Кардио-рено-метаболический синдром: обзор патогенеза через призму инсулинорезистетности

В статье представлен обзор патогенеза кардио-рено-метаболического синдрома – мультифакторного состояния, при котором сердечно-сосудистые, почечные и метаболические нарушения взаимно отягощают друг друга. Центральным звеном синдрома выступает инсулинорезистентность, приводящая к компенсаторной гиперинсулинемии. Последняя активирует симпатическую нервную систему и ренин-ангиотензин-альдостероновую систему, способствуя задержке натрия, эндотелиальной дисфункции, артериальной гипертензии и атеросклерозу. В почках гипергликемия запускает сигнальные пути PKC и JAK-STAT/NF-κB, а также накопление конечных продуктов гликирования (AGE), что вызывает воспаление, фиброз и прогрессирование диабетической нефропатии.

1. Ferdinand KC. An overview of cardiovascular-kidney metabolic syndrome. Am J Manag Care. 2024;30(10 Suppl):S181S188. PMID: 39705194. https://doi.org/10.37765/ajmc.2024.89670

2. Ibrahim M, Ba-Essa EM, Baker J, et al. Cardio-renal-metabolic disease in primary care setting. Diabetes Metab Res Rev. 2024;40(3):e3755. PMID: 38115715. PMCID: PMC11320716. https://doi.org/10.1002/dmrr.3755

3. Nichols GA, Amitay EL, Chatterjee S, Steubl D. The Bidirectional Association of Chronic Kidney Disease, Type 2 Diabetes, Atherosclerotic Cardiovascular Disease, and Heart Failure: The Cardio-Renal-Metabolic Syndrome. Metab Syndr Relat Disord. 2023;21(5):261-266. PMID: 37130317. https://doi.org/10.1089/met.2023.0006

4. Koufakis T, Vlahakos D, Vlachopoulos C, et al. Definition, Classification, Diagnosis, and Management of an Emerging Threat: Cardio-Renal-Metabolic Syndrome. Am J Cardiovasc Drugs. 2026;26(1):11-19. PMID: 40858968. https://doi.org/10.1007/s40256-025-00761-w

5. Wang XL, Zhang L, Youker K, et al. Free fatty acids inhibit insulin signaling-stimulated endothelial nitric oxide synthase activation through upregulating PTEN or inhibiting Akt kinase. Diabetes. 2006;55(8):2301-2310. PMID: 16873694. https://doi.org/10.2337/db05-1574

6. Stefanovski D, Punjabi NM, Boston RC, Watanabe RM. гипертензия. 2012;18(2):164-176. https://doi.org/10.18705/1607419X-2012-18-2-164-176

7. Patel DM, Bose M, Cooper ME. Glucose and Blood Pressure-Dependent Pathways-The Progression of Diabetic Kidney Disease. Int J Mol Sci. 2020;21(6):2218. PMID: 32210089. PMCID: PMC7139394. https://doi.org/10.3390/ijms21062218

8. Samuel OO. Review on multifaceted involvement of perivascular adipose tissue in vascular pathology. Cardiovasc Pathol. 2020;49:107259. PMID: 32692664. https://doi.org/10.1016/j.carpath.2020.107259

9. Koenen M, Hill MA, Cohen P, Sowers JR. Obesity, Adipose Tissue and Vascular Dysfunction. Circ Res. 2021;128(7):951-968. PMID: 33793327. PMCID: PMC8026272. https://doi.org/10.1161/circresaha.121.318093

10. Шестопалов А.В., Шатова О.П., Карбышев М.С., Гапонов А.М., Москалева Н.Е., Апполонова С.А., Тутельян А.В., Макаров В.В., Юдин С.М., Румянцев С.А. «Кинурениновый переключатель» и ожирение. Бюллетень сибирской медицины. 2021;20(4):103-111. https://doi.org/10.20538/1682-0363-2021-4103-111

