Skeletal muscle as a treatment target for older adults with diabetes mellitus: The importance of a multimodal intervention based on functional category
Takuya Omura
Department of Diabetes, Metabolism and Endocrinology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan
Search for more papers by this authorCorresponding Author
Atsushi Araki
Department of Diabetes, Metabolism and Endocrinology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan
Correspondence
Atsushi Araki MD PhD, Department of Diabetes, Metabolism, and Endocrinology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2, Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan.
Email: [email protected]
Search for more papers by this authorTakuya Omura
Department of Diabetes, Metabolism and Endocrinology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan
Search for more papers by this authorCorresponding Author
Atsushi Araki
Department of Diabetes, Metabolism and Endocrinology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan
Correspondence
Atsushi Araki MD PhD, Department of Diabetes, Metabolism, and Endocrinology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2, Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan.
Email: [email protected]
Search for more papers by this authorAbstract
Although the lifespan of people with diabetes has increased in many countries, the age-related increase in comorbidities (sarcopenia, frailty and disabilities) and diabetic complications has become a major issue. Diabetes accelerates the aging of skeletal muscles and blood vessels through mechanisms, such as increased oxidative stress, chronic inflammation, insulin resistance, mitochondrial dysfunction, genetic polymorphism (fat mass and obesity-associated genes) and accumulation of advanced glycation end-products. Diabetes is associated with early onset, and progression of muscle weakness and sarcopenia, thus resulting in diminished daily life function. The type and duration of diabetes, insulin section/resistance, hyperglycemia, diabetic neuropathy, malnutrition and low physical activity might affect muscular loss and weakness. To prevent the decline in daily activities in older adults with diabetes, resistance training or multicomponent exercise should be recommended. To maintain muscle function, optimal energy and sufficient protein intake are necessary. Although no specific drug enhances muscle mass and function, antidiabetic drugs that increase insulin sensitivity or secretion could be candidates for improvement of sarcopenia. The goals of glycemic control for older patients are determined based on three functional categories through an assessment of cognitive function and activities of daily living, and the presence or absence of medications that pose a hypoglycemic risk. As these functional categories are associated with muscle weakness, frailty and mortality risk, providing multimodal interventions (exercise, nutrition, social network or support and optimal medical treatment) is important, starting at the category II stage for maintenance or improvement in daily life functions. Geriatr Gerontol Int 2022; 22: 110–120.
Open Research
Data availability statement
Data sharing is not applicable to this narrative review article as no new data were generated or analyzed in this study.
References
- 1Umegaki H. Sarcopenia and frailty in older patients with diabetes mellitus. Geriatr Gerontol Int 2016; 16: 293–299. https://doi.org/10.1111/ggi.12688.
- 2Tamura Y, Omura T, Toyoshima K, Araki A. Nutrition Management in Older Adults with diabetes: a review on the importance of shifting prevention strategies from metabolic syndrome to frailty. Nutrients 2021; 12(11): 3367. https://doi.org/10.3390/nu12113367.
- 3Abudawood M. Diabetes and cancer: a comprehensive review. J Res Med Sci 2019; 24: 94. https://doi.org/10.4103/jrms.JRMS_242_19.
- 4Pontzer H, Yamada Y, Sagayama H et al. Daily energy expenditure through the human life course. Science 2021; 373: 808–812. https://doi.org/10.1126/science.abe5017.
- 5 Dietary Reference Intakes for Japanese 2020 Ministry of Health, Labour and Welfare, Japan (in Japanese). Available from URL: https://www.mhlw.go.jp/stf/newpage_08517.html
- 6Heymsfield SB, Peterson CM, Bourgeois B et al. Human energy expenditure: advances in organ-tissue prediction models. Obes Rev 2018; 19: 1177–1188. https://doi.org/10.1111/obr.12718.
- 7Lawrence D. Body physics: motion to metabolism. 84 Efficiency of the Human Body. Available from URL: https://openoregon.pressbooks.pub/bodyphysics/
- 8Lopes de Pontes T, Dos Santos Pessanha FPA, Junior RCF et al. Total energy expenditure and functional status in older adults: a doubly Labelled water study. J Nutr Health Aging 2021; 25: 201–208. https://doi.org/10.1007/s12603-020-1482-5.
- 9Katsukawa F. Energy requirements for older patients with type 2 diabetes: a narrative review of the current findings and future tasks. Nutrients 2021; 13(3): 753. https://doi.org/10.3390/nu13030753.
- 10Steinbacher P, Eckl P. Impact of oxidative stress on exercising skeletal muscle. Biomolecules 2015; 5: 356–377. https://doi.org/10.3390/biom5020356.
- 11Ishikura K, Ra S-G, Ohmori H. Exercise-induced changes in amino acid levels in skeletal muscle and plasma. J Sports Med Phys Fitness 2013; 2: 301–310. https://doi.org/10.7600/jpfsm.2.301.
10.7600/jpfsm.2.301 Google Scholar
- 12Dympna G, Heymsfield SB, Wang Z-M. 12 Skeletal Muscle Markers. The Role of Protein and Amino Acids in Sustaining and Enhancing Performance. Available from URL: https://www.ncbi.nlm.nih.gov/books/NBK224632/
- 13Li H, Malhotra S, Kumar A. Nuclear factor-kappa B signaling in skeletal muscle atrophy. J Mol Med (Berl) 2008; 86: 1113–1126. https://doi.org/10.1007/s00109-008-0373-8.
