Diabetes Metab J.  2023 Nov;47(6):719-742. 10.4093/dmj.2023.0112.

Type 2 Diabetes Mellitus and Sarcopenia as Comorbid Chronic Diseases in Older Adults: Established and Emerging Treatments and Therapies

• Mesinovic J
• Fyfe JJ
• Talevski J
• Wheeler MJ
• Leung GK
• George ES
• Hunegnaw MT
• Glavas C
• Jansons P
• Daly RM
• Scott D

• KMID: 2548149
• DOI: http://doi.org/10.4093/dmj.2023.0112

Abstract

Type 2 diabetes mellitus (T2DM) and sarcopenia (low skeletal muscle mass and function) share a bidirectional relationship. The prevalence of these diseases increases with age and they share common risk factors. Skeletal muscle fat infiltration, commonly referred to as myosteatosis, may be a major contributor to both T2DM and sarcopenia in older adults via independent effects on insulin resistance and muscle health. Many strategies to manage T2DM result in energy restriction and subsequent weight loss, and this can lead to significant declines in muscle mass in the absence of resistance exercise, which is also a first-line treatment for sarcopenia. In this review, we highlight recent evidence on established treatments and emerging therapies targeting weight loss and muscle mass and function improvements in older adults with, or at risk of, T2DM and/or sarcopenia. This includes dietary, physical activity and exercise interventions, new generation incretin-based agonists and myostatin-based antagonists, and endoscopic bariatric therapies. We also highlight how digital health technologies and health literacy interventions can increase uptake of, and adherence to, established and emerging treatments and therapies in older adults with T2DM and/or sarcopenia.

Keyword

Aging; Diabetes mellitus, type 2; Exercise; Sarcopenia; Weight loss

Figure

• 

  Fig. 1. Major causes and outcomes of myosteatosis in older adults with type 2 diabetes mellitus and sarcopenia.

• 

  Fig. 2. Proposed relationships between emerging and established treatments for type 2 diabetes mellitus and sarcopenia.

• 

Reference

1. Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, et al. IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022; 183:109119.

2. Daousi C, Casson IF, Gill GV, MacFarlane IA, Wilding JP, Pinkney JH. Prevalence of obesity in type 2 diabetes in secondary care: association with cardiovascular risk factors. Postgrad Med J. 2006; 82:280–4.

3. Emerging Risk Factors Collaboration, Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010; 375:2215–22.

4. Mesinovic J, Scott D, Seibel MJ, Cumming RG, Naganathan V, Blyth FM, et al. Risk factors for incident falls and fractures in older men with and without type 2 diabetes mellitus: the concord health and ageing in men project. J Gerontol A Biol Sci Med Sci. 2021; 76:1090–100.

5. Liu ZJ, Zhu CF. Causal relationship between insulin resistance and sarcopenia. Diabetol Metab Syndr. 2023; 15:46.

6. Mesinovic J, Zengin A, De Courten B, Ebeling PR, Scott D. Sarcopenia and type 2 diabetes mellitus: a bidirectional relationship. Diabetes Metab Syndr Obes. 2019; 12:1057–72.

7. Scott D, de Courten B, Ebeling PR. Sarcopenia: a potential cause and consequence of type 2 diabetes in Australia’s ageing population? Med J Aust. 2016; 205:329–33.

8. Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyere O, Cederholm T, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019; 48:16–31.

9. Chen LK, Woo J, Assantachai P, Auyeung TW, Chou MY, Iijima K, et al. Asian Working Group for Sarcopenia: 2019 consensus update on sarcopenia diagnosis and treatment. J Am Med Dir Assoc. 2020; 21:300–7.

10. Bhasin S, Travison TG, Manini TM, Patel S, Pencina KM, Fielding RA, et al. Sarcopenia definition: the position statements of the Sarcopenia Definition and Outcomes Consortium. J Am Geriatr Soc. 2020; 68:1410–8.

11. Petermann-Rocha F, Balntzi V, Gray SR, Lara J, Ho FK, Pell JP, et al. Global prevalence of sarcopenia and severe sarcopenia: a systematic review and meta-analysis. J Cachexia Sarcopenia Muscle. 2022; 13:86–99.

12. Cawthon PM, Manini T, Patel SM, Newman A, Travison T, Kiel DP, et al. Putative cut-points in sarcopenia components and incident adverse health outcomes: an SDOC analysis. J Am Geriatr Soc. 2020; 68:1429–37.

13. Gandham A, Mesinovic J, Jansons P, Zengin A, Bonham MP, Ebeling PR, et al. Falls, fractures, and areal bone mineral density in older adults with sarcopenic obesity: a systematic review and meta-analysis. Obes Rev. 2021; 22:e13187.

14. Yeung SS, Reijnierse EM, Pham VK, Trappenburg MC, Lim WK, Meskers CG, et al. Sarcopenia and its association with falls and fractures in older adults: a systematic review and meta-analysis. J Cachexia Sarcopenia Muscle. 2019; 10:485–500.

15. Zanker J, Scott D, Reijnierse EM, Brennan-Olsen SL, Daly RM, Girgis CM, et al. Establishing an operational definition of sarcopenia in Australia and New Zealand: Delphi method based consensus statement. J Nutr Health Aging. 2019; 23:105–10.

16. Keevil VL, Luben R, Dalzell N, Hayat S, Sayer AA, Wareham NJ, et al. Cross-sectional associations between different measures of obesity and muscle strength in men and women in a British cohort study. J Nutr Health Aging. 2015; 19:3–11.

17. Stenholm S, Sallinen J, Koster A, Rantanen T, Sainio P, Heliovaara M, et al. Association between obesity history and hand grip strength in older adults: exploring the roles of inflammation and insulin resistance as mediating factors. J Gerontol A Biol Sci Med Sci. 2011; 66:341–8.

18. Janssen I, Heymsfield SB, Wang ZM, Ross R. Skeletal muscle mass and distribution in 468 men and women aged 18-88 yr. J Appl Physiol (1985). 2000; 89:81–8.

19. Dai S, Shu D, Meng F, Chen Y, Wang J, Liu X, et al. Higher risk of sarcopenia in older adults with type 2 diabetes: NHANES 1999-2018. Obes Facts. 2023; 16:237–48.

20. Veronese N, Pizzol D, Demurtas J, Soysal P, Smith L, Sieber C, et al. Association between sarcopenia and diabetes: a systematic review and meta-analysis of observational studies. Eur Geriatr Med. 2019; 10:685–96.

21. Anagnostis P, Gkekas NK, Achilla C, Pananastasiou G, Taouxidou P, Mitsiou M, et al. Type 2 diabetes mellitus is associated with increased risk of sarcopenia: a systematic review and meta-analysis. Calcif Tissue Int. 2020; 107:453–63.

22. Cuthbertson DJ, Bell JA, Ng SY, Kemp GJ, Kivimaki M, Hamer M. Dynapenic obesity and the risk of incident type 2 diabetes: the English Longitudinal Study of Ageing. Diabet Med. 2016; 33:1052–9.

23. Feng L, Gao Q, Hu K, Wu M, Wang Z, Chen F, et al. Prevalence and risk factors of sarcopenia in patients with diabetes: a meta-analysis. J Clin Endocrinol Metab. 2022; 107:1470–83.

24. Nakamura K, Yoshida D, Honda T, Hata J, Shibata M, Hirakawa Y, et al. Midlife and late-life diabetes and sarcopenia in a general older Japanese population: the Hisayama Study. J Diabetes Investig. 2021; 12:1899–907.

25. Bellou V, Belbasis L, Tzoulaki I, Evangelou E. Risk factors for type 2 diabetes mellitus: an exposure-wide umbrella review of meta-analyses. PLoS One. 2018; 13:e0194127.

26. Narici MV, Maffulli N. Sarcopenia: characteristics, mechanisms and functional significance. Br Med Bull. 2010; 95:139–59.

27. Correa-de-Araujo R, Addison O, Miljkovic I, Goodpaster BH, Bergman BC, Clark RV, et al. Myosteatosis in the context of skeletal muscle function deficit: an Interdisciplinary Workshop at the National Institute on Aging. Front Physiol. 2020; 11:963.

