Sarcopenia represents the progressive loss of muscle mass and function during aging. The most widely accepted definition of sarcopenia is proposed by the European Working Group of Sarcopenia in Older People, which combines muscle mass, strength and physical performance as required criteria for diagnosis. The Asia Working Group for Sarcopenia definition is similar, but provides modified criteria for Asian people 1 . The prevalence of sarcopenia ranges from 10 to 40% in people aged ≥65 years 2 .
Type 2 diabetes is a highly prevalent health problem in the elderly, affecting >25% of people aged >65 years. Older adults with diabetes are known to have a higher rate of functional decline and disability 3 . In older adults with diabetes, sarcopenia has recently been recognized as another comorbidity 4 .
Several studies showed that the muscle mass index and muscle strength were lower in older patients with diabetes than those without diabetes 5 . Older adults with diabetes have been reported to have lower handgrip strength 6 . Greater loss in thigh muscle was also observed in older women with diabetes compared with the non‐diabetes population 7 . A recent meta‐analysis showed that the prevalence of sarcopenia is higher in the diabetes group in respect to normoglycemic controls 8 . Lower body mass index (<24 kg/m2) and longer duration of diabetes were reported to increase the risk of sarcopenia in people with diabetes 9 , 10 .
In contrast, sarcopenia might also increase the risk of developing diabetes among older people. Individuals with low skeletal muscle mass have greater risk of developing diabetes compared with those with higher muscle mass. Coexistence of low muscle mass and obesity contributed to an even higher risk of diabetes 1 .
Pathogenesis
Diabetes has been reported to accelerate the reduction of muscle mass and strength by several mechanisms. Protein synthesis is stimulated by insulin, and impairment in the insulin‐associated signaling pathway might lead to reduced muscle anabolism and increased protein catabolism, which contribute to sarcopenia 11 .
Furthermore, hyperglycemia increases the production of advanced glycation end‐products. The accumulation of advanced glycation end‐products in the muscle causes deterioration of muscle function by increasing intramuscular protein cross‐linking, interfering the muscle contractility, upregulating inflammation, developing oxidative stress and impairing endothelium function, all of which might lead to sarcopenia 12 .
The major causes of sarcopenia include insufficient nutrition intake, inadequate physical activities, and declined hormonal and neuromuscular function 11 . Patients with peripheral neuropathy have more intermuscular adipose tissue, which is associated with poor muscle strength and function. Inflammatory markers, such as tumor necrosis factor and interleukin‐6, were negatively associated with muscle mass, strength and physical performance 13 .
Glucose‐lowering medications and sarcopenia
Various glucose‐lowering medications might have different effects on the muscle metabolism. Currently, the most widely used glucose‐lowering drugs included metformin, thiazolidinediones (TZDs), sulfonylureas, dipeptidyl peptidase‐4 inhibitors, glucagon‐like peptide‐1 receptor agonists, sodium–glucose cotransporter 2 inhibitors (SGLT2i) and insulin.
Metformin activates the adenosine monophosphate‐activated protein kinase (AMPK) pathway, which upregulates fatty acid oxidation and reduces intramuscular lipid accumulation. In contrast, however, AMPK also inhibits the mechanistic target of rapamycin, which plays a key role in muscle growth, so activation of the AMPK pathway might also lead to a possible decrease in muscle protein synthesis. Current clinical trials showed inconsistent conclusions about the effects of metformin on sarcopenia 14 .
TZDs activate peroxisome proliferator‐activated receptor‐γ, which facilitates the attenuation of insulin resistance. TZDs also activate the AMPK pathway and thus promote fat oxidation in skeletal muscles. However, data from clinical trials investigating the effects of TZDs on sarcopenia are still limited and the results are conflicting 15 .
Sulfonylurea induces atrophy in rat skeletal muscle mass. The caspase‐3‐dependent or independent pathways might participate in the activation of atrophy signaling in muscles. Muscle atrophy was observed in 0.27% of the diabetes patients receiving glibenclamide or glyburide, compared with 0.02% in individuals using medications other than sulfonylureas in an observational study 14 .
A cross‐sectional study showed that parameters associated with sarcopenia, such as skeletal muscle mass, muscle strength and gait speed, were better in people with type 2 diabetes taking dipeptidyl peptidase‐4 inhibitors compared with sulfonylureas 16 . Another study also reported that skeletal muscle mass increased significantly in overweight people with type 2 diabetes receiving dipeptidyl peptidase‐4 inhibitors compared sulfonylurea after 24 weeks of treatment 17 .