- 14Ali S, Garcia JM. Sarcopenia, cachexia and aging: diagnosis, mechanisms and therapeutic options - a mini-review. Gerontology 2014; 60: 294–305. https://doi.org/10.1159/000356760.
- 15Barr EL, Zimmet PZ, Welborn TA et al. Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian diabetes, obesity, and lifestyle study (AusDiab). Circulation 2007; 116: 151–157. https://doi.org/10.1161/CIRCULATIONAHA.106.685628.
- 16Cai X, Zhang Y, Li M et al. Association between prediabetes and risk of all cause mortality and cardiovascular disease: updated meta-analysis. BMJ (Clinical Research Ed) 2020; 370: m2297. https://doi.org/10.1136/bmj.m2297.
- 17Tanaka K, Kanazawa I, Sugimoto T. Reduction in endogenous insulin secretion is a risk factor of sarcopenia in men with type 2 diabetes mellitus. Calcif Tissue Int 2015; 97: 385–390. https://doi.org/10.1007/s00223-015-9990-8.
- 18Zhang J, Liu F. Tissue-specific insulin signaling in the regulation of metabolism and aging. IUBMB Life 2014; 66: 485–495. https://doi.org/10.1002/iub.1293.
- 19Gratas-Delamarche A, Derbre F, Vincent S, Cillard J. Physical inactivity, insulin resistance, and the oxidative-inflammatory loop. Free Radic Res 2014; 48: 93–108. https://doi.org/10.3109/10715762.2013.847528.
- 20Ferri E, Marzetti E, Calvani R, Picca A, Cesari M, Arosio B. Role of age-related mitochondrial dysfunction in sarcopenia. Int J Mol Sci 2020; 21(15): 5236. https://doi.org/10.3390/ijms21155236.
- 21Lanza IR, Zabielski P, Klaus KA et al. Chronic caloric restriction preserves mitochondrial function in senescence without increasing mitochondrial biogenesis. Cell Metab 2012; 16: 777–788. https://doi.org/10.1016/j.cmet.2012.11.003.
- 22Vina J, Gomez-Cabrera MC, Borras C et al. Mitochondrial biogenesis in exercise and in ageing. Adv Drug Deliv Rev 2009; 61: 1369–1374. https://doi.org/10.1016/j.addr.2009.06.006.
- 23Toledo FG, Goodpaster BH. The role of weight loss and exercise in correcting skeletal muscle mitochondrial abnormalities in obesity, diabetes and aging. Mol Cell Endocrinol 2013; 379: 30–34. https://doi.org/10.1016/j.mce.2013.06.018.
- 24Dina C, Meyre D, Gallina S et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 2007; 39: 724–726. https://doi.org/10.1038/ng2048.
- 25Do R, Bailey SD, Desbiens K et al. Genetic variants of FTO influence adiposity, insulin sensitivity, leptin levels, and resting metabolic rate in the Quebec family study. Diabetes 2008; 57: 1147–1150. https://doi.org/10.2337/db07-1267.
- 26Tanaka M, Yoshida T, Bin W, Fukuo K, Kazumi T. FTO, abdominal adiposity, fasting hyperglycemia associated with elevated HbA1c in Japanese middle-aged women. J Atheroscler Thromb 2012; 19: 633–642. https://doi.org/10.5551/jat.11940.
- 27Jacobsson JA, Almen MS, Benedict C et al. Detailed analysis of variants in FTO in association with body composition in a cohort of 70-year-olds suggests a weakened effect among elderly. PloS One 2011; 6: e20158. https://doi.org/10.1371/journal.pone.0020158.
- 28Jacobsson JA, Riserus U, Axelsson T, Lannfelt L, Schioth HB, Fredriksson R. The common FTO variant rs9939609 is not associated with BMI in a longitudinal study on a cohort of Swedish men born 1920-1924. BMC Med Genet 2009; 10: 131. https://doi.org/10.1186/1471-2350-10-131.
- 29Rampersaud E, Mitchell BD, Pollin TI et al. Physical activity and the association of common FTO gene variants with body mass index and obesity. Arch Intern Med 2008; 168: 1791–1797. https://doi.org/10.1001/archinte.168.16.1791.
- 30Andreasen CH, Stender-Petersen KL, Mogensen MS et al. Low physical activity accentuates the effect of the FTO rs9939609 polymorphism on body fat accumulation. Diabetes 2008; 57: 95–101. https://doi.org/10.2337/db07-0910.
- 31Wang X, Huang N, Yang M et al. FTO is required for myogenesis by positively regulating mTOR-PGC-1alpha pathway-mediated mitochondria biogenesis. Cell Death Dis 2017; 8: e2702. https://doi.org/10.1038/cddis.2017.122.
- 32Bravard A, Lefai E, Meugnier E et al. FTO is increased in muscle during type 2 diabetes, and its overexpression in myotubes alters insulin signaling, enhances lipogenesis and ROS production, and induces mitochondrial dysfunction. Diabetes 2011; 60: 258–268. https://doi.org/10.2337/db10-0281.
- 33Ran S, Jiang ZX, He X et al. Replication of FTO gene associated with lean mass in a meta-analysis of genome-wide association studies. Sci Rep 2020; 10: 5057. https://doi.org/10.1038/s41598-020-61406-3.
