley J, Kain K. Ferritin levels and risk of type 2 diabetes mellitus: an updated systematic review and meta-analysis of prospective evidence. Diabetes Metab Res Rev. 2013;29(4):308-318. doi: https://doi.org/10.1002/dmrr.2394

21. Gan W, Guan Y, Wu Q, et al. Association of TMPRSS6 polymorphisms with ferritin, hemoglobin, and type 2 diabetes risk in a Chinese Han population. Am J Clin Nutr. 2012;95(3):626-632. doi: https://doi.org/10.3945/ajcn.111.025684

22. Fernández-Real JM, Mercader JM, Ortega FJ, et al. Transferrin receptor-1 gene polymorphisms are associated with type 2 diabetes. Eur J Clin Invest. 2010;40(7):600-607. doi: https://doi.org/10.1111/j.1365-2362.2010.02306.x

23. Jouihan HA, Cobine PA, Cooksey RC, et al. Iron-mediated inhibition of mitochondrial manganese uptake mediates mitochondrial dysfunction in a mouse model of hemochromatosis. Mol Med. 2008;14(3-4):98-108. doi: https://doi.org/10.2119/2007-00114.Jouihan

24. Koch RO, Zoller H, Theuri I, et al. Distribution of DMT 1 within the human glandular system. Histol Histopathol. 2003;18(4):1095-1101. doi: https://doi.org/10.14670/HH-18.1095

25. Hudson DM, Curtis SB, Smith VC, et al. Human hephaestin expression is not limited to enterocytes of the gastrointestinal tract but is also found in the antrum, the enteric nervous system, and pancreatic {beta}-cells. Am J Physiol Gastrointest Liver Physiol. 2010;298(3):G425-G432. doi: https://doi.org/10.1152/ajpgi.00453.2009

26. MacDonald MJ, Cook JD, Epstein ML, Flowers CH. Large amount of (apo)ferritin in the pancreatic insulin cell and its stimulation by glucose. FASEB J. 1994;8(10):777-781. doi: https://doi.org/10.1096/fasebj.8.10.8050678

27. Krause A, Neitz S, Mägert HJ, et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 2000;480(2-3):147-150. doi: https://doi.org/10.1016/s0014-5793(00)01920-7

28. Sangkhae V, Nemeth E. Regulation of the iron homeostatic hormone hepcidin. Adv Nutr. 2017;8(1):126-136. doi: https://doi.org/10.3945/an.116.013961

29. McClain DA, Abraham D, Rogers J, et al. High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis. Diabetologia. 2006;49(7):1661-1669. doi: https://doi.org/10.1007/s00125-006-0200-0

30. Noetzli LJ, Mittelman SD, Watanabe RM, et al. Pancreatic iron and glucose dysregulation in thalassemia major. Am J Hematol. 2012;87(2):155-160. doi: https://doi.org/10.1002/ajh.22223

31. Manco M. Metabolic syndrome in childhood from impaired carbohydrate metabolism to nonalcoholic fatty liver disease. J Am Coll Nutr. 2011;30(5):295-303. doi: https://doi.org/10.1080/07315724.2011.10719972

32. Ferrannini E. Insulin resistance, iron, and the liver. Lancet. 2000;355(9222):2181-2182. doi: https://doi.org/10.1016/S0140-6736(00)02397-7

33. Angelucci E, Brittenham GM, McLaren CE, et al. Hepatic iron concentration and total body iron stores in thalassemia major [published correction appears in N Engl J Med. 2000;343(23):1740]. N Engl J Med. 2000;343(5):327-331. doi: https://doi.org/10.1056/NEJM200008033430503

34. Kowdley KV, Belt P, Wilson LA, et al. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology. 2012;55(1):77-85. doi: https://doi.org/10.1002/hep.24706

35. Donovan A, Brownlie A, Zhou Y, et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature. 2000;403(6771):776-781. doi: https://doi.org/10.1038/35001596

36. Turlin B, Mendler MH, Moirand R, et al. Histologic features of the liver in insulin resistance-associated iron overload. A study of 139 patients. Am J Clin Pathol. 2001;116(2):263-270. doi: https://doi.org/10.1309/WWNE-KW2C-4KTW-PTJ5

37. Simcox JA, McClain DA. Iron and diabetes risk. Cell Metab. 2013;17(3):329-341. doi: https://doi.org/10.1016/j.cmet.2013.02.007

38. Aigner E, Theurl I, Haufe H, et al. Copper availability contributes to iron perturbations in human nonalcoholic fatty liver disease. Gastroenterology. 2008;135(2):680-688. doi: https://doi.org/10.1053/j.gastro.2008.04.007

39. Dongiovanni P, Fracanzani AL, Fargion S, Valenti L. Iron in fatty liver and in the metabolic syndrome: a promising therapeutic target. J Hepatol. 2011;55(4):920-932. doi: https://doi.org/10.1016/j.jhep.2011.05.008

40. Simcox JA, Mitchell TC, Gao Y, et al. Dietary iron controls circadian hepatic glucose metabolism through heme synthesis. Diabetes. 2015;64(4):1108-1119. doi: https://doi.org/10.2337/db14-0646

41. Li W, Chen Z, Ruan W, et al. A meta-analysis of cohort studies including dose-response relationship between shift work and the risk of diabetes mellitus. Eur J Epidemiol. 2019;34(11):1013-1024. doi: https://doi.org/10.1007/s10654-019-00561-y

42. Stynen B, Abd-Rabbo D, Kowarzyk J, et al. Changes of cell biochemical states are revealed in protein homomeric complex dynamics. Cell. 2018;175(5):1418-1429.e9. doi: https://doi.org/10.1016/j.cell.2018.09.050