28. Addison O, Marcus RL, Lastayo PC, Ryan AS. Intermuscular fat: a review of the consequences and causes. Int J Endocrinol. 2014; 2014:309570.

29. Sachs S, Zarini S, Kahn DE, Harrison KA, Perreault L, Phang T, et al. Intermuscular adipose tissue directly modulates skeletal muscle insulin sensitivity in humans. Am J Physiol Endocrinol Metab. 2019; 316:E866–79.

30. Boettcher M, Machann J, Stefan N, Thamer C, Haring HU, Claussen CD, et al. Intermuscular adipose tissue (IMAT): association with other adipose tissue compartments and insulin sensitivity. J Magn Reson Imaging. 2009; 29:1340–5.

31. Goodpaster BH, Krishnaswami S, Resnick H, Kelley DE, Haggerty C, Harris TB, et al. Association between regional adipose tissue distribution and both type 2 diabetes and impaired glucose tolerance in elderly men and women. Diabetes Care. 2003; 26:372–9.

32. Goodpaster BH, Thaete FL, Kelley DE. Thigh adipose tissue distribution is associated with insulin resistance in obesity and in type 2 diabetes mellitus. Am J Clin Nutr. 2000; 71:885–92.

33. Bergman BC, Brozinick JT, Strauss A, Bacon S, Kerege A, Bui HH, et al. Muscle sphingolipids during rest and exercise: a C18:0 signature for insulin resistance in humans. Diabetologia. 2016; 59:785–98.

34. Bergman BC, Hunerdosse DM, Kerege A, Playdon MC, Perreault L. Localisation and composition of skeletal muscle diacylglycerol predicts insulin resistance in humans. Diabetologia. 2012; 55:1140–50.

35. Goodpaster BH. CrossTalk proposal: intramuscular lipid accumulation causes insulin resistance. J Physiol. 2020; 598:3803–6.

36. DeFronzo RA, Tripathy D. Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care. 2009; 32(Suppl 2):S157–63.

37. Amati F, Dube JJ, Alvarez-Carnero E, Edreira MM, Chomentowski P, Coen PM, et al. Skeletal muscle triglycerides, diacylglycerols, and ceramides in insulin resistance: another paradox in endurance-trained athletes? Diabetes. 2011; 60:2588–97.

38. Goodpaster BH, He J, Watkins S, Kelley DE. Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab. 2001; 86:5755–61.

39. Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiol Rev. 2018; 98:2133–223.

40. Bosma M, Kersten S, Hesselink MK, Schrauwen P. Re-evaluating lipotoxic triggers in skeletal muscle: relating intramyocellular lipid metabolism to insulin sensitivity. Prog Lipid Res. 2012; 51:36–49.

41. Li X, Li Z, Zhao M, Nie Y, Liu P, Zhu Y, et al. Skeletal muscle lipid droplets and the athlete’s paradox. Cells. 2019; 8:249.

42. Marcus RL, Addison O, Dibble LE, Foreman KB, Morrell G, Lastayo P. Intramuscular adipose tissue, sarcopenia, and mobility function in older individuals. J Aging Res. 2012; 2012:629637.

43. Scott D, Trbojevic T, Skinner E, Clark RA, Levinger P, Haines TP, et al. Associations of calf inter- and intra-muscular adipose tissue with cardiometabolic health and physical function in community-dwelling older adults. J Musculoskelet Neuronal Interact. 2015; 15:350–7.

44. Santanasto AJ, Zmuda JM, Cvejkus RK, Gordon CL, Nair S, Carr JJ, et al. Thigh and calf myosteatosis are strongly associated with muscle and physical function in african caribbean men. J Gerontol A Biol Sci Med Sci. 2023; 78:527–34.

45. Scott D, Shore-Lorenti C, McMillan LB, Mesinovic J, Clark RA, Hayes A, et al. Calf muscle density is independently associated with physical function in overweight and obese older adults. J Musculoskelet Neuronal Interact. 2018; 18:9–17.

46. Scott D, Johansson J, McMillan LB, Ebeling PR, Nordstrom A, Nordstrom P. Mid-calf skeletal muscle density and its associations with physical activity, bone health and incident 12-month falls in older adults: the Healthy Ageing Initiative. Bone. 2019; 120:446–51.

47. Frank-Wilson AW, Farthing JP, Chilibeck PD, Arnold CM, Davison KS, Olszynski WP, et al. Lower leg muscle density is independently associated with fall status in community-dwelling older adults. Osteoporos Int. 2016; 27:2231–40.

48. Biltz NK, Collins KH, Shen KC, Schwartz K, Harris CA, Meyer GA. Infiltration of intramuscular adipose tissue impairs skeletal muscle contraction. J Physiol. 2020; 598:2669–83.

49. The Royal Australian College of General Practitioners. Management of type 2 diabetes: a handbook for general practice. East Melbourne: RACGP;2020.

50. Villani A. Lifestyle strategies for the management of obesity in older adults: from controversies to alternative interventions. Healthcare (Basel). 2022; 10:2107.

51. Winter JE, MacInnis RJ, Wattanapenpaiboon N, Nowson CA. BMI and all-cause mortality in older adults: a meta-analysis. Am J Clin Nutr. 2014; 99:875–90.

52. Batsis JA, Gill LE, Masutani RK, Adachi-Mejia AM, Blunt HB, Bagley PJ, et al. Weight loss interventions in older adults with obesity: a systematic review of randomized controlled trials since 2005. J Am Geriatr Soc. 2017; 65:257–68.

53. Sardeli AV, Komatsu TR, Mori MA, Gaspari AF, Chacon-Mikahil MP. Resistance training prevents muscle loss induced by caloric restriction in obese elderly individuals: a systematic review and meta-analysis. Nutrients. 2018; 10:423.

54. Mesinovic J, Jansons P, Zengin A, de Courten B, Rodriguez AJ, Daly RM, et al. Exercise attenuates bone mineral density loss during diet-induced weight loss in adults with overweight and obesity: a systematic review and meta-analysis. J Sport Health Sci. 2021; 10:550–9.

55. Goisser S, Kiesswetter E, Schoene D, Torbahn G, Bauer JM. Dietary weight-loss interventions for the management of obesity in older adults. Rev Endocr Metab Disord. 2020; 21:355–68.

56. Volkert D, Beck AM, Cederholm T, Cruz-Jentoft A, Goisser S, Hooper L, et al. ESPEN guideline on clinical nutrition and hydration in geriatrics. Clin Nutr. 2019; 38:10–47.

57. Lean ME, Leslie WS, Barnes AC, Brosnahan N, Thom G, McCombie L, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, clusterrandomised trial. Lancet. 2018; 391:541–51.

58. Esposito K, Kastorini CM, Panagiotakos DB, Giugliano D. Mediterranean diet and weight loss: meta-analysis of randomized controlled trials. Metab Syndr Relat Disord. 2011; 9:1–12.

59. Esposito K, Maiorino MI, Bellastella G, Chiodini P, Panagiotakos D, Giugliano D. A journey into a Mediterranean diet and type 2 diabetes: a systematic review with meta-analyses. BMJ Open. 2015; 5:e008222.

60. Ajala O, English P, Pinkney J. Systematic review and meta-analysis of different dietary approaches to the management of type 2 diabetes. Am J Clin Nutr. 2013; 97:505–16.

61. Isanejad M, Sirola J, Mursu J, Rikkonen T, Kroger H, Tuppurainen M, et al. Association of the Baltic Sea and Mediterranean diets with indices of sarcopenia in elderly women, OSPTRE-FPS study. Eur J Nutr. 2018; 57:1435–48.

62. Silva R, Pizato N, da Mata F, Figueiredo A, Ito M, Pereira MG. Mediterranean diet and musculoskeletal-functional outcomes in community-dwelling older people: a systematic review and meta-analysis. J Nutr Health Aging. 2018; 22:655–63.

63. Davis R, Rogers M, Coates AM, Leung GK, Bonham MP. The impact of meal timing on risk of weight gain and development of obesity: a review of the current evidence and opportunities for dietary intervention. Curr Diab Rep. 2022; 22:147–55.

