SYSTEMATIC REVIEW published: 23 December 2021 doi: 10.3389/fendo.2021.782391 The Association Between Diabetes Mellitus and Risk of Sarcopenia: Accumulated Evidences From Observational Studies Yu-Shun Qiao 1, Yin-He Chai 1, Hong-Jian Gong 1, Zhiyessova Zhuldyz 1, Coen D. A. Stehouwer 2, Jian-Bo Zhou 3* and Rafael Simó 4,5,6 1 Beijing Tongren Hospital, Capital Medical University, Beijing, China, 2 Department of Internal Medicine and Cardiovascular Research Institute Maastricht (CARIM) School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, Netherlands, 3 Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China, 4 Endocrinology and Nutrition Derpartment, Vall d’Hebron University Hospital, Autonomous University, Barcelona, Spain, 5 Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain, 6 Centro de Edited by: Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Paulo Matafome, Carlos III (ICSIII), Madrid, Spain University of Coimbra, Portugal Reviewed by: Hiroyasu Mori, Aim: We performed a meta-analysis of observational studies to evaluate the association Tokushima University, Japan between the presence of sarcopenia and HbA1c, prediabetes, diabetes and diabetic Kei Nakajima, Kanagawa University of Human complications. Services, Japan Method: The PubMed, Embase, Cochrane and Web of Science databases were searched *Correspondence: from inception to May 2021. We included full-text English language articles that reported Jian-Bo Zhou jianbo.zhou@foxmail.com the prevalence of sarcopenia in patients with and without diabetes. Quality assessment was performed according to the Newcastle- Ottawa scale for observational studies. Specialty section: This article was submitted to Results: Sixteen studies were included in the meta-analysis. Three studies showed that Clinical Diabetes, high HbA1c levels lead to loss of muscle mass, and one study involving prediabetes a section of the journal showed that people with prediabetes had lower muscle mass, strength, and performance Frontiers in Endocrinology than non-diabetic population. Seven studies showed that people with diabetes had a Received: 01 October 2021 Accepted: 17 November 2021 higher risk of sarcopenia than those without diabetes (combined OR: 2.09, 95% CI:1.62- Published: 23 December 2021 2.70). The remaining five studies suggested that diabetic complications increased the risk Citation: of sarcopenia (combined OR: 2.09,95% CI:1.62-2.70). Qiao Y-S, Chai Y-H, Gong H-J, Zhuldyz Z, Stehouwer CDA, Zhou J-B Conclusion: High HbA1c levels, prediabetes, diabetes and diabetes complications were and Simó R (2021) The Association associated with an increased risk of sarcopenia. Therapeutic strategies addressed to Between Diabetes Mellitus and Risk of Sarcopenia: Accumulated Evidences avoid the conversion of IGT to diabetes and to optimize glycemic control are warranted to From Observational Studies. prevent or arrest sarcopenia in the diabetic population Front. Endocrinol. 12:782391. doi: 10.3389/fendo.2021.782391 Keywords: sarcopenia, HbA1c, prediabetes, diabetic complications, diabetes mellitus, observational study Frontiers in Endocrinology | www.frontiersin.org 1 December 2021 | Volume 12 | Article 782391 Qiao et al. Diabetes Mellitus and Risk of Sarcopenia INTRODUCTION glucose ≥11.1 mmol/L during an oral glucose tolerance test (OGTT), according to World Health Organization (WHO) 1999 The term sarcopenia refers to the loss of muscle mass, muscle criteria. Prediabetes was defined as having 6.1 and 7.0mmol/L with strength or physical function that occurs with aging. Sarcopenia or without a 2-hour OGTT between and 11.1mmol/L. The is an emerging health concern that mainly affects the quality of diagnostic criteria for sarcopenia and involved muscle mass life of older people and is an underlying factor for falls, fractures, measured by dual X-ray absorptiometry (DXA) or bioelectrical deaths and a series of adverse events (1–3). Therefore, early impedance analysis (BIA), in accordance with Asian Working identification is crucial for implementing appropriate preventive Group for Sarcopenia (AWGS), European Working Group on actions and studying its pathogenesis and influencing factors, Sarcopenia in Older People (EWGSOP), or Foundation for the such as aging (4), obesity (5), cancer (6) and other diseases (7, 8). NIH (FNIH) diagnostic criteria. Diabetes has been reported as an influencing factor for sarcopenia (9). When insulin resistance occurs in skeletal Study Selection muscles, glucose utilization and protein synthesis are reduced, The inclusion criteria for the selected articles were as follows: which, in turn, aggravates insulin resistance and muscle loss, thus (1) the included study subjects were older than 60 years; (2) the evolving into a vicious circle (10, 11). According to statistics from prevalence of sarcopenia in the diabetic, prediabetic, and non- a systematic literature