- 34Khanal P, He L, Herbert AJ et al. The Association of Multiple Gene Variants with ageing skeletal muscle phenotypes in elderly women. Genes 2020; 11(12): 1459. https://doi.org/10.3390/genes11121459.
- 35Tamura Y, Izumiyama-Shimomura N, Kimbara Y et al. Beta-cell telomere attrition in diabetes: inverse correlation between HbA1c and telomere length. J Clin Endocrinol Metab 2014; 99: 2771–2777. https://doi.org/10.1210/jc.2014-1222.
- 36Jiang H, Ju Z, Rudolph KL. Telomere shortening and ageing. Z Gerontol Geriatr 2007; 40: 314–324. https://doi.org/10.1007/s00391-007-0480-0.
- 37Di Donna S, Mamchaoui K, Cooper RN et al. Telomerase can extend the proliferative capacity of human myoblasts, but does not lead to their immortalization. Mol Cancer Res 2003; 1: 643–653.
- 38Chang KV, Chen YC, Wu WT et al. Expression of Telomeric repeat-containing RNA decreases in sarcopenia and increases after exercise and nutrition intervention. Nutrients 2020; 12(12): 3766. https://doi.org/10.3390/nu12123766.
- 39Bernabeu-Wittel M, Gomez-Diaz R, Gonzalez-Molina A et al. Oxidative stress, telomere shortening, and apoptosis associated to sarcopenia and frailty in patients with multimorbidity. J Clin Med 2020; 9(8): 2669. https://doi.org/10.3390/jcm9082669.
- 40Kuo CL, Pilling LC, Kuchel GA, Ferrucci L, Melzer D. Telomere length and aging-related outcomes in humans: a Mendelian randomization study in 261,000 older participants. Aging Cell 2019; 18: e13017. https://doi.org/10.1111/acel.13017.
- 41Rippberger PL, Emeny RT, Mackenzie TA, Bartels SJ, Batsis JA. The association of sarcopenia, telomere length, and mortality: data from the NHANES 1999-2002. Eur J Clin Nutr 2018; 72: 255–263. https://doi.org/10.1038/s41430-017-0011-z.
- 42Liguori I, Russo G, Curcio F et al. Oxidative stress, aging, and diseases. Clin Interv Aging 2018; 13: 757–772. https://doi.org/10.2147/CIA.S158513.
- 43Egawa T, Ohno Y, Yokoyama S et al. The effect of advanced glycation end products on cellular signaling molecules in skeletal muscle. J Sports Med Phys Fitness 2018; 7: 229–238. https://doi.org/10.7600/jpfsm.7.229.
10.7600/jpfsm.7.229 Google Scholar
- 44Sugimoto K, Rakugi H. Transdisciplinary approach for sarcopenia. The application of life style diseases-animal models to the research for sarcopenia. Clin Calcium 2014; 24: 1479–1486.
- 45Haus JM, Carrithers JA, Trappe SW, Trappe TA. Collagen, cross-linking, and advanced glycation end products in aging human skeletal muscle. J Appl Physiol 1985; 2007: 2068–2076. https://doi.org/10.1152/japplphysiol.00670.2007.
- 46Mori H, Kuroda A, Ishizu M et al. Association of accumulated advanced glycation end-products with a high prevalence of sarcopenia and dynapenia in patients with type 2 diabetes. J Diabetes Investig 2019; 10: 1332–1340. https://doi.org/10.1111/jdi.13014.
- 47Eguchi Y, Toyoguchi T, Inage K et al. Advanced glycation end products are associated with sarcopenia in older women: aging marker dynamics. J Women Aging 2021; 33: 328–340. https://doi.org/10.1080/08952841.2019.1697161.
- 48Brooks SV. Current topics for teaching skeletal muscle physiology. Adv Physiol Educ 2003; 27: 171–182. https://doi.org/10.1152/advan.2003.27.4.171.
- 49Abe T, Sakamaki M, Yasuda T et al. Age-related, site-specific muscle loss in 1507 Japanese men and women aged 20 to 95 years. J Sports Sci Med 2011; 10: 145–150.
- 50Hughes VA, Frontera WR, Wood M et al. Longitudinal muscle strength changes in older adults: influence of muscle mass, physical activity, and health. J Gerontol A Biol Sci Med Sci 2001; 56: B209–B217. https://doi.org/10.1093/gerona/56.5.b209.
- 51Larsson L, Degens H, Li M et al. Sarcopenia: aging-related loss of muscle mass and function. Physiol Rev 2019; 99: 427–511. https://doi.org/10.1152/physrev.00061.2017.
- 52Mitchell 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. https://doi.org/10.3389/fphys.2012.00260.
- 53McCormick R, Vasilaki A. Age-related changes in skeletal muscle: changes to life-style as a therapy. Biogerontology 2018; 19: 519–536. https://doi.org/10.1007/s10522-018-9775-3.
- 54Marcus RL, Addison O, Kidde JP, Dibble LE, Lastayo PC. Skeletal muscle fat infiltration: impact of age, inactivity, and exercise. J Nutr Health Aging 2010; 14: 362–366. https://doi.org/10.1007/s12603-010-0081-2.
- 55Li X, Li Z, Zhao M et al. Skeletal muscle lipid droplets and the Athlete's paradox. Cell 2019; 8(3): 249. https://doi.org/10.3390/cells8030249.
- 56Liu L, Zhang Y, Chen N, Shi X, Tsang B, Yu YH. Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance. J Clin Investig 2007; 117: 1679–1689. https://doi.org/10.1172/jci30565.