Recently, several clinical trials aimed to investigate the effects of SGLT2i on sarcopenia. Dapagliflozin was shown to significantly decrease skeletal muscle mass in people with type 2 diabetes and non‐alcoholic liver disease after 24 weeks of treatment compared with the standard treatment group 18 . Other studies showed that luseogliflozin caused a significant reduction in skeletal muscle mass and skeletal muscle mass index after 12–36 weeks of treatment 19 . A Japanese open label study of ipragliflozin and metformin showed a non‐significant decrease in abdominal muscle, and an increase in handgrip strength while combined with sitagliptin 20 . A study showed that tofogliflozin is associated with a significant decrease in skeletal muscle mass after 12 weeks of treatment in people with type 2 diabetes 21 . These studies consistently showed that SGLT2i could increase the risk of sarcopenia in diabetes patients.
Most studies with glucagon‐like peptide‐1 receptor agonists did not show significantly reductions in muscle mass or worsening sarcopenia parameters in diabetes patients. A study with liraglutide did not show decreased muscle mass or deteriorated parameters associated with sarcopenia in people with type 2 diabetes. Similarly, another study with exenatide did not show significant changes in skeletal muscle mass after 12 weeks of treatment 14 .
Insulin therapy was shown to prevent a decrease in the skeletal muscle index of lower extremities in people with type 2 diabetes in a retrospective observational study 22 . Similarly, another study showed that patients taking glucose‐lowering drugs have a greater decline in skeletal muscle index compared with insulin therapy. However, the time required to complete the Timed Up and Go test was significantly increased in the insulin group compared with patients taking oral glucose‐lowering drugs 23 . Table 1 summarizes the effect of glucose‐lowering medications on muscle mass in type 2 diabetes patients.
Table 1.
Effect of glucose‐lowering medications on muscle mass in type 2 diabetes patients
| Glucose‐lowering medications | Effect on muscle mass |
|---|---|
| Metformin | Inconclusive 14 |
| Thiazolidinedione | Inconclusive 15 |
| Sulfonylurea | Decreases 14 |
| Dipeptidyl peptidase‐4 inhibitors | Inconclusive/increases 16 , 17 |
| Sodium–glucose cotransporter 2 inhibitors | Decreases 18 , 19 , 20 , 21 |
| Glucagon‐like peptide‐1 receptor agonists | Inconclusive 14 |
| Insulin | Inconclusive/increases 22 , 23 |
Conclusions
Sarcopenia represents an age‐related loss of skeletal muscle mass and function, which has been shown to be one of the important comorbidities of diabetes. Type 2 diabetes contributes to the development of sarcopenia through various mechanisms, including impaired insulin‐associated signaling pathways, accumulation of advanced glycation end‐products, peripheral neuropathy and chronic inflammatory status. Sulfonylurea and SGLT2i should be cautiously prescribed for elderly diabetes patients. Further studies are required to elucidate the relationship between sarcopenia, type 2 diabetes and glucose‐lowering medications.
J Diabetes Investig. 2022; 13: 944–946
References
- 1. Mesinovic J, Zengin A, De Courten B, et al. Sarcopenia and type 2 diabetes mellitus: a bidirectional relationship. Diabetes Metab Syndr Obes 2019; 12: 1057–1072. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Mori H, Kuroda A, Yoshida S, et al. High prevalence and clinical impact of dynapenia and sarcopenia in Japanese patients with type 1 and type 2 diabetes: findings from the Impact of Diabetes Mellitus on Dynapenia study. J Diabetes Investig 2021; 12: 1050–1059. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. American Diabetes Association . Older adults: standards of medical care in Diabetes‐2021. Diabetes Care 2021; 44(Suppl 1): S168–S179. [DOI] [PubMed] [Google Scholar]
- 4. Wong E, Backholer K, Gearon E, et al. Diabetes and risk of physical disability in adults: a systematic review and meta‐analysis. Lancet Diabetes Endocrinol 2013; 1: 106–114. [DOI] [PubMed] [Google Scholar]