64. O’Connor SG, Boyd P, Bailey CP, Nebeling L, Reedy J, Czajkowski SM, et al. A qualitative exploration of facilitators and barriers of adherence to time-restricted eating. Appetite. 2022; 178:106266.

65. Bjerre N, Holm L, Quist JS, Færch K, Hempler NF. Watching, keeping and squeezing time to lose weight: implications of time-restricted eating in daily life. Appetite. 2021; 161:105138.

66. Lee SA, Sypniewski C, Bensadon BA, McLaren C, Donahoo WT, Sibille KT, et al. Determinants of adherence in time-restricted feeding in older adults: lessons from a pilot study. Nutrients. 2020; 12:874.

67. Anton SD, Lee SA, Donahoo WT, McLaren C, Manini T, Leeuwenburgh C, et al. The effects of time restricted feeding on overweight, older adults: a pilot study. Nutrients. 2019; 11:1500.

68. Chaudhury A, Duvoor C, Reddy Dendi VS, Kraleti S, Chada A, Ravilla R, et al. Clinical review of antidiabetic drugs: implications for type 2 diabetes mellitus management. Front Endocrinol (Lausanne). 2017; 8:6.

69. Corley BT, Carroll RW, Hall RM, Weatherall M, Parry-Strong A, Krebs JD. Intermittent fasting in type 2 diabetes mellitus and the risk of hypoglycaemia: a randomized controlled trial. Diabet Med. 2018; 35:588–94.

70. Uldal S, Clemmensen KK, Persson F, Faerch K, Quist JS. Is time-restricted eating safe in the treatment of type 2 diabetes?: a review of intervention studies. Nutrients. 2022; 14:2299.

71. Arnason TG, Bowen MW, Mansell KD. Effects of intermittent fasting on health markers in those with type 2 diabetes: a pilot study. World J Diabetes. 2017; 8:154–64.

72. Che T, Yan C, Tian D, Zhang X, Liu X, Wu Z. Time-restricted feeding improves blood glucose and insulin sensitivity in overweight patients with type 2 diabetes: a randomised controlled trial. Nutr Metab (Lond). 2021; 18:88.

73. Kahleova H, Belinova L, Malinska H, Oliyarnyk O, Trnovska J, Skop V, et al. Eating two larger meals a day (breakfast and lunch) is more effective than six smaller meals in a reduced-energy regimen for patients with type 2 diabetes: a randomised crossover study. Diabetologia. 2014; 57:1552–60.

74. Huang JH, Cheng FC, Tsai LC, Lee NY, Lu YF. Appropriate physical activity and dietary intake achieve optimal metabolic control in older type 2 diabetes patients. J Diabetes Investig. 2014; 5:418–27.

75. Borsheim E, Bui QU, Tissier S, Kobayashi H, Ferrando AA, Wolfe RR. Effect of amino acid supplementation on muscle mass, strength and physical function in elderly. Clin Nutr. 2008; 27:189–95.

76. Tieland M, van de Rest O, Dirks ML, van der Zwaluw N, Mensink M, van Loon LJ, et al. Protein supplementation improves physical performance in frail elderly people: a randomized, double-blind, placebo-controlled trial. J Am Med Dir Assoc. 2012; 13:720–6.

77. van Loon LJ, Kruijshoop M, Menheere PP, Wagenmakers AJ, Saris WH, Keizer HA. Amino acid ingestion strongly enhances insulin secretion in patients with long-term type 2 diabetes. Diabetes Care. 2003; 26:625–30.

78. Yu Z, Nan F, Wang LY, Jiang H, Chen W, Jiang Y. Effects of high-protein diet on glycemic control, insulin resistance and blood pressure in type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Clin Nutr. 2020; 39:1724–34.

79. Chiang SW, Liu HW, Loh EW, Tam KW, Wang JY, Huang WL, et al. Whey protein supplementation improves postprandial glycemia in persons with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. Nutr Res. 2022; 104:44–54.

80. Gannon MC, Nuttall FQ, Saeed A, Jordan K, Hoover H. An increase in dietary protein improves the blood glucose response in persons with type 2 diabetes. Am J Clin Nutr. 2003; 78:734–41.

81. Phillips SM, Chevalier S, Leidy HJ. Protein “requirements” beyond the RDA: implications for optimizing health. Appl Physiol Nutr Metab. 2016; 41:565–72.

82. Yoshimura Y, Wakabayashi H, Yamada M, Kim H, Harada A, Arai H. Interventions for treating sarcopenia: a systematic review and meta-analysis of randomized controlled studies. J Am Med Dir Assoc. 2017; 18:553.

83. Wu PY, Huang KS, Chen KM, Chou CP, Tu YK. Exercise, nutrition, and combined exercise and nutrition in older adults with sarcopenia: a systematic review and network meta-analysis. Maturitas. 2021; 145:38–48.

84. Naseeb MA, Volpe SL. Protein and exercise in the prevention of sarcopenia and aging. Nutr Res. 2017; 40:1–20.

85. Phillips SM. Nutritional supplements in support of resistance exercise to counter age-related sarcopenia. Adv Nutr. 2015; 6:452–60.

86. Dang M, Shore-Lorenti C, McMillan LB, Mesinovic J, Hayes A, Ebeling PR, et al. Associations of serum 25-hydroxyvitamin D with physical performance and bone health in overweight and obese older adults. Int J Environ Res Public Health. 2019; 16:509.

87. Scott D, Blizzard L, Fell J, Ding C, Winzenberg T, Jones G. A prospective study of the associations between 25-hydroxy-vitamin D, sarcopenia progression and physical activity in older adults. Clin Endocrinol (Oxf). 2010; 73:581–7.

88. Zhu A, Kuznia S, Niedermaier T, Holleczek B, Schottker B, Brenner H. Consistent inverse associations of total, “bioavailable”, free, and “non-bioavailable” vitamin D with incidence of diabetes among older adults with lower baseline HbA1c (≤6%) levels. Nutrients. 2022; 14:3282.

89. Drincic AT, Armas LA, Van Diest EE, Heaney RP. Volumetric dilution, rather than sequestration best explains the low vitamin D status of obesity. Obesity (Silver Spring). 2012; 20:1444–8.

90. Hu Z, Chen J, Sun X, Wang L, Wang A. Efficacy of vitamin D supplementation on glycemic control in type 2 diabetes patients: a meta-analysis of interventional studies. Medicine (Baltimore). 2019; 98:e14970.

91. Tang H, Li D, Li Y, Zhang X, Song Y, Li X. Effects of vitamin D supplementation on glucose and insulin homeostasis and incident diabetes among nondiabetic adults: a meta-analysis of randomized controlled trials. Int J Endocrinol. 2018; 2018:7908764.

92. Mirhosseini N, Vatanparast H, Mazidi M, Kimball SM. Vitamin D supplementation, glycemic control, and insulin resistance in prediabetics: a meta-analysis. J Endocr Soc. 2018; 2:687–709.

93. Zhang Y, Tan H, Tang J, Li J, Chong W, Hai Y, et al. Effects of vitamin D supplementation on prevention of type 2 diabetes in patients with prediabetes: a systematic review and meta-analysis. Diabetes Care. 2020; 43:1650–8.

94. Jamka M, Wozniewicz M, Jeszka J, Mardas M, Bogdanski P, Stelmach-Mardas M. The effect of vitamin D supplementation on insulin and glucose metabolism in overweight and obese individuals: systematic review with meta-analysis. Sci Rep. 2015; 5:16142.

95. Beaudart C, Buckinx F, Rabenda V, Gillain S, Cavalier E, Slomian J, et al. The effects of vitamin D on skeletal muscle strength, muscle mass, and muscle power: a systematic review and meta-analysis of randomized controlled trials. J Clin Endocrinol Metab. 2014; 99:4336–45.

96. Stockton KA, Mengersen K, Paratz JD, Kandiah D, Bennell KL. Effect of vitamin D supplementation on muscle strength: a systematic review and meta-analysis. Osteoporos Int. 2011; 22:859–71.

97. Bislev LS, Grove-Laugesen D, Rejnmark L. Vitamin D and muscle health: a systematic review and meta-analysis of randomized placebo-controlled trials. J Bone Miner Res. 2021; 36:1651–60.