review, up to 70% of adults with diabetes diabetic groups was calculated; (3) type of diabetes mellitus was have difficulty performing routine physical tasks, with lower T2DM; (4) low muscle mass was considered for the extremity mobility limitations particularly evident (12). indispensable diagnosis of sarcopenia; (5) research design Further, literature shows that many previous studies (13) have belonged to observational (cross-sectional or case–control or suggested that patients with diabetes have a significantly cohort) studies (6) extractable data was available on sarcopenia increased risk of sarcopenia. However, it is unknown whether in adults with diabetes or prediabetes and euglycemic subjects. this relationship is also present in subjects with prediabetes. In The exclusion criteria for selected articles were as follows: addition, the role of glycemic control and diabetic complications (1) control group (euglycemic subjects) was not set up; remains to be elucidated. Therefore, we conducted a meta- (2) reviews, letters or conference abstracts; (3) repeat publications; analysis of the literature to study the relationship between (4) studies that were not written in English; (5) individuals with sarcopenia and diabetes, prediabetes, glycemic control and severe diabetes and complications who are unable to walk or lack diabetic complications. activity capability; (6) participants with acute disease, history of stroke, myocardial infarction or cancer; (7) individuals aged >85 years, severe heart failure (New York Heart Association Class II- METHOD IV), or had severe liver impairment (liver enzyme ALT≥3-fold the upper limit of normal range), severe renal dysfunction (estimated Search Strategy glomerular filtration rate [eGFR]<30 mL/min/1.73m2), or a history This meta-analysis followed the Preferred Reporting Items for of thyroid or adrenal diseases, were also excluded. Systematic Reviews and Meta-Analysis guidelines. We There were a few exceptions that should be explained here: systematically searched for relevant literature in the PubMed, (1) the study of Sambashivaish was on the association between Embase, Cochrane and Web of Science databases for studies prediabetes and sarcopenia. Hence, we did not limit our age to published from inception to May 2021. The following items over 60 years. (2) while the mean age of participants was lesser (single or combined) were included in the search strategy: (44.3 ± 9.4 years) in Anbalagan’s study, there was a age and sex sarcopenia, skeletal muscle, muscle mass, muscle strength, match between the test group and control group. Therefore, the physical performance, gait speed, hyposthenia, grip strength, literature is involved in this study. diabetes, diabetes mellitus, hemoglobin a1c, impaired fasting glucose, impaired glucose tolerance and prediabetes. The studies Data Extraction and Quality Assessment were based on patients with type 2 diabetes mellitus (T2DM), The following data were extracted: (1) first author (2) publication rather than type 1 diabetes mellitus (T1DM) or other special types year (3) country (4) study design (5) the basic information of of diabetes. Each study was required to consider essential variables, participants (total number, mean age and proportion of female) (6) such as age (years), sex (% male), duration of diabetes (years) and the number of participants with diabetes, diabetes complications or body mass index (kg/m²). The reference lists of all retrieved prediabetes and control group subjects (7) the prevalence rate of articles were manually reviewed. Two independent authors sarcopenia. Quality assessment was conducted by using The (YHC and independently) analyzed each article and performed Newcastle-Ottawa scale (NOS), including three aspects of data extraction. A third investigator consulted (xx) in cases of assessment: selection of subjects, comparability and assessment of disagreement. Discrepancies were resolved by consensus. outcomes. NOS allows four stars for subject selection, two stars for comparability, and three stars for outcomes assessment, therefore, a Diagnostic Criteria study can get up to nine stars. The quality of each study was graded This study only discussed the association between sarcopenia and as low (0–3), moderate (4–6), or high (7–9). Two independent T2DM rather than other types diabetes mellitus. T2DM was researchers respectively did quality assessments, and a third diagnosed as having fasting blood glucose measurement researcher rescored the different results. Differences were resolved (FPG≥7.0 mmol/L) with or without 2-hour postprandial blood by consensus. Frontiers in Endocrinology | www.frontiersin.org 2 December 2021 | Volume 12 | Article 782391 Qiao et al. Diabetes Mellitus and Risk of Sarcopenia Statistical Analyses aged <60 years (OR=3.21, 95% CI: 1.77—5.85, I²=0%) than in those We analyzed and pooled Odd Ratios and 