43. Wenzel BJ, Stults HB, Mayer J. Hypoferraemia in obese adolescents. Lancet. 1962;2(7251):327-328. doi: https://doi.org/10.1016/s0140-6736(62)90110-1

44. Cheng HL, Bryant C, Cook R, et al. The relationship between obesity and hypoferraemia in adults: a systematic review. Obes Rev. 2012;13(2):150-161. doi: https://doi.org/10.1111/j.1467-789X.2011.00938.x

45. Dongiovanni P, Ruscica M, Rametta R, et al. Dietary iron overload induces visceral adipose tissue insulin resistance. Am J Pathol. 2013;182(6):2254-2263. doi: https://doi.org/10.1016/j.ajpath.2013.02.019

46. Wlazlo N, van Greevenbroek MM, Ferreira I, et al. Iron metabolism is associated with adipocyte insulin resistance and plasma adiponectin: the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study. Diabetes Care. 2013;36(2):309-315. doi: https://doi.org/10.2337/dc12-0505

47. Moreno M, Ortega F, Xifra G, et al. Cytosolic aconitase activity sustains adipogenic capacity of adipose tissue connecting iron metabolism and adipogenesis. FASEB J. 2015;29(4):1529-1539. doi: https://doi.org/10.1096/fj.14-258996

48. Harrison A V., Lorenzo FR, McClain DA. Iron and the pathophysiology of diabetes. Annu Rev Physiol. 2023;85(1):339-362. doi: https://doi.org/10.1146/annurev-physiol-022522-102832

49. Косыгина А.В., Васюкова О.В. Новое в патогенезе ожирения: адипокины — гормоны жировой ткани // Проблемы Эндокринологии. — 2009. — Т. 55. — №1 — С. 44-50. [Kosygina AV, Vasyukova OV. New evidence for the pathogenesis of obesity: adipokines are adipose tissue hormone. Problems of Endocrinology. 2009;55(1):44-50. (In Russ.)]. doi: https://doi.org/10.14341/probl200955144-50

50. Gabrielsen JS, Gao Y, Simcox JA, et al. Adipocyte iron regulates adiponectin and insulin sensitivity. J Clin Invest. 2012;122(10):3529-3540. doi: https://doi.org/10.1172/JCI44421

51. Chung B, Matak P, McKie AT, Sharp P. Leptin increases the expression of the iron regulatory hormone hepcidin in HuH7 human hepatoma cells. J Nutr. 2007;137(11):2366-2370. doi: https://doi.org/10.1093/jn/137.11.2366

52. Amato A, Santoro N, Calabrò P, et al. Effect of body mass index reduction on serum hepcidin levels and iron status in obese children. Int J Obes (Lond). 2010;34(12):1772-1774. doi: https://doi.org/10.1038/ijo.2010.204

53. Lopez P, Taaffe DR, Galvão DA, et al. Resistance training effectiveness on body composition and body weight outcomes in individuals with overweight and obesity across the lifespan: A systematic review and meta-analysis. Obes Rev. 2022;23(5):e13428. doi: https://doi.org/10.1111/obr.13428

54. Ciudin A, Hernández C, Simó R. Iron Overload in Diabetic Retinopathy: A Cause or a Consequence of Impaired Mechanisms? Exp Diabetes Res. 2010;2010:1-8. doi: https://doi.org/10.1155/2010/714108

55. Fernández-Real JM, Manco M. Effects of iron overload on chronic metabolic diseases. Lancet Diabetes Endocrinol. 2014;2(6):513-526. doi: https://doi.org/10.1016/S2213-8587(13)70174-8

56. Ikeda Y, Enomoto H, Tajima S, et al. Dietary iron restriction inhibits progression of diabetic nephropathy in db/db mice. Am J Physiol Renal Physiol. 2013;304(7):F1028-F1036. doi: https://doi.org/10.1152/ajprenal.00473.2012

57. Rajapurkar MM, Hegde U, Bhattacharya A, et al. Effect of deferiprone, an oral iron chelator, in diabetic and non-diabetic glomerular disease. Toxicol Mech Methods. 2013;23(1):5-10. doi: https://doi.org/10.3109/15376516.2012.730558

58. Schröder N, Figueiredo LS, de Lima MN. Role of brain iron accumulation in cognitive dysfunction: evidence from animal models and human studies. J Alzheimers Dis. 2013;34(4):797-812. doi: https://doi.org/10.3233/JAD-121996

59. Tang W, Li Y, He S, et al. Caveolin-1 alleviates diabetes-associated cognitive dysfunction through modulating neuronal ferroptosis-mediated mitochondrial homeostasis. Antioxid Redox Signal. 2022;37(13-15):867-886. doi: https://doi.org/10.1089/ars.2021.0233

60. Miao R, Fang X, Zhang Y, et al. Iron metabolism and ferroptosis in type 2 diabetes mellitus and complications: mechanisms and therapeutic opportunities. Cell Death Dis. 2023;14(3):186. doi: https://doi.org/10.1038/s41419-023-05708-0


Supplementary files

1. Figure 1. Iron overload involvement in the development of carbohydrate metabolism disorders.
Subject
Type Исследовательские инструменты
View (489KB)    
Indexing metadata ▾

Review

For citations:


Musina N.N., Slavkina Ya.S., Petrukhina D.A., Zima A.P., Prokhorenko T.S., Saprina T.V. The role of dysmetabolic iron overload syndrome in non-alcoholic fatty liver disease and carbohydrate metabolism disorders induction. Obesity and metabolism. 2023;20(3):259-268. (In Russ.) https://doi.org/10.14341/omet13013

Views: 2852


ISSN 2071-8713 (Print)
ISSN 2306-5524 (Online)