Metformin in the therapy of type 2 diabetes mellitus bur dened by sarcopenic obesity in the elderly. Focus on pleiotropic effects

Progressive decline in muscle strength and body weight combined with excess body fat is predominantly found in the older age group and is one of the main signs of aging. Sarcopenia contributes to the progression of many chronic diseases, one of which is type 2 diabetes mellitus (DM2). The prevalence of DM2 in the elderly has increased dramatically in recent years, following the increase in the aging population, with sarcopenia occurring much more frequently in patients with DM2 and reported as a new complication. Based on the vast number of studies proving positive effects on skeletal muscle, cardiovascular disease outcomes, risk of malignant neoplasms and increased longevity, metformin has been proposed as a potential anti-aging drug. Metformin therapy may contribute to the prevention of age-related sarcopenia by regulating lipid metabolism in skeletal muscle, namely by enhancing lipolysis and reducing inflammatory responses through activation of AMPK — 5’-adenosine monophosphate-activated protein kinase. Studies conducted to evaluate the efficacy of metformin in individuals with sarcopenia confirm its positive effects on muscle strength and allow it to be considered for the treatment of sarcopenia.

1. Dedov II, Shestakova MV, Vikulova OK, Zheleznyakova AV, Isakov MA, Sazonova DV, Mokry`sheva NG. Saxarny`j diabet v Rossijskoj Federacii: dinamika e`pidemiologicheskix pokazatelej po danny`m Federal`nogo registra saxarnogo diabeta za period 2010–2022 gg. Diabetes mellitus. 2023;26(2):104-123. (in Russian). doi: https://doi.org/10.14341/DM13035

2. Khan RMM, Chua ZJY, Tan JC, Yang Y, Liao Z, Zhao Y. From Pre-Diabetes to Diabetes: Diagnosis, Treatments and Translational Research. Medicina (Kaunas). 2019;55(9):546. doi: https://doi.org/10.3390/medicina55090546

3. Liccini A, Malmstrom TK. Frailty and Sarcopenia as Predictors of Adverse Health Outcomes in Persons With Diabetes Mellitus. J Am Med Dir Assoc. 2016;17(9):846-851. doi: https://doi.org/10.1016/j.jamda.2016.07.007

4. Yuan S, Larsson SC. Epidemiology of sarcopenia: Prevalence, risk factors, and consequences. Metabolism. 2023;144:155533. doi: https://doi.org/10.1016/j.metabol.2023.155533

5. Qiao YS, Chai YH, Gong HJ, et al. The Association Between Diabetes Mellitus and Risk of Sarcopenia: Accumulated Evidences From Observational Studies. Front Endocrinol (Lausanne). 2021;12:782391. doi: https://doi.org/10.3389/fendo.2021.782391

6. Feng L, Gao Q, Hu K, et al. Prevalence and Risk Factors of Sarcopenia in Patients With Diabetes: A Meta analysis. J Clin Endocrinol Metab. 2022;107(5):1470-1483. doi: https://doi.org/10.1210/clinem/dgab884

7. Rossijskaja associacija gerontologov i geriatrov. Klinicheskie rekomendacii. Starcheskaja astenija. Moscow; 2021. 170 p. (In Russ.)

8. Mitchell WK, Williams J, Atherton P, Larvin M, Lund J, Narici M. Sarcopenia, dynapenia, and the impact of advancing age on human skeletal muscle size and strength; a quantitative review. Front Physiol. 2012;3:260. doi: https://doi.org/10.3389/fphys.2012.00260

9. Petermann-Rocha F, Balntzi V, Gray SR, et al. Global prevalence of sarcopenia and severe sarcopenia: a systematic review and meta-analysis. J Cachexia Sarcopenia Muscle. 2022;13(1):86-99. doi: https://doi.org/10.1002/jcsm.12783

10. Beretta MV, Dantas Filho FF, Freiberg RE, Feldman JV, Nery C, Rodrigues TC. Sarcopenia and Type 2 diabetes mellitus as predictors of 2-year mortality after hospital discharge in a cohort of hospitalized older adults. Diabetes Res Clin Pract. 2020;159:107969. doi: https://doi.org/10.1016/j.diabres.2019.107969