95% Confidence Intervals aged ≥60 years (OR 1.69, 95% CI: 1.03—2.78, I²=70.6%). After of the association between sarcopenia and diabetes or diabetes removing studies one by one, the sensitivity analysis conclusively complications from the raw prevalence data, respectively. The ORs showed that patients with diabetes had a significantly higher risk of of the relationship between sarcopenia and diabetes complications sarcopenia than patients without diabetes. were calculated by adjusting for confounding factors and other diabetes complications, such as age, sex, and hypertension, to Systemic Review of the reduce the interaction between various diabetes complications. The Association Between HbA1c and ORs and 95%CIs were converted into the natural logarithm (ln OR) the Risk of Sarcopenia and standard error values. Heterogeneity testing was evaluated using Three studies (14–16) mentioned the relationship between the I² statistic, and a fixed effects model was applied when different HbA1c levels and the risk of sarcopenia. heterogeneity was small (I² ≤50%); otherwise, a random effects Unfortunately, we could not combine their data because of the model was used. Funnel plots were used to assess the potential for different grouping standards. The first study (14) showed that publication bias. However, to avoid the possible impact of visual men with class 1 sarcopenia (6.87< appendicular muscle mass perception, Egger’s test was conducted to assess publication bias (AMM)/height²<7.77 kg/m2) had higher levels of HbA1c than more accurately (P-values <0.1 indicated that there was no patients with normoglycemia. However, this association was not publication bias). To explore the source of heterogeneity, subgroup significant among women. In the second study (15), regardless analyses were used to evaluate age (<60 and ≥60 years), types of sex, sarcopenia was positively correlated with HbA1c levels in diabetes vascular disease (microvascular and macrovascular), and subjects with T2DM. In addition, the authors reported that types of diabetes complications (diabetic nephropathy, diabetic foot, HbA1c levels were associated with low muscle mass rather diabetic retinopathy and diabetic neuropathy). A sensitivity analysis than low muscle strength and performance. The third study was used to evaluate the robustness of the meta-analysis results. All (16) reported a negative relationship between HbA1c levels, analyses were performed using Stata 12.0 software (StataCorp LP, muscle mass, and performance in patients with T2D, which TX). Statistical significance was set at P <0.05. was more evident when the HbA1c level was ≥8.5%. Overall, these studies confirmed the association between high HbA1c levels and sarcopenia. RESULTS Systemic Review of the Association Literature Search Outcomes Between Prediabetes and the Risk and Validity Assessment of Sarcopenia The search strategy identified 2,331 potentially relevant records, Only one study (17) focused on the association between from multiple scientific studies and 713 were excluded as prediabetes and the risk of sarcopenia. The participants in the duplicates. The remaining manuscripts were searched for study were all male, with ages ranging from 20 to 50 years. The screening the title and abstract, and 1,559 publications were study showed that subjects with prediabetes presented lower excluded because they were reviews, letters, or conference muscle mass, strength, and performance than non-diabetic abstracts. Thus, 59 articles were eligible for full-text review and subjects, suggesting that prediabetes is closely associated with data assessment. Finally, 16 studies (14–29) were included in the the risk of sarcopenia. current meta-analysis and systemic review. Among those publications, three (14–16) mentioned the relationship between Meta-Analysis of the Association Between HbA1c and sarcopenia, one (17) mentioned prediabetes, seven Diabetes Complications and the Risk (18–24) mentioned diabetes, and five (25–29) mentioned of Sarcopenia diabetes-related complications, (Figure 1). The characteristics A total of five studies (25–29) (n=3286 participants, females: of studies included were shown in Table 1. The total sample size 46.4%) were included. The combined OR of the relationship in 16 studies was 15,326, and all participants were >18 years old. between diabetes complications and the risk of sarcopenia was All studies included control groups. 