- 57Saltin B, Gollnick PD. Skeletal muscle adaptability: significance for metabolism and performance. In: LD Peachey, RH Adrian, SR Geiger, eds. Handbook of Physiology. Section 10: Skeletal Muscle. Bethesda, MD: American Physiological Society. 1983; 555–631.
10.1002/cphy.cp100119 Google Scholar
- 58Simoneau JA, Bouchard C. Genetic determinism of fiber type proportion in human skeletal muscle. FASEB J 1995; 9: 1091–1095. https://doi.org/10.1096/fasebj.9.11.7649409.
- 59Schiaffino S, Reggiani C. Fiber types in mammalian skeletal muscles. Physiol Rev 2011; 91: 1447–1531. https://doi.org/10.1152/physrev.00031.2010.
- 60Lexell J. Human aging, muscle mass, and fiber type composition. J Gerontol A Biol Sci Med Sci 1995; 50: 11–16. https://doi.org/10.1093/gerona/50a.special_issue.11.
- 61Tanganelli F, Meinke P, Hofmeister F et al. Type-2 muscle fiber atrophy is associated with sarcopenia in elderly men with hip fracture. Exp Gerontol 2021; 144: 111171. https://doi.org/10.1016/j.exger.2020.111171.
- 62Simoneau JA, Lortie G, Boulay MR, Thibault MC, Theriault G, Bouchard C. Skeletal muscle histochemical and biochemical characteristics in sedentary male and female subjects. Can J Physiol Pharmacol 1985; 63: 30–35. https://doi.org/10.1139/y85-005.
- 63Yoshida S, Nakagami H, Hayashi H et al. The CD153 vaccine is a senotherapeutic option for preventing the accumulation of senescent T cells in mice. Nat Commun 2020; 11: 2482. https://doi.org/10.1038/s41467-020-16347-w.
- 64Aguayo-Mazzucato C, Andle J, Lee TB Jr et al. Acceleration of beta cell aging determines diabetes and Senolysis improves disease outcomes. Cell Metab 2019; 30: e4. https://doi.org/10.1016/j.cmet.2019.05.006.
- 65Barinda AJ, Ikeda K, Nugroho DB et al. Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype. Nat Commun 2020; 11: 481. https://doi.org/10.1038/s41467-020-14387-w.
- 66Araki A, Ito H. Diabetes mellitus and geriatric syndromes. Geriatr Gerontol Int 2009; 9: 105–114. https://doi.org/10.1111/j.1447-0594.2008.00495.x.
- 67Cigolle CT, Lee PG, Langa KM, Lee YY, Tian Z, Blaum CS. Geriatric conditions develop in middle-aged adults with diabetes. J Gen Intern Med 2011; 26: 272–279. https://doi.org/10.1007/s11606-010-1510-y.
- 68Sarkar D, Shetty K. Chapter 6 - diabetes as a disease of aging, and the role of oxidative stress. In: VR Preedy, ed. Aging. San Diego, CA: Academic Press, 2014; 61–69. https://doi.org/10.1016/B978-0-12-405933-7.00006-8.
10.1016/B978-0-12-405933-7.00006-8 Google Scholar
- 69Furman D, Campisi J, Verdin E et al. Chronic inflammation in the etiology of disease across the life span. Nat Med 2019; 25: 1822–1832. https://doi.org/10.1038/s41591-019-0675-0.
- 70Shou J, Chen PJ, Xiao WH. Mechanism of increased risk of insulin resistance in aging skeletal muscle. Diabetol Metab Syndr 2020; 12: 14. https://doi.org/10.1186/s13098-020-0523-x.
- 71Muller DC, Elahi D, Tobin JD, Andres R. The effect of age on insulin resistance and secretion: a review. Semin Nephrol 1996; 16: 289–298.
- 72Pinti MV, Fink GK, Hathaway QA, Durr AJ, Kunovac A, Hollander JM. Mitochondrial dysfunction in type 2 diabetes mellitus: an organ-based analysis. Am J Physiol Endocrinol Metab 2019; 316: E268–E285. https://doi.org/10.1152/ajpendo.00314.2018.
- 73Cheng F, Carroll L, Joglekar MV et al. Diabetes, metabolic disease, and telomere length. Lancet Diabetes Endocrinol 2021; 9: 117–126. https://doi.org/10.1016/S2213-8587(20)30365-X.
- 74Gao Z, Daquinag AC, Fussell C et al. Age-associated telomere attrition in adipocyte progenitors predisposes to metabolic disease. Nat Metab 2020; 2: 1482–1497. https://doi.org/10.1038/s42255-020-00320-4.
- 75Nagai R, Mori T, Yamamoto Y, Kaji Y, Yonei Y. Significance of advanced Glycation end products in aging-related disease. Anti-Aging Med 2010; 7: 112–119. https://doi.org/10.3793/jaam.7.112.
10.3793/jaam.7.112 Google Scholar
- 76Hanlon P, Faure I, Corcoran N et al. Frailty measurement, prevalence, incidence, and clinical implications in people with diabetes: a systematic review and study-level meta-analysis. Lancet Healthy Longev 2020; 1: e106–e116. https://doi.org/10.1016/S2666-7568(20)30014-3.