11. Queiroz M, Sena CM. Perivascular adipose tissue: a central player in the triad of diabetes, obesity, and cardiovascular health. Cardiovasc Diabetol. 2024;23(1):455. PMID: 39732729. PMCID: PMC11682657. https://doi.org/10.1186/s12933-024-02549-9

12. Hillock-Watling C, Gotlieb AI. The pathobiology of perivascular adipose tissue (PVAT), the fourth layer of the blood vessel wall. Cardiovasc Pathol. 2022;61:107459. PMID: 35907442. https://doi.org/10.1016/j.carpath.2022.107459

13. Красильникова Е.И., Благосклонная Я.В., Быстрова А.А., Баранова Е.И., Чилашвили М.А., Степанова В.Л., Рюмина И.Л., Симаненкова А.В. Адипозопатия — ключевое звено развития состояния инсулинорезистентности. Артериальная гипертензия. 2012;18(2):164-176. https://doi.org/10.18705/1607-419X-2012-18-2-164-176

14. Hill MA, Yang Y, Zhang L, et al. Insulin resistance, cardiovascular stiffening and cardiovascular disease. Metabolism. 2021;119:154766. PMID: 33766485. https://doi.org/10.1016/j.metabol.2021.154766

15. Измайлова М.Я., Демидова Т.Ю., Валентович В.В. Кардио-рено-метаболическое здоровье: обсуждаем рекомендации Американской кардиологической ассоциации. FOCUS Эндокринология. 2024;5(2):35-45. https://doi.org/10.62751/27130177-2024-5-2-16

16. Mîinea CP, Sano H, Kane S, et al. AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain. Biochem J. 2005;391(Pt 1):87-93. PMID: 15971998. PMCID: PMC1237142. https://doi.org/10.1042/bj20050887

17. Lee SH, Park SY, Choi CS. Insulin Resistance: From Mechanisms to Therapeutic Strategies. Diabetes Metab J. 2022;46(1):15-37. PMID: 34965646. PMCID: PMC8831809. tes Metab J. PMC8831809.

18. Huang X, Liu G, Guo J, Su Z. The PI3K/AKT pathway in obesity and type 2 diabetes. Int J Biol Sci. 2018;14(11):1483-1496. PMID: 30263000. PMCID: PMC6158718. https://doi.org/10.7150/ijbs.27173

19. Chen Q, Rong P, Zhu S, et al. Targeting RalGAPα1 in skeletal muscle to simultaneously improve postprandial glucose and lipid control. Sci Adv. 2019;5(4):eaav4116. PMID: 30989113. PMCID: PMC6459767. https://doi.org/10.1126/sciadv.aav4116

20. Wen X, Zhang B, Wu B, et al. Signaling pathways in obesity: mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2022;7(1):298. PMID: 36031641. PMCID: PMC9420733. https://doi.org/10.1038/s41392-022-01149-x

21. Ortega R, Liu B, Persaud SJ. Effects of miR-33 Deficiency on Metabolic and Cardiovascular Diseases: Implications for Therapeutic Intervention. Int J Mol Sci. 2023;24(13):10777. PMID: 37445956. PMCID: PMC10342147. https://doi.org/10.3390/ijms241310777

22. Godoy-Matos AF, Valério CM, Júnior WSS, de Araujo-Neto JM, Sposito AC, Suassuna JHR. CARDIAL-MS (CArdio-Renal-DIAbetes-Liver-Metabolic Syndrome): a new proposition for an integrated multisystem metabolic disease. Diabetol Metab Syndr. 2025;17(1):218. PMID: 40524210. PMCID: PMC12168269. https://doi.org/10.1186/s13098-025-01796-4

23. Avagimyan A, Pogosova N, Fogacci F, et al. Triglycerideglucose index (TyG) as a novel biomarker in the era of cardiometabolic medicine. Int J Cardiol. 2025;418:132663. PMID: 39426418. https://doi.org/10.1016/j.ijcard.2024.132663

24. Avagimyan A, Fogacci F, Pogosova N, et al. Diabetic Cardiomyopathy: 2023 Update by the International Multidisciplinary Board of Experts. Curr Probl Cardiol. 2024;49(1 Pt A):102052. PMID: 37640176. https://doi.org/10.1016/j.cpcardiol.2023.102052