98. Prokopidis K, Giannos P, Katsikas Triantafyllidis K, Kechagias KS, Mesinovic J, Witard OC, et al. Effect of vitamin D monotherapy on indices of sarcopenia in community-dwelling older adults: a systematic review and meta-analysis. J Cachexia Sarcopenia Muscle. 2022; 13:1642–52.

99. Bischoff-Ferrari HA, Dawson-Hughes B, Orav EJ, Staehelin HB, Meyer OW, Theiler R, et al. Monthly high-dose vitamin D treatment for the prevention of functional decline: a randomized clinical trial. JAMA Intern Med. 2016; 176:175–83.

100. Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010; 303:1815–22.

101. Antoniak AE, Greig CA. The effect of combined resistance exercise training and vitamin D3 supplementation on musculoskeletal health and function in older adults: a systematic review and meta-analysis. BMJ Open. 2017; 7:e014619.

102. Mesinovic J, Rodriguez AJ, Cervo MM, Gandham A, Xu CL, Glavas C, et al. Vitamin D supplementation and exercise for improving physical function, body composition and metabolic health in overweight or obese older adults with vitamin D deficiency: a pilot randomized, double-blind, placebo-controlled trial. Eur J Nutr. 2023; 62:951–64.

103. Mølmen KS, Hammarstrom D, Pedersen K, Lian Lie AC, Steile RB, Nygaard H, et al. Vitamin D3 supplementation does not enhance the effects of resistance training in older adults. J Cachexia Sarcopenia Muscle. 2021; 12:599–628.

104. Savolainen L, Timpmann S, Mooses M, Maestu E, Medijainen L, Tonutare L, et al. Vitamin D supplementation does not enhance resistance training-induced gains in muscle strength and lean body mass in vitamin D deficient young men. Eur J Appl Physiol. 2021; 121:2077–90.

105. Sinclair AJ, Abdelhafiz AH, Rodriguez-Manas L. Frailty and sarcopenia: newly emerging and high impact complications of diabetes. J Diabetes Complications. 2017; 31:1465–73.

106. Chow LS, Nair KS. Sarcopenia of male aging. Endocrinol Metab Clin North Am. 2005; 34:833–52.

107. Johns N, Stephens NA, Fearon KC. Muscle wasting in cancer. Int J Biochem Cell Biol. 2013; 45:2215–29.

108. Cohen S, Nathan JA, Goldberg AL. Muscle wasting in disease: molecular mechanisms and promising therapies. Nat Rev Drug Discov. 2015; 14:58–74.

109. O’Mahoney LL, Matu J, Price OJ, Birch KM, Ajjan RA, Farrar D, et al. Omega-3 polyunsaturated fatty acids favourably modulate cardiometabolic biomarkers in type 2 diabetes: a meta-analysis and meta-regression of randomized controlled trials. Cardiovasc Diabetol. 2018; 17:98.

110. Akinkuolie AO, Ngwa JS, Meigs JB, Djousse L. Omega-3 polyunsaturated fatty acid and insulin sensitivity: a meta-analysis of randomized controlled trials. Clin Nutr. 2011; 30:702–7.

111. Chen C, Yu X, Shao S. Effects of omega-3 fatty acid supplementation on glucose control and lipid levels in type 2 diabetes: a meta-analysis. PLoS One. 2015; 10:e0139565.

112. Bird JK, Troesch B, Warnke I, Calder PC. The effect of long chain omega-3 polyunsaturated fatty acids on muscle mass and function in sarcopenia: a scoping systematic review and meta-analysis. Clin Nutr ESPEN. 2021; 46:73–86.

113. Norman K, Hab U, Pirlich M. Malnutrition in older adults-recent advances and remaining challenges. Nutrients. 2021; 13:2764.

114. Bauer JM, Verlaan S, Bautmans I, Brandt K, Donini LM, Maggio M, et al. Effects of a vitamin D and leucine-enriched whey protein nutritional supplement on measures of sarcopenia in older adults, the PROVIDE study: a randomized, double-blind, placebo-controlled trial. J Am Med Dir Assoc. 2015; 16:740–7.

115. Lin CC, Shih MH, Chen CD, Yeh SL. Effects of adequate dietary protein with whey protein, leucine, and vitamin D supplementation on sarcopenia in older adults: an open-label, parallel-group study. Clin Nutr. 2021; 40:1323–9.

116. Caspersen CJ, Powell KE, Christenson GM. Physical activity, exercise, and physical fitness: definitions and distinctions for health-related research. Public Health Rep. 1985; 100:126–31.

117. Bull FC, Al-Ansari SS, Biddle S, Borodulin K, Buman MP, Cardon G, et al. World Health Organization 2020 guidelines on physical activity and sedentary behaviour. Br J Sports Med. 2020; 54:1451–62.

118. Ross R, Chaput JP, Giangregorio LM, Janssen I, Saunders TJ, Kho ME, et al. Canadian 24-hour movement guidelines for adults aged 18-64 years and adults aged 65 years or older: an integration of physical activity, sedentary behaviour, and sleep. Appl Physiol Nutr Metab. 2020; 45(10 Suppl 2):S57–102.

119. Berkemeyer K, Wijndaele K, White T, Cooper AJ, Luben R, Westgate K, et al. The descriptive epidemiology of accelerometer-measured physical activity in older adults. Int J Behav Nutr Phys Act. 2016; 13:2.

120. Harvey JA, Chastin SF, Skelton DA. How sedentary are older people?: a systematic review of the amount of sedentary behavior. J Aging Phys Act. 2015; 23:471–87.

121. Ballin M, Nordstrom P, Niklasson J, Alamaki A, Condell J, Tedesco S, et al. Daily step count and incident diabetes in community-dwelling 70-year-olds: a prospective cohort study. BMC Public Health. 2020; 20:1830.

122. Yerramalla MS, McGregor DE, van Hees VT, Fayosse A, Dugravot A, Tabak AG, et al. Association of daily composition of physical activity and sedentary behaviour with incidence of cardiovascular disease in older adults. Int J Behav Nutr Phys Act. 2021; 18:83.

123. Ramsey KA, Rojer AG, D’Andrea L, Otten RH, Heymans MW, Trappenburg MC, et al. The association of objectively measured physical activity and sedentary behavior with skeletal muscle strength and muscle power in older adults: a systematic review and meta-analysis. Ageing Res Rev. 2021; 67:101266.

124. Ekelund U, Tarp J, Steene-Johannessen J, Hansen BH, Jefferis B, Fagerland MW, et al. Dose-response associations between accelerometry measured physical activity and sedentary time and all cause mortality: systematic review and harmonised meta-analysis. BMJ. 2019; 366:l4570.

125. Davies MJ, Aroda VR, Collins BS, Gabbay RA, Green J, Maruthur NM, et al. Management of hyperglycemia in type 2 diabetes, 2022: a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2022; 45:2753–86.

126. Kanaley JA, Colberg SR, Corcoran MH, Malin SK, Rodriguez NR, Crespo CJ, et al. Exercise/physical activity in individuals with type 2 diabetes: a consensus statement from the American College of Sports Medicine. Med Sci Sports Exerc. 2022; 54:353–68.

127. Mosalman Haghighi M, Mavros Y, Fiatarone Singh MA. The effects of structured exercise or lifestyle behavior interventions on long-term physical activity level and health outcomes in individuals with type 2 diabetes: a systematic review, meta-analysis, and meta-regression. J Phys Act Health. 2018; 15:697–707.

128. Tan KH, Siah CJ. Effects of low-to-moderate physical activities on older adults with chronic diseases: a systematic review and meta-analysis. J Clin Nurs. 2022; 31:2072–86.

129. Look AHEAD Research Group, Wadden TA, West DS, Delahanty L, Jakicic J, Rejeski J, et al. The Look AHEAD study: a description of the lifestyle intervention and the evidence supporting it. Obesity (Silver Spring). 2006; 14:737–52.

130. Rejeski WJ, Bray GA, Chen SH, Clark JM, Evans M, Hill JO, et al. Aging and physical function in type 2 diabetes: 8 years of an intensive lifestyle intervention. J Gerontol A Biol Sci Med Sci. 2015; 70:345–53.