11. Kreidieh F, Temraz S. SARS-CoV-2 Infected Patient: from a Hematologist’s Perspective. Mediterr J Hematol Infect Dis. 2020;12(1):e2020078. doi: https://doi.org/10.4084/MJHID.2020.078

12. van den Broek-Altenburg E, Atherly A, Holladay E. Changes in healthcare spending attributable to obesity and overweight: payer- and service-specific estimates. BMC Public Health. 2022;22(1):962. doi: https://doi.org/10.1186/s12889-022-13176-y

13. Nnodim JO, Yung RL. Balance and its Clinical Assessment in Older Adults - A Review. J Geriatr Med Gerontol. 2015;1(1):003. doi: https://doi.org/10.23937/2469-5858/1510003

14. Winter JE, MacInnis RJ, Wattanapenpaiboon N, Nowson CA. BMI and all-cause mortality in older adults: a meta-analysis. Am J Clin Nutr. 2014;99(4):875-890. doi: https://doi.org/10.3945/ajcn.113.068122

15. Kim TN, Yang SJ, Yoo HJ, et al. Prevalence of sarcopenia and sarcopenic obesity in Korean adults: the Korean sarcopenic obesity study. Int J Obes (Lond). 2009;33(8):885-892. doi: https://doi.org/10.1038/ijo.2009.130

16. Wagenaar CA, Dekker LH, Navis GJ. Prevalence of sarcopenic obesity and sarcopenic overweight in the general population: The lifelines cohort study. Clin Nutr. 2021;40(6):4422-4429. doi: https://doi.org/10.1016/j.clnu.2021.01.005

17. Gao Q, Mei F, Shang Y, et al. Global prevalence of sarcopenic obesity in older adults: A systematic review and meta-analysis. Clin Nutr. 2021;40(7):4633-4641. doi: https://doi.org/10.1016/j.clnu.2021.06.009

18. Onuchina YuS, et al. Osobennosti sarkopenii u pacientov s saxarny`m diabetom 2 tipa. Diabetes mellitus-2017: from monitoring to management. 2017: 98-101. (In Russ.)

19. Mkrtumyan AM, Markova TN, Ovchinnikova MA, Ivanova IA, Kuz`menko KV. Metformin — aktivator AMF zavisimoj proteinkinazy`. Izvestny`e i novy`e mexanizmy` dejstviya. Diabetes Mellitus. 2023;26(6):585-595. (In Russ.). doi: https://doi.org/10.14341/DM13044

20. Sabarathinam S, Dhanasekaran D, Ganamurali N. Insight on sarcopenic obesity and epicatechin as a promising treatment option. Diabetes Metab Syndr. 2023;17(10):102856. doi: https://doi.org/10.1016/j.dsx.2023.102856

21. Sakuma K, Yamaguchi A. Sarcopenic obesity and endocrinal adaptation with age. Int J Endocrinol. 2013;2013:204164. doi: https://doi.org/10.1155/2013/204164

22. Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia. 2011;54(10):2506-2514. doi: https://doi.org/10.1007/s00125-011-2204-7

23. Kob R, Bollheimer LC, Bertsch T, et al. Sarcopenic obesity: molecular clues to a better understanding of its pathogenesis? Biogerontology. 2015;16(1):15-29. doi: https://doi.org/10.1007/s10522-014-9539-7

24. Xie WQ, Xiao GL, Fan YB, He M, Lv S, Li YS. Sarcopenic obesity: research advances in pathogenesis and diagnostic criteria. Aging Clin Exp Res. 2021;33(2):247-252. doi: https://doi.org/10.1007/s40520-019-01435-9

25. Ruegsegger GN, Creo AL, Cortes TM, Dasari S, Nair KS. Altered mitochondrial function in insulin-deficient and insulin-resistant states. J Clin Invest. 2018;128(9):3671-3681. doi: https://doi.org/10.1172/JCI120843

26. Dickinson JM, Fry CS, Drummond MJ, Gundermann DM, Walker DK, Glynn EL, et al. Mammalian target of rapamycin complex 1 activation is required for the stimulation of human skeletal muscle protein synthesis by essential amino acids. J Nutr. 2011;141:856–62. doi: https://doi.org/10.3945/jn.111.139485