- 77Park SW, Goodpaster BH, Strotmeyer ES et al. Accelerated loss of skeletal muscle strength in older adults with type 2 diabetes: the health, aging, and body composition study. Diabetes Care 2007; 30: 1507–1512. https://doi.org/10.2337/dc06-2537.
- 78Park 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. https://doi.org/10.2337/dc09-0264.
- 79Lee CG, Boyko EJ, Strotmeyer ES et al. Association between insulin resistance and lean mass loss and fat mass gain in older men without diabetes mellitus. J Am Geriatr Soc 2011; 59: 1217–1224. https://doi.org/10.1111/j.1532-5415.2011.03472.x.
- 80Mori H, Kuroda A, Matsuhisa M. Clinical impact of sarcopenia and dynapenia on diabetes. Diabetol Int 2019; 10: 183–187. https://doi.org/10.1007/s13340-019-00400-1.
- 81Mori 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. https://doi.org/10.1111/jdi.13436.
- 82Mori H, Kuroda A, Araki M et al. Advanced glycation end-products are a risk for muscle weakness in Japanese patients with type 1 diabetes. J Diabetes Investig 2017; 8: 377–382. https://doi.org/10.1111/jdi.12582.
- 83Monaco CMF, Gingrich MA, Hawke TJ. Considering type 1 diabetes as a form of accelerated muscle aging. Exerc Sport Sci Rev 2019; 47: 98–107. https://doi.org/10.1249/JES.0000000000000184.
- 84Hata S, Mori H, Yasuda T et al. A low serum IGF-1 is correlated with sarcopenia in subjects with type 1 diabetes mellitus: findings from a post-hoc analysis of the iDIAMOND study. Diabetes Res Clin Pract 2021; 179: 108998. https://doi.org/10.1016/j.diabres.2021.108998.
- 85Wang M, Tan Y, Shi Y, Wang X, Liao Z, Wei P. Diabetes and Sarcopenic obesity: pathogenesis, diagnosis, and treatments. Front Endocrinol 2020; 11: 568. https://doi.org/10.3389/fendo.2020.00568.
- 86Kawano R, Takahashi F, Hashimoto Y et al. Short energy intake is associated with muscle mass loss in older patients with type 2 diabetes: a prospective study of the KAMOGAWA-DM cohort. Clin Nutr 2021; 40: 1613–1620. https://doi.org/10.1016/j.clnu.2021.02.049.
- 87Volkert D, Beck AM, Cederholm T et al. ESPEN guideline on clinical nutrition and hydration in geriatrics. Clin Nutr 2019; 38: 10–47. https://doi.org/10.1016/j.clnu.2018.05.024.
- 88Turnbull PJ, Sinclair AJ. Evaluation of nutritional status and its relationship with functional status in older citizens with diabetes mellitus using the mini nutritional assessment (MNA) tool-a preliminary investigation. J Nutr Health Aging 2002; 6: 185–189.
- 89Sanz Paris A, Garcia JM, Gomez-Candela C, Burgos R, Martin A, Matia P. Malnutrition prevalence in hospitalized elderly diabetic patients. Nutr Hospital 2013; 28: 592–599. https://doi.org/10.3305/nh.2013.28.3.6472.
- 90Tanaka S, Tanaka S, Iimuro S et al. Body mass index and mortality among Japanese patients with type 2 diabetes: pooled analysis of the Japan diabetes complications study and the Japanese elderly diabetes intervention trial. J Clin Endocrinol Metab 2014; 99: E2692–E2696. https://doi.org/10.1210/jc.2014-1855.
- 91Alfonso-Rosa RM, Del Pozo-Cruz B, Del Pozo-Cruz J, Del Pozo-Cruz JT, Sanudo B. The relationship between nutritional status, functional capacity, and health-related quality of life in older adults with type 2 diabetes: a pilot explanatory study. J Nutr Health Aging 2013; 17: 315–321. https://doi.org/10.1007/s12603-013-0028-5.
- 92Omura T, Tamura Y, Yamaoka T et al. Assessing the association between optimal energy intake and all-cause mortality in older patients with diabetes mellitus using the Japanese elderly diabetes intervention trial. Geriatr Gerontol Int 2020; 20: 59–65. https://doi.org/10.1111/ggi.13820.
- 93Moro T, Ebert SM, Adams CM, Rasmussen BB. Amino acid sensing in skeletal muscle. Trends Endocrinol Metab 2016; 27: 796–806. https://doi.org/10.1016/j.tem.2016.06.010.
- 94Henning W. Molecular exercise physiology: An Introduction 2014. Available from URL: http://tarbiatbadani.urmia.ac.ir/sites/tarbiatbadani.urmia.ac.ir/files/u801/Molecular%20Exercise%20Physiology-2014.pdf
- 95Komar B, Schwingshackl L, Hoffmann G. Effects of leucine-rich protein supplements on anthropometric parameter and muscle strength in the elderly: a systematic review and meta-analysis. J Nutr Health Aging 2015; 19: 437–446. https://doi.org/10.1007/s12603-014-0559-4.
- 96Sener A, Malaisse WJ. The stimulus-secretion coupling of amino acid-induced insulin release: insulinotropic action of branched-chain amino acids at physiological concentrations of glucose and glutamine. Eur J Clin Invest 1981; 11: 455–460. https://doi.org/10.1111/j.1365-2362.1981.tb02013.x.