131. Houston DK, Leng X, Bray GA, Hergenroeder AL, Hill JO, Jakicic JM, et al. A long-term intensive lifestyle intervention and physical function: the look AHEAD Movement and Memory Study. Obesity (Silver Spring). 2015; 23:77–84.

132. Houston DK, Neiberg RH, Miller ME, Hill JO, Jakicic JM, Johnson KC, et al. Physical function following a long-term lifestyle intervention among middle aged and older adults with type 2 diabetes: the look AHEAD study. J Gerontol A Biol Sci Med Sci. 2018; 73:1552–9.

133. Gray P, Murphy M, Gallagher A, Simpson EE. A qualitative investigation of physical activity compensation among older adults. Br J Health Psychol. 2018; 23:208–24.

134. Careau V, Halsey LG, Pontzer H, Ainslie PN, Andersen LF, Anderson LJ, et al. Energy compensation and adiposity in humans. Curr Biol. 2021; 31:4659–66.

135. Melanson EL. The effect of exercise on non-exercise physical activity and sedentary behavior in adults. Obes Rev. 2017; 18(Suppl 1):40–9.

136. Madden KM, Feldman B, Chase J. Sedentary time and metabolic risk in extremely active older adults. Diabetes Care. 2021; 44:194–200.

137. Homer AR, Taylor FC, Dempsey PC, Wheeler MJ, Sethi P, Townsend MK, et al. Frequency of interruptions to sitting time: benefits for postprandial metabolism in type 2 diabetes. Diabetes Care. 2021; 44:1254–63.

138. Duvivier BM, Schaper NC, Hesselink MK, van Kan L, Stienen N, Winkens B, et al. Breaking sitting with light activities vs structured exercise: a randomised crossover study demonstrating benefits for glycaemic control and insulin sensitivity in type 2 diabetes. Diabetologia. 2017; 60:490–8.

139. DiPietro L, Gribok A, Stevens MS, Hamm LF, Rumpler W. Three 15-min bouts of moderate postmeal walking significantly improves 24-h glycemic control in older people at risk for impaired glucose tolerance. Diabetes Care. 2013; 36:3262–8.

140. van Dijk JW, Venema M, van Mechelen W, Stehouwer CD, Hartgens F, van Loon LJ. Effect of moderate-intensity exercise versus activities of daily living on 24-hour blood glucose homeostasis in male patients with type 2 diabetes. Diabetes Care. 2013; 36:3448–53.

141. Dempsey PC, Larsen RN, Sethi P, Sacre JW, Straznicky NE, Cohen ND, et al. Benefits for type 2 diabetes of interrupting prolonged sitting with brief bouts of light walking or simple resistance activities. Diabetes Care. 2016; 39:964–72.

142. Dempsey PC, Blankenship JM, Larsen RN, Sacre JW, Sethi P, Straznicky NE, et al. Interrupting prolonged sitting in type 2 diabetes: nocturnal persistence of improved glycaemic control. Diabetologia. 2017; 60:499–507.

143. Taylor FC, Dunstan DW, Homer AR, Dempsey PC, Kingwell BA, Climie RE, et al. Acute effects of interrupting prolonged sitting on vascular function in type 2 diabetes. Am J Physiol Heart Circ Physiol. 2021; 320:H393–403.

144. Blankenship JM, Chipkin SR, Freedson PS, Staudenmayer J, Lyden K, Braun B. Managing free-living hyperglycemia with exercise or interrupted sitting in type 2 diabetes. J Appl Physiol (1985). 2019; 126:616–25.

145. Eriksen L, Dahl-Petersen I, Haugaard SB, Dela F. Comparison of the effect of multiple short-duration with single long-duration exercise sessions on glucose homeostasis in type 2 diabetes mellitus. Diabetologia. 2007; 50:2245–53.

146. Reynolds AN, Mann JI, Williams S, Venn BJ. Advice to walk after meals is more effective for lowering postprandial glycaemia in type 2 diabetes mellitus than advice that does not specify timing: a randomised crossover study. Diabetologia. 2016; 59:2572–8.

147. Chastin S, Gardiner PA, Harvey JA, Leask CF, Jerez-Roig J, Rosenberg D, et al. Interventions for reducing sedentary behaviour in community-dwelling older adults. Cochrane Database Syst Rev. 2021; 6:CD012784.

148. Ramsey KA, Zhou W, Rojer AG, Reijnierse EM, Maier AB. Associations of objectively measured physical activity and sedentary behaviour with fall-related outcomes in older adults: a systematic review. Ann Phys Rehabil Med. 2022; 65:101571.

149. Johansson J, Morseth B, Scott D, Strand BH, Hopstock LA, Grimsgaard S. Moderate-to-vigorous physical activity modifies the relationship between sedentary time and sarcopenia: the Tromsø Study 2015-2016. J Cachexia Sarcopenia Muscle. 2021; 12:955–63.

150. Scott D, Johansson J, Gandham A, Ebeling PR, Nordstrom P, Nordstrom A. Associations of accelerometer-determined physical activity and sedentary behavior with sarcopenia and incident falls over 12 months in community-dwelling Swedish older adults. J Sport Health Sci. 2021; 10:577–84.

151. Grant D, Tomlinson D, Tsintzas K, Kolic P, Onambele-Pearson G. Minimizing sedentary behavior (without increasing medium-to-vigorous exercise) associated functional improvement in older women is somewhat dependent on a measurable increase in muscle size. Aging (Albany NY). 2020; 12:24081–100.

152. Harvey JA, Chastin SF, Skelton DA. Breaking sedentary behaviour has the potential to increase/maintain function in frail older adults. J Frailty Sarcopenia Falls. 2018; 3:26–31.

153. Barone Gibbs B, Brach JS, Byard T, Creasy S, Davis KK, McCoy S, et al. Reducing sedentary behavior versus increasing moderate-to-vigorous intensity physical activity in older adults. J Aging Health. 2017; 29:247–67.

154. Rosenberg DE, Anderson ML, Renz A, Matson TE, Lee AK, Greenwood-Hickman MA, et al. Reducing sitting time in obese older adults: the I-STAND randomized controlled trial. J Aging Phys Act. 2020; 28:864–74.

155. Greenwood-Hickman MA, Renz A, Rosenberg DE. Motivators and barriers to reducing sedentary behavior among overweight and obese older adults. Gerontologist. 2016; 56:660–8.

156. Bird SR, Hawley JA. Update on the effects of physical activity on insulin sensitivity in humans. BMJ Open Sport Exerc Med. 2017; 2:e000143.

157. Ismail AD, Alkhayl FF, Wilson J, Johnston L, Gill JM, Gray SR. The effect of short-duration resistance training on insulin sensitivity and muscle adaptations in overweight men. Exp Physiol. 2019; 104:540–5.

158. Evans PL, McMillin SL, Weyrauch LA, Witczak CA. Regulation of skeletal muscle glucose transport and glucose metabolism by exercise training. Nutrients. 2019; 11:2432.

159. Grgic J, Mcllvenna LC, Fyfe JJ, Sabol F, Bishop DJ, Schoenfeld BJ, et al. Does aerobic training promote the same skeletal muscle hypertrophy as resistance training?: a systematic review and meta-analysis. Sports Med. 2019; 49:233–54.

160. Suchomel TJ, Nimphius S, Bellon CR, Stone MH. The importance of muscular strength: training considerations. Sports Med. 2018; 48:765–85.

161. Farup J, Kjolhede T, Sorensen H, Dalgas U, Moller AB, Vestergaard PF, et al. Muscle morphological and strength adaptations to endurance vs. resistance training. J Strength Cond Res. 2012; 26:398–407.

162. Santos L, Elliott-Sale KJ, Sale C. Exercise and bone health across the lifespan. Biogerontology. 2017; 18:931–46.

163. Konopka AR, Harber MP. Skeletal muscle hypertrophy after aerobic exercise training. Exerc Sport Sci Rev. 2014; 42:53–61.