27. Dong XC, Copps KD, Guo S, et al. Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation. Cell Metab. 2008;8(1):65-76. doi: https://doi.org/10.1016/j.cmet.2008.06.006

28. Zhguleva AS, Zementova MS, Sel`kov SA, Sokolov DI. Makrofagi M1/M2: proisxozhdenie, fenotip, sposoby` polucheniya, vzaimodejstvie s estestvenny`mi killerami i trofoblastom. Medical Immunology. 2024;26(3):425-448. (In Russ.) doi: https://doi.org/10.15789/1563-0625-MMO-2877

29. Barazzoni R, Bischoff S, Boirie Y, et al. Sarcopenic Obesity: Time to Meet the Challenge. Obes Facts. 2018;11(4):294-305. doi: https://doi.org/10.1159/000490361

30. Xie WQ, Xiao GL, Fan YB, He M, Lv S, Li YS. Sarcopenic obesity: research advances in pathogenesis and diagnostic criteria. Aging Clin Exp Res. 2021;33(2):247-252. doi: https://doi.org/10.1007/s40520-019-01435-9

31. Zhang L, Wang X, Cueto R, et al. Biochemical basis and metabolic interplay of redox regulation. Redox Biol. 2019;26:101284. doi: https://doi.org/10.1016/j.redox.2019.101284

32. Liguori I, Russo G, Curcio F, et al. Oxidative stress, aging, and diseases. Clin Interv Aging. 2018;13:757-772. doi: https://doi.org/10.2147/CIA.S158513

33. Wang J, Leung KS, Chow SK, Cheung WH. Inflammation and age-associated skeletal muscle deterioration (sarcopaenia). J Orthop Translat. 2017;10:94-101. doi: https://doi.org/10.1016/j.jot.2017.05.006

34. Bannister CA, Holden SE, Jenkins-Jones S, et al. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes Metab. 2014;16(11):1165-1173. doi: https://doi.org/10.1111/dom.12354

35. Lyu Q, Wen Y, He B, et al. The ameliorating effects of metformin on disarrangement ongoing in gastrocnemius muscle of sarcopenic and obese sarcopenic mice. Biochim Biophys Acta Mol Basis Dis. 2022;1868(11):166508. doi: https://doi.org/10.1016/j.bbadis.2022.166508

36. Sokolova AV, Klimova AV, Dragunov DO, Arutyunov GP. Ocenka vliyaniya terapii metforminom na velichinu my`shechnoj massy` i my`shechnoj sily` u bol`ny`x s i bez saxarnogo diabeta. Metaanaliz 15 issledovanij // RKZh. — 2021;3. (In Russ.)

37. Algoritmy` specializirovannoj medicinskoj pomoshhi ИНФОРМАЦИЯ ОБ АВТОРАХ [AUTHORS INFO]: bol`ny`m saxarny`m diabetom / Pod redakciej II Dedova, MV Shestakovoj, AYu Majorova. 11-j vy`pusk. M.; 2023. (In Russ.). doi: https://doi.org/10.14341/DM13042

38. De Nicola L, Zoccali C. Chronic kidney disease prevalence in the general population: heterogeneity and concerns. Nephrol Dial Transplant. 2016;31(3):331-335. doi: https://doi.org/10.1093/ndt/gfv427

39. Lovczova LV, et al. Vzaimodejstvie lekarstvenny`x sredstv v klinicheskoj praktike. 2020. (In Russ.).

40. Stafford G, Villén N, Roso-Llorach A, Troncoso-Mariño A, Monteagudo M, Violán C. Combined Multimorbidity and Polypharmacy Patterns in the Elderly: A Cross-Sectional Study in Primary Health Care. Int J Environ Res Public Health. 2021;18(17):9216. doi: https://doi.org/10.3390/ijerph18179216

41. Mkrtumyan AM, Biryukova EV. Osobennosti sakharnogo diabeta v pozhilom vozraste i printsipy terapii. Diabetes mellitus. 2005;8(4):14-21. (In Russ.). doi: https://doi.org/10.14341/2072-0351-5960