- 97Rennie MJ. Anabolic resistance: the effects of aging, sexual dimorphism, and immobilization on human muscle protein turnover. Appl Physiol Nutr Metab 2009; 34: 377–381. https://doi.org/10.1139/h09-012.
- 98Breen L, Phillips SM. Skeletal muscle protein metabolism in the elderly: interventions to counteract the 'anabolic resistance' of ageing. Nutr Metab 2011; 8: 68. https://doi.org/10.1186/1743-7075-8-68.
- 99Rahi B, Morais JA, Gaudreau P, Payette H, Shatenstein B. Energy and protein intakes and their association with a decline in functional capacity among diabetic older adults from the NuAge cohort. Eur J Nutr 2016; 55: 1729–1739. https://doi.org/10.1007/s00394-015-0991-1.
- 100Levine ME, Suarez JA, Brandhorst S et al. Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. Cell Metab 2014; 19: 407–417. https://doi.org/10.1016/j.cmet.2014.02.006.
- 101Smeuninx B, Greig CA, Breen L. Amount, source and pattern of dietary protein intake across the adult lifespan: a cross-sectional study. Front Nutr 2020; 7: 25. https://doi.org/10.3389/fnut.2020.00025.
- 102Ten Haaf DSM, Nuijten MAH, Maessen MFH, Horstman AMH, Eijsvogels TMH, Hopman MTE. Effects of protein supplementation on lean body mass, muscle strength, and physical performance in nonfrail community-dwelling older adults: a systematic review and meta-analysis. Am J Clin Nutr 2018; 108: 1043–1059. https://doi.org/10.1093/ajcn/nqy192.
- 103Hanson ED, Srivatsan SR, Agrawal S et al. Effects of strength training on physical function: influence of power, strength, and body composition. J Strength Cond Res 2009; 23: 2627–2637. https://doi.org/10.1519/JSC.0b013e3181b2297b.
- 104Escriche-Escuder A, Fuentes-Abolafio IJ, Roldán-Jiménez C, Cuesta-Vargas AI. Effects of exercise on muscle mass, strength, and physical performance in older adults with sarcopenia: a systematic review and meta-analysis according to the EWGSOP criteria. Exp Gerontol 2021; 151: 111420. https://doi.org/10.1016/j.exger.2021.111420.
- 105Yoo SZ, No MH, Heo JW et al. Role of exercise in age-related sarcopenia. J Exerc Rehabil 2018; 14: 551–558. https://doi.org/10.12965/jer.1836268.134.
- 106McGlory C, Devries MC, Phillips SM. Skeletal muscle and resistance exercise training; the role of protein synthesis in recovery and remodeling. J Appl Physiol 1985; 2017: 541–548. https://doi.org/10.1152/japplphysiol.00613.2016.
- 107Taaffe DR, Henwood TR, Nalls MA, Walker DG, Lang TF, Harris TB. Alterations in muscle attenuation following detraining and retraining in resistance-trained older adults. Gerontology 2009; 55: 217–223. https://doi.org/10.1159/000182084.
- 108Johnston AP, De Lisio M, Parise G. Resistance training, sarcopenia, and the mitochondrial theory of aging. Appl Physiol Nutr Metab 2008; 33: 191–199. https://doi.org/10.1139/h07-141.
- 109Borde R, Hortobagyi T, Granacher U. Dose-response relationships of resistance training in healthy old adults: a systematic review and meta-analysis. Sports Med (Auckland, NZ) 2015; 45: 1693–1720. https://doi.org/10.1007/s40279-015-0385-9.
- 110Mayer F, Scharhag-Rosenberger F, Carlsohn A, Cassel M, Muller S, Scharhag J. The intensity and effects of strength training in the elderly. Dtsch Arztebl Int 2011; 108: 359–364. https://doi.org/10.3238/arztebl.2011.0359.
- 111Yamada M, Kimura Y, Ishiyama D et al. Synergistic effect of bodyweight resistance exercise and protein supplementation on skeletal muscle in sarcopenic or dynapenic older adults. Geriatr Gerontol Int 2019; 19: 429–437. https://doi.org/10.1111/ggi.13643.
- 112Brellenthin AG, Lee DC, Bennie JA, Sui X, Blair SN. Resistance exercise, alone and in combination with aerobic exercise, and obesity in Dallas, Texas, US: a prospective cohort study. PLoS Med 2021; 18: e1003687. https://doi.org/10.1371/journal.pmed.1003687.
- 113Lee J, Kim D, Kim C. Resistance training for glycemic control, muscular strength, and lean body mass in old type 2 diabetic patients: a meta-analysis. Diabetes Ther 2017; 8: 459–473. https://doi.org/10.1007/s13300-017-0258-3.
- 114Hashimoto Y, Kaji A, Sakai R et al. Effect of exercise habit on skeletal muscle mass varies with protein intake in elderly patients with type 2 diabetes: a retrospective cohort study. Nutrients 2020; 12(10): 3220. https://doi.org/10.3390/nu12103220.
- 115Rodriguez-Manas L, Laosa O, Vellas B et al. Effectiveness of a multimodal intervention in functionally impaired older people with type 2 diabetes mellitus. J Cachexia Sarcopenia Muscle 2019; 10: 721–733. https://doi.org/10.1002/jcsm.12432.
- 116Yoshimura 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.e1–553.e16. https://doi.org/10.1016/j.jamda.2017.03.019.