164. Frank P, Andersson E, Ponten M, Ekblom B, Ekblom M, Sahlin K. Strength training improves muscle aerobic capacity and glucose tolerance in elderly. Scand J Med Sci Sports. 2016; 26:764–73.

165. Kadoglou NP, Fotiadis G, Kapelouzou A, Kostakis A, Liapis CD, Vrabas IS. The differential anti-inflammatory effects of exercise modalities and their association with early carotid atherosclerosis progression in patients with type 2 diabetes. Diabet Med. 2013; 30:e41–50.

166. Castaneda C, Layne JE, Munoz-Orians L, Gordon PL, Walsmith J, Foldvari M, et al. A randomized controlled trial of resistance exercise training to improve glycemic control in older adults with type 2 diabetes. Diabetes Care. 2002; 25:2335–41.

167. Terada T, Friesen A, Chahal BS, Bell GJ, McCargar LJ, Boule NG. Feasibility and preliminary efficacy of high intensity interval training in type 2 diabetes. Diabetes Res Clin Pract. 2013; 99:120–9.

168. Miller EG, Nowson CA, Dunstan DW, Kerr DA, Menzies D, Daly RM. Effects of whey protein plus vitamin D supplementation combined with progressive resistance training on glycaemic control, body composition, muscle function and cardiometabolic risk factors in middle-aged and older overweight/obese adults with type 2 diabetes: a 24-week randomized controlled trial. Diabetes Obes Metab. 2021; 23:938–49.

169. Dunstan DW, Daly RM, Owen N, Jolley D, De Courten M, Shaw J, et al. High-intensity resistance training improves glycemic control in older patients with type 2 diabetes. Diabetes Care. 2002; 25:1729–36.

170. Loimaala A, Groundstroem K, Rinne M, Nenonen A, Huhtala H, Parkkari J, et al. Effect of long-term endurance and strength training on metabolic control and arterial elasticity in patients with type 2 diabetes mellitus. Am J Cardiol. 2009; 103:972–7.

171. Hou L, Wang Q, Pan B, Li R, Li Y, He J, et al. Exercise modalities for type 2 diabetes: a systematic review and network meta-analysis of randomized trials. Diabetes Metab Res Rev. 2023; 39:e3591.

172. Pan B, Ge L, Xun YQ, Chen YJ, Gao CY, Han X, et al. Exercise training modalities in patients with type 2 diabetes mellitus: a systematic review and network meta-analysis. Int J Behav Nutr Phys Act. 2018; 15:72.

173. Lu L, Mao L, Feng Y, Ainsworth BE, Liu Y, Chen N. Effects of different exercise training modes on muscle strength and physical performance in older people with sarcopenia: a systematic review and meta-analysis. BMC Geriatr. 2021; 21:708.

174. Vlietstra L, Hendrickx W, Waters DL. Exercise interventions in healthy older adults with sarcopenia: a systematic review and meta-analysis. Australas J Ageing. 2018; 37:169–83.

175. Csapo R, Alegre LM. Effects of resistance training with moderate vs heavy loads on muscle mass and strength in the elderly: a meta-analysis. Scand J Med Sci Sports. 2016; 26:995–1006.

176. Rafiei H, Omidian K, Myette-Cote E, Little JP. Metabolic effect of breaking up prolonged sitting with stair climbing exercise snacks. Med Sci Sports Exerc. 2021; 53:150–8.

177. Islam H, Gibala MJ, Little JP. Exercise snacks: a novel strategy to improve cardiometabolic health. Exerc Sport Sci Rev. 2022; 50:31–7.

178. Wolfe AS, Burton HM, Vardarli E, Coyle EF. Hourly 4-s sprints prevent impairment of postprandial fat metabolism from inactivity. Med Sci Sports Exerc. 2020; 52:2262–9.

179. Little JP, Langley J, Lee M, Myette-Cote E, Jackson G, Durrer C, et al. Sprint exercise snacks: a novel approach to increase aerobic fitness. Eur J Appl Physiol. 2019; 119:1203–12.

180. Jenkins EM, Nairn LN, Skelly LE, Little JP, Gibala MJ. Do stair climbing exercise “snacks” improve cardiorespiratory fitness? Appl Physiol Nutr Metab. 2019; 44:681–4.

181. Fyfe JJ, Dalla Via J, Jansons P, Scott D, Daly RM. Feasibility and acceptability of a remotely delivered, home-based, pragmatic resistance ‘exercise snacking’ intervention in community-dwelling older adults: a pilot randomised controlled trial. BMC Geriatr. 2022; 22:521.

182. Perkin OJ, McGuigan PM, Stokes KA. Exercise snacking to improve muscle function in healthy older adults: a pilot study. J Aging Res. 2019; 2019:7516939.

183. Jansons P, Dalla Via J, Daly RM, Fyfe JJ, Gvozdenko E, Scott D. Delivery of home-based exercise interventions in older adults facilitated by amazon alexa: a 12-week feasibility trial. J Nutr Health Aging. 2022; 26:96–102.

184. Liang IJ, Perkin OJ, McGuigan PM, Thompson D, Western MJ. Feasibility and acceptability of home-based exercise snacking and Tai Chi snacking delivered remotely to self-isolating older adults during COVID-19. J Aging Phys Act. 2022; 30:33–43.

185. Waters DL, Aguirre L, Gurney B, Sinacore DR, Fowler K, Gregori G, et al. Effect of aerobic or resistance exercise, or both, on intermuscular and visceral fat and physical and metabolic function in older adults with obesity while dieting. J Gerontol A Biol Sci Med Sci. 2022; 77:131–9.

186. Villareal DT, Chode S, Parimi N, Sinacore DR, Hilton T, Armamento-Villareal R, et al. Weight loss, exercise, or both and physical function in obese older adults. N Engl J Med. 2011; 364:1218–29.

187. Villareal DT, Aguirre L, Gurney AB, Waters DL, Sinacore DR, Colombo E, et al. Aerobic or resistance exercise, or both, in dieting obese older adults. N Engl J Med. 2017; 376:1943–55.

188. Madrid DA, Beavers KM, Walkup MP, Ambrosius WT, Rejeski WJ, Marsh AP, et al. Effect of exercise modality and weight loss on changes in muscle and bone quality in older adults with obesity. Exp Gerontol. 2023; 174:112126.

189. Massimino E, Izzo A, Riccardi G, Della Pepa G. The impact of glucose-lowering drugs on sarcopenia in type 2 diabetes: current evidence and underlying mechanisms. Cells. 2021; 10:1958.

190. Lee YS, Jun HS. Anti-diabetic actions of glucagon-like peptide-1 on pancreatic beta-cells. Metabolism. 2014; 63:9–19.

191. Wilding JP, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021; 384:989–1002.

192. Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022; 387:205–16.

193. Frias JP, Davies MJ, Rosenstock J, Perez Manghi FC, Fernandez Lando L, Bergman BK, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021; 385:503–15.

194. Wharton S, Blevins T, Connery L, Rosenstock J, Raha S, Liu R, et al. Daily oral GLP-1 receptor agonist orforglipron for adults with obesity. N Engl J Med. 2023; 389:877–88.

195. Jastreboff AM, Kaplan LM, Frias JP, Wu Q, Du Y, Gurbuz S, et al. Triple-hormone-receptor agonist retatrutide for obesity: a phase 2 trial. N Engl J Med. 2023; 389:514–26.

196. Latres E, Pangilinan J, Miloscio L, Bauerlein R, Na E, Potocky TB, et al. Myostatin blockade with a fully human monoclonal antibody induces muscle hypertrophy and reverses muscle atrophy in young and aged mice. Skelet Muscle. 2015; 5:34.

197. Lv Q, Yuan L, Deng J, Chen M, Wang Y, Zeng J, et al. Efficient generation of myostatin gene mutated rabbit by CRISPR/Cas9. Sci Rep. 2016; 6:25029.

198. Becker C, Lord SR, Studenski SA, Warden SJ, Fielding RA, Recknor CP, et al. Myostatin antibody (LY2495655) in older weak fallers: a proof-of-concept, randomised, phase 2 trial. Lancet Diabetes Endocrinol. 2015; 3:948–57.

