Telomere biology and target-based approach in correction of insulin resistance in patients with prediabetes

• Ekaterina N. Dudinskaya
• Olga N. Tkacheva

Abstract

Changes in arterial wall properties due to carbohydrate metabolism disorders include an increase in their rigidity and an increase in wall thickness (primarily due to intimal thickening), appearance of subclinical atherosclerosis and endothelial dysfunction.

It is possible that a key role in changes in arterial wall properties is played not only by chronic hyperglycemia, but also by insulin resistance (IR), which, by activating and enhancing oxidative stress and chronic inflammation, induces accelerated changes in the vascular wall, forming the basis for cardiovascular diseases development.

Probably one of the reasons for different rates of vascular changes in patients with IR, prediabetes and type 2 diabetes mellitus is initially different “genetic protection” of vascular wall from external damaging factors. In this regard, in recent years, more and more attention has been paid to studying the role of replicative cell aging in development of vascular wall changes. Biomarkers of cellular aging are telomere length and telomerase activity. Both indicators make up the concept of “telomere biology”.

In search of ways to slow down age-related arterial wall changes, scientists turned to studying the possibility of influencing telomere biology, primarily by modulating telomerase activity. A promising method for preventing vascular aging in patients with carbohydrate disorders may be correction of carbohydrate metabolism using various glucose-lowering drugs, a review of which is given in this article.

Keywords:telomeres; vascular aging; insulin resistance; prediabetes; type 2 diabetes mellitus; anti-aging; telomerase; telomere biology; hypoglycemic drugs; prevention

References

1. Algorithms for specialized medical care for patients with diabetes. Edited by I.I. Dedov, M.V. Shestakova, A. Yu. Mayorov. 11th is. Moscow, 2023. DOI: https://doi.org/10.14341/DM13042 (in Russian)

2. American Diabetes Association. Standards of Medical Care in Diabetes – 2017. Diabetes Care. 2017; 40 (Suppl. 1): S 1–S 2. DOI: https://doi.org/10.2337/dc17-S 001

3. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia. Report of WHO/IDF Consultation, 2006.

4. Santaguida P.L., Balion C., Hunt D., Morrison K., Gerstein H., Raina P., et al. Diagnosis, prognosis, and treatment of impaired glucose tolerance and impaired fasting glucose. Evidence Report/Technology Assessment No. 128. (Prepared by the McMaster University Evidence-based Practice Center under Contract No. 290-02-0020). AHRQ Pub. No 05-E 026-2. Rockville, MD: Agency for Healthcare Research and Quality. September 2005.

5. Glucose tolerance and mortality: comparison of WHO and ADA diagnostic criteria. The DECODE study group. European Diabetes Epidemiology Group. Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe. Lancet. 1999; 354 (9179): 617–21.

6. Huang Y., Cai X., Mai W., Li M., Hu Y. Association between prediabetes and risk of cardiovascular disease and all cause mortality: systematic review and meta-analysis. BMJ. 2016; 355: i5953. DOI: https://doi.org/10.1136/bmj.i5953

7. Tominaga M., Eguchi H., Manaka H. et al. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. The Funagata Diabetes Study. Diabetes Care. 1999; 22 (6): 920–4. DOI: https://doi.org/10.2337/diacare.22.6.920

8. Li H., Meng Y., He S., Tan X., Zhang Y., Zhang X., et al. Macrophages, chronic inflammation, and insulin resistance. Cells. 2022; 11: 3001. DOI: https://doi.org/10.3390/cells11193001

9. Dudinskaya E.N., Brailova N.V., Strazhesko I.D., Akasheva D.U., Tkacheva O.N., Shestakova M.V. Role of insulin resistance in vascular aging processes (a review of literature). Profilakticheskaya Meditsina. 2014; 17 (2): 35–41. (in Russian)

10. Evans J.L., Maddux B.A., Goldgine I.D. The molecular basis fir oxidqative stress-induced insulin resistance. Antioxid Redox Signal. 2005; 7: 7–8: 1040–5.

11. Patti M., Corvera S. The role of mitochondria in the pathogenesis of type 2 diabetes. Endocr Rev 2010; 31: 3: 364–95.

12. Nandakumar J., Cech T.R. Finding the end: recruitment of telomerase to telomeres. Nat Rev Mol Cell Biol. 2013; 14 (2): 69–82. DOI: https://doi.org/10.1038/nrm3505

13. Blackburn E.H., Collins K. Telomerase: an RNP enzyme synthesizes DNA // Cold Spring Harb Perspect Biol. 2011; 3 (5): a003558. DOI: https://doi.org/10.1101/cshperspect.a003558

14. Levy M.Z., Allsopp R.C., Futcher A.B., et al. Telomere end-replication problem and cell aging. J Mol Biol. 1992; 225 (4): 951–60. DOI: https://doi.org/10.1016/0022-2836(92)90096-3

15. Shay J.W. Role of telomeres and telomerase in aging and cancer. Cancer Discov. 2016; 6 (6): 584–93. DOI: https://doi.org/10.1158/2159-8290.CD-16-0062

16. Adaikalakoteswari A., Balasubramanyam M., Ravikumar R., et al. Association of telomere shortening with impaired glucose tolerance and diabetic macroangiopathy. Atherosclerosis. 2007; 195 (1): 83–9. DOI: https://doi.org/10.1016/j.atherosclerosis.2006.12.003

17. Sampson M.J., Winterbone M.S., Hughes J.C., et al. Monocyte telomere shortening and oxidative DNA damage in type 2 diabetes. Diabetes Care. 2006; 29: 283–9.