- 5. Kang S, Oh TJ, Cho BL, et al. Sex differences in sarcopenia and frailty among community‐dwelling Korean older adults with diabetes: the Korean Frailty and Aging Cohort Study. J Diabetes Investig 2021; 12: 155–164. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Kitagawa N, Okamura T, Kitagawa N. Handgrip measurement as a useful benchmark for locomotive syndrome in patients with type 2 diabetes mellitus: a KAMOGAWA‐DM cohort study. J Diabetes Investig 2020; 11: 1602–1611. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Park SW, Goodpaster BH, Lee JS, et al. Excessive loss of skeletal muscle mass in older adults with type 2 diabetes. Diabetes Care 2009; 32: 1993–1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Anagnostis P, Gkekas NK, Achilla C, et al. Type 2 diabetes mellitus is associated with increased risk of sarcopenia: a systematic review and meta‐analysis. Calcif Tissue Int 2020; 107: 453–463. [DOI] [PubMed] [Google Scholar]
- 9. Nakamura K, Yoshida D, Honda T, et al. Midlife and late‐life diabetes and sarcopenia in a general older Japanese population: the Hisayama Study. J Diabetes Investig 2021; 12: 1899–1907. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Nakanishi S, Iwamoto M, Shinohara H, et al. Significance of body mass index for diagnosing sarcopenia is equivalent to slow gait speed in Japanese individuals with type 2 diabetes: cross‐sectional study using outpatient clinical data. J Diabetes Investig 2021; 12: 417–424. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Alemán‐Mateo H, López Teros MT, Ramírez FA, et al. Association between insulin resistance and low relative appendicular skeletal muscle mass: evidence from a cohort study in community‐dwelling older men and women participants. J Gerontol A Biol Sci Med Sci 2014; 69: 871–877. [DOI] [PubMed] [Google Scholar]
- 12. Nowotny K, Jung T, Höhn A, et al. Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules 2015; 5: 194–222. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Sinclair AJ, Abdelhafiz AH, Rodríguez‐Mañas L. Frailty and sarcopenia ‐ newly emerging and high impact complications of diabetes. J Diabetes Complications 2017; 31: 1465–1473. [DOI] [PubMed] [Google Scholar]
- 14. Massimino E, Izzo A, Riccardi G, et al. The impact of glucose‐lowering drugs on sarcopenia in type 2 diabetes current evidence and underlying mechanisms. Cells 2021; 10: 1958. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Yokota T, Kinugawa S, Hirabayashi K, et al. Pioglitazone improves whole‐body aerobic capacity and skeletal muscle energy metabolism in patients with metabolic syndrome. J Diabetes Investig 2017; 8: 535–541. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Rizzo MR, Barbieri M, Fava I, et al. Sarcopenia in elderly diabetic patients: role of dipeptidyl peptidase 4 inhibitors. J Am Med Dir Assoc 2016; 17: 896–901. [DOI] [PubMed] [Google Scholar]
- 17. Ishii S, Nagai Y, Kato H, et al. Effect of the dipeptidyl peptidase‐4 inhibitor sitagliptin on muscle mass and the muscle/fat ratio in patients with type 2 diabetes. J Clin Med Res 2020; 12: 122–126. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Yasuda M, Iizuka K, Kato T, et al. Sodium‐glucose cotransporter 2 inhibitor and sarcopenia in a lean elderly adult with type 2 diabetes: a case report. J Diabetes Investig 2020; 11: 745–747. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Sasaki T, Sugawara M, Fukuda M. Sodium‐glucose cotransporter 2 inhibitor‐induced changes in body composition and simultaneous changes in metabolic profile: 52‐week prospective LIGHT (Luseogliflozin: the Components of Weight Loss in Japanese Patients with Type 2 Diabetes Mellitus) Study. J Diabetes Investig 2019; 10: 108–117. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Koshizaka M, Ishikawa K, Ishibashi R, et al. Effects of ipragliflozin versus metformin in combination with sitagliptin on bone and muscle in Japanese patients with type 2 diabetes mellitus: subanalysis of a prospective, randomized, controlled study (PRIME‐V study). J Diabetes Investig 2021; 12: 200–206. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Matsuba R, Matsuba I, Shimokawa M, et al. Tofogliflozin decreases body fat mass and improves peripheral insulin resistance. Diabetes Obes Metab 2018; 20: 1311–1315. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Bouchi R, Fukuda T, Takeuchi T, et al. Insulin treatment attenuates decline of muscle mass in Japanese patients with type 2 diabetes. Calcif Tissue Int 2017; 101: 1–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Ferrari U, Then C, Rottenkolber M, et al. Longitudinal association of type 2 diabetes and insulin therapy with muscle parameters in the KORA‐Age study. Acta Diabetol 2020; 57: 1057–1063. [DOI] [PubMed] [Google Scholar]