- 117Law TD, Clark LA, Clark BC. Resistance exercise to prevent and manage sarcopenia and Dynapenia. Annu Rev Gerontol Geriatr 2016; 36: 205–228. https://doi.org/10.1891/0198-8794.36.205.
- 118Zech A, Drey M, Freiberger E et al. Residual effects of muscle strength and muscle power training and detraining on physical function in community-dwelling prefrail older adults: a randomized controlled trial. BMC Geriatr 2012; 12: 68. https://doi.org/10.1186/1471-2318-12-68.
- 119Massimino E, Izzo A, Riccardi G, Della PG. The impact of glucose-lowering drugs on sarcopenia in type 2 diabetes: current evidence and underlying mechanisms. Cells 2021; 10(8): 1958. https://doi.org/10.3390/cells10081958.
- 120Tricarico D, Mele A, Camerino GM et al. The KATP channel is a molecular sensor of atrophy in skeletal muscle. J Physiol 2010; 588: 773–784. https://doi.org/10.1113/jphysiol.2009.185835.
- 121Musi N, Hirshman MF, Nygren J et al. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 2002; 51: 2074–2081. https://doi.org/10.2337/diabetes.51.7.2074.
- 122Lee CG, Boyko EJ, Barrett-Connor E et al. Insulin sensitizers may attenuate lean mass loss in older men with diabetes. Diabetes Care 2011; 34: 2381–2386. https://doi.org/10.2337/dc11-1032.
- 123Sumantri S, Setiati S, Purnamasari D, Dewiasty E. Relationship between metformin and frailty syndrome in elderly people with type 2 diabetes. Acta Med Indones 2014; 46: 183–188.
- 124Laksmi PW, Setiati S, Tamin TZ et al. Effect of metformin on handgrip strength, gait speed, Myostatin serum level, and health-related quality of life: a double blind randomized controlled trial among non-diabetic pre-frail elderly patients. Acta Med Indones 2017; 49: 118–127.
- 125Wang CP, Lorenzo C, Habib SL, Jo B, Espinoza SE. Differential effects of metformin on age related comorbidities in older men with type 2 diabetes. J Diabetes Complications 2017; 31: 679–686. https://doi.org/10.1016/j.jdiacomp.2017.01.013.
- 126Walton RG, Dungan CM, Long DE et al. Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: a randomized, double-blind, placebo-controlled, multicenter trial: the MASTERS trial. Aging Cell 2019; 18: e13039. https://doi.org/10.1111/acel.13039.
- 127Espinoza SE, Musi N, Wang CP et al. Rationale and study Design of a Randomized Clinical Trial of metformin to prevent frailty in older adults with Prediabetes. J Gerontol A Biol Sci Med Sci 2020; 75: 102–109. https://doi.org/10.1093/gerona/glz078.
- 128Hallakou-Bozec S, Vial G, Kergoat M et al. Mechanism of action of Imeglimin: a novel therapeutic agent for type 2 diabetes. Diabetes Obes Metab 2021; 23: 664–673. https://doi.org/10.1111/dom.14277.
- 129Detaille D, Vial G, Borel AL et al. Imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration. Cell Death Discov 2016; 2: 15072. https://doi.org/10.1038/cddiscovery.2015.72.
- 130Hallakou-Bozec S, Kergoat M, Fouqueray P, Bolze S, Moller DE. Imeglimin amplifies glucose-stimulated insulin release from diabetic islets via a distinct mechanism of action. PLoS One 2021; 16: e0241651. https://doi.org/10.1371/journal.pone.0241651.
- 131Stromsdorfer KL, Yamaguchi S, Yoon MJ et al. NAMPT-mediated NAD(+) biosynthesis in adipocytes regulates adipose tissue function and multi-organ insulin sensitivity in mice. Cell Rep 2016; 16: 1851–1860. https://doi.org/10.1016/j.celrep.2016.07.027.
- 132Imai SI. The NAD World 2.0: the importance of the inter-tissue communication mediated by NAMPT/NAD(+)/SIRT1 in mammalian aging and longevity control. NPJ Syst Biol Appl2016; 2: 16018. doi: https://doi.org/10.1038/npjsba.2016.18
- 133Kurinami N, Sugiyama S, Nishimura H et al. Clinical factors associated with initial decrease in body-fat percentage induced by add-on sodium-glucose co-transporter 2 inhibitors in patient with type 2 diabetes mellitus. Clin Drug Investig 2018; 38: 19–27. https://doi.org/10.1007/s40261-017-0580-6.
- 134Sugiyama S, Jinnouchi H, Kurinami N et al. Dapagliflozin reduces fat mass without affecting muscle mass in type 2 diabetes. J Atheroscler Thromb 2018; 25: 467–476. https://doi.org/10.5551/jat.40873.
- 135Yasuda 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. https://doi.org/10.1111/jdi.13137.
- 136Kluess HA. Dipeptidyl peptidase IV as a muscle Myokine. Front Physiol 2020; 11: 148. https://doi.org/10.3389/fphys.2020.00148.
- 137Bouchi R, Fukuda T, Takeuchi T et al. Dipeptidyl peptidase 4 inhibitors attenuates the decline of skeletal muscle mass in patients with type 2 diabetes. Diabetes/Metab Res Rev 2018; 34(2): e2957. https://doi.org/10.1002/dmrr.2957.
- 138Ishii S, Nagai Y, Kato H, Fukuda H, Tanaka Y. 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. https://doi.org/10.14740/jocmr4078.