199. Rooks D, Swan T, Goswami B, Filosa LA, Bunte O, Panchaud N, et al. Bimagrumab vs optimized standard of care for treatment of sarcopenia in community-dwelling older adults: a randomized clinical trial. JAMA Netw Open. 2020; 3:e2020836.

200. Hanna MG, Badrising UA, Benveniste O, Lloyd TE, Needham M, Chinoy H, et al. Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial. Lancet Neurol. 2019; 18:834–44.

201. Heymsfield SB, Coleman LA, Miller R, Rooks DS, Laurent D, Petricoul O, et al. Effect of bimagrumab vs placebo on body fat mass among adults with type 2 diabetes and obesity: a phase 2 randomized clinical trial. JAMA Netw Open. 2021; 4:e2033457.

202. Garito T, Roubenoff R, Hompesch M, Morrow L, Gomez K, Rooks D, et al. Bimagrumab improves body composition and insulin sensitivity in insulin-resistant individuals. Diabetes Obes Metab. 2018; 20:94–102.

203. De Spiegeleer A, Beckwee D, Bautmans I, Petrovic M; Sarcopenia Guidelines Development Group of the Belgian Society of Gerontology and Geriatrics (BSGG). Pharmacological interventions to improve muscle mass, muscle strength and physical performance in older people: an umbrella review of systematic reviews and meta-analyses. Drugs Aging. 2018; 35:719–34.

204. Skinner JW, Otzel DM, Bowser A, Nargi D, Agarwal S, Peterson MD, et al. Muscular responses to testosterone replacement vary by administration route: a systematic review and meta-analysis. J Cachexia Sarcopenia Muscle. 2018; 9:465–81.

205. Wittert G, Bracken K, Robledo KP, Grossmann M, Yeap BB, Handelsman DJ, et al. Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial. Lancet Diabetes Endocrinol. 2021; 9:32–45.

206. Robledo KP, Marschner IC, Handelsman DJ, Bracken K, Stuckey BG, Yeap BB, et al. Mediation analysis of the testosterone treatment effect to prevent type 2 diabetes in the Testosterone for Prevention of Type 2 Diabetes Mellitus trial. Eur J Endocrinol. 2023; 188:613–20.

207. Grossmann M, Hoermann R, Wittert G, Yeap BB. Effects of testosterone treatment on glucose metabolism and symptoms in men with type 2 diabetes and the metabolic syndrome: a systematic review and meta-analysis of randomized controlled clinical trials. Clin Endocrinol (Oxf). 2015; 83:344–51.

208. Calof OM, Singh AB, Lee ML, Kenny AM, Urban RJ, Tenover JL, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci. 2005; 60:1451–7.

209. Shufelt CL, Braunstein GD. Safety of testosterone use in women. Maturitas. 2009; 63:63–6.

210. Narayanan R, Coss CC, Dalton JT. Development of selective androgen receptor modulators (SARMs). Mol Cell Endocrinol. 2018; 465:134–42.

211. Xie Y, Tian Y, Zhang Y, Zhang Z, Chen R, Li M, et al. Overview of the development of selective androgen receptor modulators (SARMs) as pharmacological treatment for osteoporosis (1998-2021). Eur J Med Chem. 2022; 230:114119.

212. Papanicolaou DA, Ather SN, Zhu H, Zhou Y, Lutkiewicz J, Scott BB, et al. A phase IIA randomized, placebo-controlled clinical trial to study the efficacy and safety of the selective androgen receptor modulator (SARM), MK-0773 in female participants with sarcopenia. J Nutr Health Aging. 2013; 17:533–43.

213. Dobs AS, Boccia RV, Croot CC, Gabrail NY, Dalton JT, Hancock ML, et al. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. Lancet Oncol. 2013; 14:335–45.

214. Dalton JT, Barnette KG, Bohl CE, Hancock ML, Rodriguez D, Dodson ST, et al. The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial. J Cachexia Sarcopenia Muscle. 2011; 2:153–61.

215. Lee DY, Lee CM. Surgical treatment for obesity. J Korean Med Assoc. 2022; 65:417–22.

216. Hollanda A, Lecube A, Rubio MA, Sanchez E, Vilarrasa N, Oliva JG, et al. New metrics to assess type 2 diabetes after bariatric surgery: the “time-within-remission range”. J Clin Med. 2020; 9:1070.

217. Chumakova-Orin M, Vanetta C, Moris DP, Guerron AD. Diabetes remission after bariatric surgery. World J Diabetes. 2021; 12:1093–101.

218. Basu R. Precision medicine in diabetes: a multidisciplinary approach to an emerging paradigm. Cham: Springer;2022. Chapter 11, Surgical management for diabetes remission. p. 217–31.

219. Alba DL, Wu L, Cawthon PM, Mulligan K, Lang T, Patel S, et al. Changes in lean mass, absolute and relative muscle strength, and physical performance after gastric bypass surgery. J Clin Endocrinol Metab. 2019; 104:711–20.

220. Sylivris A, Mesinovic J, Scott D, Jansons P. Body composition changes at 12months following different surgical weight loss interventions in adults with obesity: a systematic review and meta-analysis of randomized control trials. Obes Rev. 2022; 23:e13442.

221. Staudenmann DA, Sui Z, Saxena P, Kaffes AJ, Marinos G, Kumbhari V, et al. Endoscopic bariatric therapies for obesity: a review. Med J Aust. 2021; 215:183–8.

222. Gazdzinska AP, Mojkowska A, Zielinski P, Gazdzinski SP. Changes in resting metabolic rate and body composition due to intragastric balloon therapy. Surg Obes Relat Dis. 2020; 16:34–9.

223. Shah RH, Vedantam S, Kumar S, Amin S, Pearlman M, Bhalla S. Intragastric balloon significantly improves metabolic parameters at 6 months: a meta-analysis. Obes Surg. 2023; 33:725–32.

224. Dantas WS, Roschel H, Murai IH, Gil S, Davuluri G, Axelrod CL, et al. Exercise-induced increases in insulin sensitivity after bariatric surgery are mediated by muscle extracellular matrix remodeling. Diabetes. 2020; 69:1675–91.

225. Bellicha A, van Baak MA, Battista F, Beaulieu K, Blundell JE, Busetto L, et al. Effect of exercise training before and after bariatric surgery: a systematic review and meta-analysis. Obes Rev. 2021; 22(Suppl 4):e13296.

226. Hunsaker A, Hargittai E. A review of Internet use among older adults. New Media Soc. 2018; 20:3937–54.

227. Jones RB, Ashurst EJ, Atkey J, Duffy B. Older people going online: its value and before-after evaluation of volunteer support. J Med Internet Res. 2015; 17:e122.

228. Kruse CS, Krowski N, Rodriguez B, Tran L, Vela J, Brooks M. Telehealth and patient satisfaction: a systematic review and narrative analysis. BMJ Open. 2017; 7:e016242.

229. Flodgren G, Rachas A, Farmer AJ, Inzitari M, Shepperd S. Interactive telemedicine: effects on professional practice and health care outcomes. Cochrane Database Syst Rev. 2015; 2015:CD002098.

230. Al-Badri M, Kilroy CL, Shahar JI, Tomah S, Gardner H, Sin M, et al. In-person and virtual multidisciplinary intensive lifestyle interventions are equally effective in patients with type 2 diabetes and obesity. Ther Adv Endocrinol Metab. 2022; 13:20420188221093220.

231. Hamdy O, Mottalib A, Morsi A, El-Sayed N, Goebel-Fabbri A, Arathuzik G, et al. Long-term effect of intensive lifestyle intervention on cardiovascular risk factors in patients with diabetes in real-world clinical practice: a 5-year longitudinal study. BMJ Open Diabetes Res Care. 2017; 5:e000259.

232. Hansel B, Giral P, Gambotti L, Lafourcade A, Peres G, Filipecki C, et al. A fully automated web-based program improves lifestyle habits and HbA1c in patients with type 2 diabetes and abdominal obesity: randomized trial of patient e-coaching nutritional support (The ANODE Study). J Med Internet Res. 2017; 19:e360.

233. Murray E, Sweeting M, Dack C, Pal K, Modrow K, Hudda M, et al. Web-based self-management support for people with type 2 diabetes (HeLP-Diabetes): randomised controlled trial in English primary care. BMJ Open. 2017; 7:e016009.