18. Zhou M., Zhu L., Cu X., et al. Influence of diet on leukocyte telomere length, markers of inflammation and oxidative stress in individuals with varied glucose tolerance: a Chinese population study. Nutr J. 2016; 15: 39. DOI: https://doi.org/10.1186/s12937-016-0157-x

19. Aix E., Gallinat A., Flores I. Telomeres and telomerase in heart regeneration. Differentiation. 2018; 100: 26–30. DOI: https://doi.org/10.1016/j.diff.2018.01.003

20. Dudinskaya E.N. Morphofunctional state of vascular wall and replicative cellular aging with different insulin sensitivity: Dissertation. Moscow. 2022: 283 p. (in Russian)

21. Brouilette S.W., Moore J.S., McMahon A.D., et al. Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case-control study. Lancet. 2007; 369 (9556): 107–14. DOI: https://doi.org/10.1016/S0140-6736(07)60071-3

22. Daubenmier J., Lin J., Blackburn E., et al. Changes in stress, eating, and metabolic factors are related to changes in telomerase activity in a randomized mindfulness intervention pilot study. Psychoneuroendocrinology. 2012; 37 (7): 917–28. DOI: https://doi.org/10.1016/j.psyneuen.2011.10.00

23. Dudinskaya E.N., Tkacheva O.N., Brailova N.V., Strazhesko I.D., Shestakova M.V. Telomere biology and metabolic disorders: the role of insulin resistance and type 2 diabetes. Problems of Endocrinology. 2020; 66 (4): 35–44. DOI: https://doi.org/10.14341/probl12510 (in Russian)

24. Rentoukas E., Tsarouhas K., Kaplanis I., et al. Connection between telomerase activity in PBMC and markers of inflammation and endothelial dysfunction in patients with metabolic syndrome. PLoS One. 2012; 7 (4): e35739. DOI: https://doi.org/10.1371/journal.pone.0035739

25. Olivieri F., Albertini M.C., Orciani M., et al. DNA damage response (DDR) and senescence: shuttled inflamma-miRNAs on the stage of inflamm-aging. Oncotarget. 2015; 6 (34): 35509–21. DOI: https://doi.org/10.18632/oncotarget.589

26. Demissie S., Levy D., Benjamin E.J., et al. Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart Study. Aging Cell. 2006; 5 (4): 325−30. DOI: https://doi.org/10.1111/j.1474-9726.2006.00224.x

27. Gardner J.P., Li S., Srinivasan S.R., et al. Rise in insulin resistance is associated with escalated telomere attrition. Circulation. 2005; 111 (17): 2171–7. DOI: https://doi.org/10.1161/01.CIR.0000163550.70487.0B

28. Madsen K.S., Chi Y., Metzendorf M.I., Richter B., Hemmingsen B. Metformin for prevention or delay of type 2 diabetes mellitus and its associated complications in persons at increased risk for the development of type 2 diabetes mellitus. Cochrane Database Syst Rev. 2019; Is 12. Art. No. CD 008558. DOI: https://doi.org/10.1002/14651858.CD 008558.pub2

29. Bogacka I., Ukropcova B., McNei M., et al. Structural and functional consequences of mitochondrial biogenesis in human adipocytes in vitro. J Clin Endocrinol Metab. 2005; 90 (12): 6650–6. DOI: https://doi.org/10.1210/jc.2005-1024

30. Anisimov V.N., Berstein L.M., Egormin P.A., et al. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle. 2008; 7 (17): 2769–73. DOI: https://doi.org/10.4161/cc.7.17.6625

31. Ma D., Yu Y., Yu X., et al. The changes of leukocyte telomere length and telomerase activity after sitagliptin intervention in newly diagnosed type 2 diabetes. Diabetes Metab Res Rev. 2015; 31 (3): 256–61. DOI: https://doi.org/10.1002/dmrr.2578

32. Instruction for medical use of Subetta. https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=1c2e38fc-4204-4e5b-9839-48f134266015

33. Gorbunov E.A., Nicoll J., Kachaeva E.V., et al. Subetta increases phosphorylation of insulin receptor β-subunit alone and in the presence of insulin. Nutr Diabetes. 2015; 5 (7): e169. DOI: https://doi.org/10.1038/nutd.2015.20

34. Gorbunov E.A., Nicoll J., Myslivets A.A., Kachaeva E.V., Tarasov S.A. Subetta enhances sensitivity of human muscle cells to insulin. Bull Exp Biol Med. 2015; 159 (4): 463–5. DOI: https://doi.org/10.1007/s10517-015-2992-8; PMID: 26388576.

35. Nicoll J., Gorbunov E.A., Tarasov S.A., Epstein O.I. Subetta treatment increases adiponectin secretion by mature human adipocytes in vitro. Int J Endocrinol. 2013; 2013: 925874. DOI: https://doi.org/10.1155/2013/925874

36. Mkrtumyan A., Ametov A., Demidova T., Volkova A., Dudinskaya E., Vertkin A., et al. A new approach to overcome insulin resistance in patients with impaired glucose tolerance: the results of a multicenter, double-blind, placebo-controlled, randomized clinical trial of efficacy and safety of Subetta. J Clin Med. 2022; 11 (5): 1390. DOI: https://doi.org/10.3390/jcm11051390

37. Shinkin M.V., Zvenigorodskaya L.A., Mkrtumyan A.M. Laser doppler flowmetry and fluorescence spectroscopy use to assess the condition of the microcirculatory bed and tissue metabolism in patients with type 2 diabetes mellitus on the background of Subetta therapy. Effective Pharmacotherapy. 2020; 16 (12): 8–14. DOI: https://doi.org/10.33978/2307-3586-2020-16-12-8-1

All articles in our journal are distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0 license)