- 139Rizzo 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. https://doi.org/10.1016/j.jamda.2016.04.016.
- 140Hong Y, Lee JH, Jeong KW, Choi CS, Jun HS. Amelioration of muscle wasting by glucagon-like peptide-1 receptor agonist in muscle atrophy. J Cachexia Sarcopenia Muscle 2019; 10: 903–918. https://doi.org/10.1002/jcsm.12434.
- 141Gurjar AA, Kushwaha S, Chattopadhyay S et al. Long acting GLP-1 analog liraglutide ameliorates skeletal muscle atrophy in rodents. Metab Clin Exp 2020; 103: 154044. https://doi.org/10.1016/j.metabol.2019.154044.
- 142Lambadiari V, Triantafyllou K, Dimitriadis GD. Insulin action in muscle and adipose tissue in type 2 diabetes: the significance of blood flow. World J Diabetes 2015; 6: 626–633. https://doi.org/10.4239/wjd.v6.i4.626.
- 143Ferrari 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. https://doi.org/10.1007/s00592-020-01523-7.
- 144Sugimoto K, Ikegami H, Takata Y et al. Glycemic control and insulin improve muscle mass and gait speed in type 2 diabetes: the MUSCLES-DM study. J Am Med Dir Assoc 2021; 22: 834–838. https://doi.org/10.1016/j.jamda.2020.11.003.
- 145Mele A, Calzolaro S, Cannone G, Cetrone M, Conte D, Tricarico D. Database search of spontaneous reports and pharmacological investigations on the sulfonylureas and glinides-induced atrophy in skeletal muscle. Pharmacol Res Perspect 2014; 2: e00028. https://doi.org/10.1002/prp2.28.
- 146Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiol Rev 2018; 98: 2133–2223. https://doi.org/10.1152/physrev.00063.2017.
- 147Edgerton DS, Scott M, Farmer B et al. Targeting insulin to the liver corrects defects in glucose metabolism caused by peripheral insulin delivery. JCI. Insight 2019; 4(7): e126974. https://doi.org/10.1172/jci.insight.126974.
- 148Araki E, Haneda M, Kasuga M et al. New glycemic targets for patients with diabetes from the Japan diabetes society. J Diabetes Investig 2017; 8: 123–125. https://doi.org/10.1111/jdi.12600.
- 149Bramlage P, Gitt AK, Binz C, Krekler M, Deeg E, Tschöpe D. Oral antidiabetic treatment in type-2 diabetes in the elderly: balancing the need for glucose control and the risk of hypoglycemia. Cardiovasc Diabetol 2012; 11: 122. https://doi.org/10.1186/1475-2840-11-122.
- 150Araki A, Iimuro S, Sakurai T et al. Non-high-density lipoprotein cholesterol: an important predictor of stroke and diabetes-related mortality in Japanese elderly diabetic patients. Geriatr Gerontol Int 2012; 12 (Suppl 1): 18–28. https://doi.org/10.1111/j.1447-0594.2011.00809.x.
- 151Zaslavsky O, Walker RL, Crane PK, Gray SL, Larson EB. Glucose levels and risk of frailty. J Gerontol A Biol Sci Med Sci 2016; 71: 1223–1229. https://doi.org/10.1093/gerona/glw024.
- 152Yau CK, Eng C, Cenzer IS, Boscardin WJ, Rice-Trumble K, Lee SJ. Glycosylated hemoglobin and functional decline in community-dwelling nursing home-eligible elderly adults with diabetes mellitus. J Am Geriatr Soc 2012; 60: 1215–1221. https://doi.org/10.1111/j.1532-5415.2012.04041.x.
- 153Huang ES, Liu JY, Moffet HH, John PM, Karter AJ. Glycemic control, complications, and death in older diabetic patients: the diabetes and aging study. Diabetes Care 2011; 34: 1329–1336. https://doi.org/10.2337/dc10-2377.
- 154 Japan Diabetes Society /Japan Geriatrics Society Joint Committee on Improving Care for Elderly Patients with D. Glycemic targets for elderly patients with diabetes. Geriatr Gerontol Int 2016; 16: 1243–1245. https://doi.org/10.1111/ggi.12986.
- 155Omura T, Tamura Y, Sakurai T et al. Functional categories based on cognition and activities of daily living predict all-cause mortality in older adults with diabetes mellitus: the Japanese elderly diabetes intervention trial. Geriatr Gerontol Int 2021; 21: 512–518. https://doi.org/10.1111/ggi.14171.
- 156Omura T, Ito H, Araki A. Which is a better predictor for adverse events in older adults with diabetes, frailty or higher-level functional incapacity? Geriatr Gerontol Int 2021; 21: 541–542. https://doi.org/10.1111/ggi.14166.
- 157Toyoshima K, Araki A, Tamura Y et al. Development of the dementia assessment sheet for community-based integrated care system 8-items, a short version of the dementia assessment sheet for community-based integrated care system 21-items, for the assessment of cognitive and daily functions. Geriatr Gerontol Int 2018; 18: 1458–1462. https://doi.org/10.1111/ggi.13512.
- 158Toyoshima K, Araki A, Tamura Y et al. Use of dementia assessment sheet for community-based integrated care system 8-items (DASC-8) for the screening of frailty and components of comprehensive geriatric assessment. Geriatr Gerontol Int 2020; 20: 1157–1163. https://doi.org/10.1111/ggi.14057.