234. Shea S, Weinstock RS, Teresi JA, Palmas W, Starren J, Cimino JJ, et al. A randomized trial comparing telemedicine case management with usual care in older, ethnically diverse, medically underserved patients with diabetes mellitus: 5 year results of the IDEATel study. J Am Med Inform Assoc. 2009; 16:446–56.

235. Gershkowitz BD, Hillert CJ, Crotty BH. Digital coaching strategies to facilitate behavioral change in type 2 diabetes: a systematic review. J Clin Endocrinol Metab. 2021; 106:e1513–20.

236. Clemson L, Fiatarone Singh MA, Bundy A, Cumming RG, Manollaras K, O’Loughlin P, et al. Integration of balance and strength training into daily life activity to reduce rate of falls in older people (the LiFE study): randomised parallel trial. BMJ. 2012; 345:e4547.

237. Taraldsen K, Mikolaizak AS, Maier AB, Mellone S, Boulton E, Aminian K, et al. Digital technology to deliver a lifestyle-integrated exercise intervention in young seniors: the PreventIT Feasibility Randomized Controlled Trial. Front Digit Health. 2020; 2:10.

238. Hsu YI, Chen YC, Lee CL, Chang NJ. Effects of diet control and telemedicine-based resistance exercise intervention on patients with obesity and knee osteoarthritis: a randomized control trial. Int J Environ Res Public Health. 2021; 18:7744.

239. Waki K, Fujita H, Uchimura Y, Omae K, Aramaki E, Kato S, et al. DialBetics: a novel smartphone-based self-management support system for type 2 diabetes patients. J Diabetes Sci Technol. 2014; 8:209–15.

240. Wilson J, Heinsch M, Betts D, Booth D, Kay-Lambkin F. Barriers and facilitators to the use of e-health by older adults: a scoping review. BMC Public Health. 2021; 21:1556.

241. Graham SA, Stein N, Shemaj F, Branch OH, Paruthi J, Kanick SC. Older adults engage with personalized digital coaching programs at rates that exceed those of younger adults. Front Digit Health. 2021; 3:642818.

242. King DE, Mainous AG 3rd, Carnemolla M, Everett CJ. Adherence to healthy lifestyle habits in US adults, 1988-2006. Am J Med. 2009; 122:528–34.

243. Bailey SC, Oramasionwu CU, Wolf MS. Rethinking adherence: a health literacy-informed model of medication selfmanagement. J Health Commun. 2013; 18(Suppl 1):20–30.

244. World Health Organization; Regional Office for South-East Asia. Health literacy toolkit for low- and middle-income countries: a series of information sheets to empower communities and strengthen health systems. New Delhi: WHO;2015.

245. O’Meara L, Williams SL, Ames K, Lawson C, Saluja S, Vandelanotte C. Low health literacy is associated with risk of developing type 2 diabetes in a nonclinical population. Diabetes Educ. 2019; 45:431–41.

246. Tajdar D, Luhmann D, Fertmann R, Steinberg T, van den Bussche H, Scherer M, et al. Low health literacy is associated with higher risk of type 2 diabetes: a cross-sectional study in Germany. BMC Public Health. 2021; 21:510.

247. Abdullah A, Liew SM, Salim H, Ng CJ, Chinna K. Prevalence of limited health literacy among patients with type 2 diabetes mellitus: a systematic review. PLoS One. 2019; 14:e0216402.

248. Chin J, Wang H, Awwad AW, Graumlich JF, Wolf MS, Morrow DG. Health literacy, processing capacity, illness knowledge, and actionable memory for medication taking in type 2 diabetes: cross-sectional analysis. J Gen Intern Med. 2021; 36:1921–7.

249. de Abreu IR, Baia C, Silva JM, Santos AM, Oliveira M, Castro F, et al. LitKDm² study: the impact of health literacy and knowledge about the disease on the metabolic control of type 2 diabetes mellitus. Acta Diabetol. 2022; 59:819–25.

250. Fan JH, Lyons SA, Goodman MS, Blanchard MS, Kaphingst KA. Relationship between health literacy and unintentional and intentional medication nonadherence in medically underserved patients with type 2 diabetes. Diabetes Educ. 2016; 42:199–208.

251. Hussain N, Said AS, Khan Z. Influence of health literacy on medication adherence among elderly females with type 2 diabetes in Pakistan. Int Q Community Health Educ. 2020; 41:35–44.

252. Friis K, Vind BD, Simmons RK, Maindal HT. The relationship between health literacy and health behaviour in people with diabetes: a Danish population-based study. J Diabetes Res. 2016; 2016:7823130.

253. McCleary-Jones V. Health literacy and its association with diabetes knowledge, self-efficacy and disease self-management among African Americans with diabetes mellitus. ABNF J. 2011; 22:25–32.

254. Dahal PK, Hosseinzadeh H. Association of health literacy and diabetes self-management: a systematic review. Aust J Prim Health. 2019; 25:526–33.

255. Beauchamp A, Talevski J, Niebauer J, Gutenberg J, Kefalianos E, Mayr B, et al. Health literacy interventions for secondary prevention of coronary artery disease: a scoping review. Open Heart. 2022; 9:e001895.

256. Talevski J, Wong Shee A, Rasmussen B, Kemp G, Beauchamp A. Teach-back: a systematic review of implementation and impacts. PLoS One. 2020; 15:e0231350.

257. George NE, Sunny SM, Sam AM, Sabu AS, Rodrigues PA. Effect of medication related educational interventions on improving medication adherence in patients with type 2 diabetes mellitus. Asian J Pharm Clin Res. 2018; 11:167–70.

258. Mahmoudirad G, Hoseini MS, Madarshahian F. The effect of teach-back education on foot self-care among patients with type II diabetes mellitus. Mod Care J. 2015; 12:1–7.

259. Negarandeh R, Mahmoodi H, Noktehdan H, Heshmat R, Shakibazadeh E. Teach back and pictorial image educational strategies on knowledge about diabetes and medication/dietary adherence among low health literate patients with type 2 diabetes. Prim Care Diabetes. 2013; 7:111–8.

260. Kim SH, Utz S. Effectiveness of a social media-based, health literacy-sensitive diabetes self-management intervention: a randomized controlled trial. J Nurs Scholarsh. 2019; 51:661–9.

261. Zeidi IM, Morshedi H, Alizadeh Otaghvar H. A theory of planned behavior-enhanced intervention to promote health literacy and self-care behaviors of type 2 diabetic patients. J Prev Med Hyg. 2021; 61:E601–13.

262. Agrali H, Akyar I. The effect of health literacy-based, health belief-constructed education on glycated hemoglobin (HbA1c) in people with type 2 diabetes: a randomized controlled study. Prim Care Diabetes. 2022; 16:173–8.

263. Lam MH, Leung AY. The effectiveness of health literacy oriented programs on physical activity behaviour in middle aged and older adults with type 2 diabetes: a systematic review. Health Psychol Res. 2016; 4:5595.

264. Uemura K, Yamada M, Okamoto H. Effects of active learning on health literacy and behavior in older adults: a randomized controlled trial. J Am Geriatr Soc. 2018; 66:1721–9.

265. Uemura K, Yamada M, Okamoto H. The effectiveness of an active learning program in promoting a healthy lifestyle among older adults with low health literacy: a randomized controlled trial. Gerontology. 2021; 67:25–35.

266. Brennan-Olsen SL, Vogrin S, Balogun S, Wu F, Scott D, Jones G, et al. Education, occupation and operational measures of sarcopenia: six years of Australian data. Australas J Ageing. 2020; 39:e498–505.

267. Gandham A, Zengin A, Bonham MP, Brennan-Olsen SL, Aitken D, Winzenberg TM, et al. Associations between socioeconomic status and obesity, sarcopenia, and sarcopenic obesity in community-dwelling older adults: the Tasmanian Older Adult Cohort Study. Exp Gerontol. 2021; 156:111627.

268. Talevski J, Daly RM. Additional insights on the osteoporosis care gap. J Bone Miner Res. 2023; 38:615–6.