25. Quaiyoom A, Kumar R. An Overview of Diabetic Cardiomyopathy. Curr Diabetes Rev. 2024;20(5):e121023222139. PMID: 37842898. https://doi.org/10.2174/0115733998255538231001122639

26. Radzioch E, Dąbek B, Balcerczyk-Lis M, et al. Diabetic Cardiomyopathy-From Basics through Diagnosis to Treatment. Biomedicines. 2024;12(4):765. PMID: 38672121. PMCID: PMC11048005. https://doi.org/10.3390/biomedicines12040765

27. Wu J, Jin Z, Zheng H, Yan LJ. Sources and implications of NADH/NAD(+) redox imbalance in diabetes and its complications. Diabetes Metab Syndr Obes. 2016;9:145-153. PMID: 27274295. PMCID: PMC4869616. https://doi.org/10.2147/dmso.s106087

28. Vilas-Boas EA, Almeida DC, Roma LP, Ortis F, Carpinelli AR. Lipotoxicity and β-Cell Failure in Type 2 Diabetes: Oxidative Stress Linked to NADPH Oxidase and ER Stress. Cells. 2021;10(12):3328. PMID: 34943836. PMCID: PMC8699655. https://doi.org/10.3390/cells10123328

29. Tuleta I, Hanna A, Humeres C, et al. Fibroblast-specific TGF-β signaling mediates cardiac dysfunction, fibrosis, and hypertrophy in obese diabetic mice. Cardiovasc Res. 2024;120(16):20472063. PMID: 39373248. PMCID: PMC12097992. https://doi.org/10.1093/cvr/cvae210

30. Frangogiannis NG. Cardiac fibrosis. Cardiovasc Res. 2021;117(6):1450-1488. PMID: 33135058. PMCID: PMC8152700. https://doi.org/10.1093/cvr/cvaa324

31. Козиолова Н.А., Караваев П.Г., Веклич А.С. Диабетическая кардиомиопатия: определение, критерии диагноза, направления терапии и предупреждение сердечной недостаточности. Южно-Российский журнал терапевтической практики. 2020;1(2):93-101. https://doi.org/10.21886/2712-8156-20201-2-93-101

32. Jankauskas SS, Kansakar U, Varzideh F, et al. Heart failure in diabetes. Metabolism. 2021;125:154910. PMID: 34627874. PMCID: PMC8941799. https://doi.org/10.1016/j.metabol.2021.154910

33. Avagimyan A, Sukiasyan L, Sahakyan K, Gevorgyan T, Aznauryan A. The Molecular Mechanism Of Diabetes Mellitus – Related Impairment Of Cardiovascular Homeostasis (Review). Georgian Med News. 2021;(315):99-103. PMID: 34365433

34. Samsu N. Diabetic Nephropathy: Challenges in Pathogenesis, Diagnosis, and Treatment. Biomed Res Int. 2021;2021:1497449. PMID: 34307650. PMCID: PMC8285185. https://doi.org/10.1155/2021/1497449

35. Liu Y, Wang W, Zhang J, Gao S, Xu T, Yin Y. JAK/sTAT signaling in diabetic kidney disease. Front Cell Dev Biol. 2023;11:1233259. PMID: 37635867. PMCID: PMC10450957. https://doi.org/10.3389/fcell.2023.1233259

36. Gupta S, Dominguez M, Golestaneh L. Diabetic Kidney Disease: An Update. Med Clin North Am. 2023;107(4):689-705. PMID: 37258007. https://doi.org/10.1016/j.mcna.2023.03.004

37. Wang N, Zhang C. Oxidative Stress: A Culprit in the Progression of Diabetic Kidney Disease. Antioxidants (Basel). 2024;13(4):455. PMID: 38671903. PMCID: PMC11047699. https://doi.org/10.3390/antiox13040455

38. Zhang H, Nair V, Saha J, et al. Podocyte-specific JAK2 overexpression worsens diabetic kidney disease in mice. Kidney Int. 2017;92(4):909-921. PMID: 28554737. PMCID: PMC5610635. https://doi.org/10.1016/j.kint.2017.03.027

39. Wang H, Gao L, Zhao C, et al. The role of PI3K/Akt signaling pathway in chronic kidney disease. Int Urol Nephrol. 2024;56(8):2623-2633. PMID: 38498274. https://doi.org/10.1007/s11255-024-03989-8

40. Rops AL, van der Vlag J, Lensen JF, et al. Heparan sulfate proteoglycans in glomerular inflammation. Kidney Int. 2004;65(3):768-785. PMID: 14871397. https://doi.org/10.1111/j.1523-1755.2004.00451.x

41. Miao C, Zhu X, Wei X, et al. Proand anti-fibrotic effects of vascular endothelial growth factor in chronic kidney diseases. Ren Fail. 2022;44(1):881-892. PMID: 35618410. PMCID: PMC9154791. https://doi.org/10.1080/0886022x.2022.2079528

42. Nam JS, Cho MH, Lee GT, et al. The activation of NFkappaB and AP-1 in peripheral blood mononuclear cells isolated from patients with diabetic nephropathy. Diabetes Res Clin Pract. 2008;81(1):25-32. PMID: 18485515. https://doi.org/10.1016/j.diabres.2008.01.032

43. Das Evcimen N, King GL. The role of protein kinase C activation and the vascular complications of diabetes. Pharmacol Res. 2007;55(6):498-510. PMID: 17574431. https://doi.org/10.1016/j.phrs.2007.04.016

44. Self-Medlin Y, Byun J, Jacob RF, Mizuno Y, Mason RP. Glucose promotes membrane cholesterol crystalline domain formation by lipid peroxidation. Biochim Biophys Acta. 2009;1788(6):1398-1403. PMID: 19376082. https://doi.org/10.1016/j.bbamem.2009.04.004

45. Pitocco D, Hatem D, Riente A, et al. Evaluating Red Blood Cells’ Membrane Fluidity in Diabetes: Insights, Mechanisms, and Future Aspects. Diabetes Metab Res Rev. 2025;41(1):e70011. PMID: 39627974. PMCID: PMC11615262. https://doi.org/10.1002/dmrr.70011

46. Xu H, Czerwinski P, Hortmann M, Sohn HY, Förstermann U, Li H. Protein kinase C alpha promotes angiogenic activity of human endothelial cells via induction of vascular endothelial growth factor. Cardiovasc Res. 2008;78(2):349-355. PMID: 18056764. https://doi.org/10.1093/cvr/cvm085

47. Galeone A, Annicchiarico A, Buccoliero C, et al. Diabetic Cardiomyopathy: Role of Cell Death, Exosomes, Fibrosis and Epicardial Adipose Tissue. Int J Mol Sci. 2024;25(17):9481. PMID: 39273428. PMCID: PMC11395197. https://doi.org/10.3390/ijms25179481

48. Yamashita N, Kramann R. Mechanisms of kidney fibrosis and routes towards therapy. Trends Endocrinol Metab. 2024;35(1):3148. PMID: 37775469. https://doi.org/10.1016/j.tem.2023.09.001

49. Huang R, Fu P, Ma L. Kidney fibrosis: from mechanisms to therapeutic medicines. Signal Transduct Target Ther. 2023;8(1):129. PMID: 36932062. PMCID: PMC10023808. https://doi.org/10.1038/s41392-023-01379-7

50. Miguel V, Shaw IW, Kramann R. Metabolism at the crossroads of inflammation and fibrosis in chronic kidney disease. Nat Rev Nephrol. 2025;21(1):39-56. PMID: 39289568. https://doi.org/10.1038/s41581-024-00889-z

51. Kaleta B. The role of osteopontin in kidney diseases. Inflamm Res. 2019;68(2):93-102. PMID: 30456594. https://doi.org/10.1007/s00011-018-1200-5

52. Xu J, Zhou L, Liu Y. Cellular Senescence in Kidney Fibrosis: Pathologic Significance and Therapeutic Strategies. Front Pharmacol. 2020;11:601325. PMID: 33362554. PMCID: 37. Wan Progression 2024;13(4):4 N, Zhang Diabetic PMID: : A Culprit in the tioxidants (Basel). : PMC11047699. PMC7759549. https://doi.org/10.3389/fphar.2020.601325

53. Hejazian SM, Hejazian SS, Mostafavi SM, et al. Targeting cellular senescence in kidney diseases and aging: A focus on mesenchymal stem cells and their paracrine factors. Cell Commun Signal. 2024;22(1):609. PMID: 39696575. PMCID: PMC11657437. https://doi.org/10.1186/s12964-024-01968-1

54. Derynck R, Zhang YE. Smad-dependent and Smadindependent pathways in TGF-beta family signalling. Nature. 2003;425(6958):577-584. PMID: 14534577. https://doi.org/10.1038/nature02006

55. Abbad L, Esteve E, Chatziantoniou C. Advances and challenges in kidney fibrosis therapeutics. Nat Rev Nephrol. 2025;21(5):314-329. PMID: 39934355. https://doi.org/10.1038/s41581-025-00934-5

56. Zamolodchikova TS, Tolpygo SM, Kotov AV. Insulin in the regulation of the renin-angiotensin system: a new perspective on the mechanism of insulin resistance and diabetic complications. Front Endocrinol (Lausanne). 2024;15:1293221. PMID: 38323106. PMCID: PMC10844507. https://doi.org/10.3389/fendo.2024.1293221

57. Hsueh WA, Wyne K. Renin-Angiotensin-aldosterone system in diabetes and hypertension. J Clin Hypertens (Greenwich). 2011;13(4):224-237. PMID: 21466617. PMCID: PMC8673350. https://doi.org/10.1111/j.1751-7176.2011.00449.x

58. Abdul-Ghani M, Maffei P, DeFronzo RA. Managing insulin resistance: the forgotten pathophysiological component of type 2 diabetes. Lancet Diabetes Endocrinol. 2024;12(9):674-680. PMID: 39098317. https://doi.org/10.1016/s2213-8587(24)00127-x

59. Zhang J, Yu Y, Liu X, et al. Evaluation of Renal Fibrosis by Mapping Histology and Magnetic Resonance Imaging. Kidney Dis (Basel). 2021;7(2):131-142. PMID: 33824869. PMCID: PMC8010230. https://doi.org/10.1159/000513332

60. Djudjaj S, Boor P. Cellular and molecular mechanisms of kidney fibrosis. Mol Aspects Med. 2019;65:16-36. PMID: 29909119. https://doi.org/10.1016/j.mam.2018.06.002

61. Durak BA, Coban M. The relationship between insulin resistance and fibroblast growth factor 23 in patients with non-diabetic predialysis chronic kidney disease: a cross-sectional study. Sao Paulo Med J. 2025;143(1):e2024103. PMID: 39879508. PMCID: PMC11774536. https://doi.org/10.1590/1516-3180.2024.0103.03072024

62. Petrica L. IJMS Special Issue-Molecular Mechanisms of Diabetic Kidney Disease 2.0. Int J Mol Sci. 2025;26(15):7315. PMID: 40806446. PMCID: PMC12347418. https://doi.org/10.3390/ijms26157315

63. Choma DP, Vanacore R, Naylor H, et al. Aquaporin 11 variant associates with kidney disease in type 2 diabetic patients. Am J Physiol Renal Physiol. 2016;310(5):F416-F425. PMID: 26719361. PMCID: PMC4773830. https://doi.org/10.1152/ajprenal.00295.2015

64. Rico-Fontalvo J, Aroca G, Cabrales J, et al. Molecular Mechanisms of Diabetic Kidney Disease. Int J Mol Sci. 2022;23(15):8668. PMID: 35955802. PMCID: PMC9369345. https://doi.org/10.3390/ijms23158668