2.09 (95% CI:1.62–2.70, I²=0%, P=0.467). This increased risk was maintained when microangiopathic and macroangiopathic Meta-Analysis of the Association Between complications were analyzed separately (Figure 2C, Table 2). Diabetes and the Risk of Sarcopenia The subgroup of diabetic complications (Figure 2D) showed that Seven studies (18–24) (n=6,783 participants, female: 52.7%) were individuals with diabetic retinopathy had a higher significant risk included. The random effect model was used according to the I2. than patients with diabetes without diabetic retinopathy, and the The combined OR was 1.95 (95% CI: 1.24–3.06, I²=69.3%, P=0.002), OR of diabetic retinopathy was 4.88 (95% CI:1.85—12.86). More showing that patients with diabetes have a significantly higher risk importantly, proliferative diabetic retinopathy increased the risk of sarcopenia than patients without diabetes (Figure 2A). of sarcopenia than non-proliferative diabetic retinopathy; the ORs The results of the subgroup analysis (Figure 2B) showed that the were 7.78 (95% CI: 1.52—39.81) and 3.79 (95% CI: 1.14—12.62), relationship between diabetes and the risk of sarcopenia was subject respectively. Patients with diabetic nephropathy (OR=2.89, 95% to age. Surprisingly, the risk of sarcopenia was higher in the patients CI: 1.11—7.52) or neuropathy (OR=1.71, 95% CI: 1.16—2.53) Frontiers in Endocrinology | www.frontiersin.org 3 December 2021 | Volume 12 | Article 782391 Qiao et al. Diabetes Mellitus and Risk of Sarcopenia FIGURE 1 | PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) study. also had a higher prevalence of sarcopenia. After removing studies distinguish real asymmetry from coincidence. In this study, the one by one, the sensitivity analysis suggests that patients with P-value of the Egger test was >0.05 (P = 0.227) for the diabetic complications have a significantly higher risk of relationship between diabetes and the risk of sarcopenia, sarcopenia than patients with diabetes without complications. indicating no significant bias. The funnel figure of these studies showed a symmetrical inverted distribution, which is consistent Quality Assessment with the results of the Egger test (Supplementary Figure 1). Quality assessment of the studies revealed scores of 6–9 on the NOS (30). Two studies scored 6, five were scored 7, seven were scored 8, and two were scored 9. Thus, high-quality studies were DISCUSSION included in this meta-analysis (Supplementary Table 1). In this systematic review and meta-analysis, we included 16 Publication Bias studies to analyze the relationship between diabetes and According to the Cochrane Handbook (31), as a rule of thumb, sarcopenia. The results showed that the presence of diabetes, tests for funnel plot asymmetry should be used only when there poor glycemic control, and related chronic complications are enough studies, included in the meta-analysis because when significantly increased the risk of sarcopenia. In addition, a there are fewer studies, the power of the tests is too low to relationship between prediabetes and sarcopenia was observed. Frontiers in Endocrinology | www.frontiersin.org 4 December 2021 | Volume 12 | Article 782391 Frontiers in Endocrinology | www.frontiersin.org Qiao et al. TABLE 1 | Characteristics of the included studies. ID First author, Country Study Mean Diabetes HbA1c Definition of sarcopenia Sarcopenia Method of Diabetic Therapy of dia- Participants Females Subjects with Sarcopenia in Subjects without Sarcopeniain Prevalence of sarcopenia Year of design age duration level diagnostic measuring complications betes (n) (%) exposure factors subjects with exposure factors subjects without in exposure factor (%) publication (years) (years) (%) criteria skeletal (n) exposure factors (n) exposure factors muscle (n) (n) mass 1. Sanada (14) Japan cross- 65 NA 5 Low muscle mass Self-definition DXA Not reported NA 168 0 NA NA NA NA NA sectional 2. Sugimoto (15) Japan cross- 68.7 Low muscle mass, strength AWGS BIA Insulin or oral 2813 NA NA NA NA NA sectional and physical performance diabetic medication 3. Yoon (16) Korea Case- 74.5 Low muscle mass, strength AWGS DXA 269 0 NA NA NA NA NA control and physical performance 4. Sambashivaish India Case- 39.2 ± 3.0 ± 1.5 Low muscle mass, strength AWGS DXA 169 0 44 125 (17) control 10.8 5. Anbalagan (18) India Case- 44.3 ± 4 ± 1.2 Low muscle mass EWGSOP DXA no Insulin or oral 152 44.7 76 30 76 12 39.5 control 9.4 diabetic medication 6. Bouchi (19) Japan Cross- 64.8 ± 7.1 Low muscle mass, strength AWGS DXA 249 38.3 208 28 41 4 13.3 sectional 9.7 7. Kim (20) Korea Case- 70.5 ± 10.7 ± 8.8 8.2 ± Low muscle mass ASM/Ht2, ASM/ DXA no Insulin or oral 189 0 59 34 130 54 57.6 control 4.3 2.0 Wt, TSM/Wt diabetic medication 8. Kim (20) Korea Case- 70.9 ± 13.0 ± 8.9 8.5 ± Low muscle mass ASM/Ht2, ASM/ DXA no Insulin or oral 225 100 85 6 140 12 7.1 control 5.4 2.3 Wt, TSM/Wt diabetic 5 medication 9. Lim (21) Korea Cross- 68.8 ± Low muscle mass DXA 3492 47 340 137 40.3 sectional 8.2 10. Mori (22) Japan Cohort 58.1 ± Not reported Not Low muscle mass, strength AWGS DXA 308 40 101 51 207 73 50.5 11.9 reported 11. Souza (23) Brazil Case- 74.8 ± Not reported Low muscle mass, strength EWGSOP Insulin or oral 1078 79.2 245 35 833 66 14.2 control 11.4 and physical performance diabetic medication 12. Wang (24) China Cross- 69.1 ± Low muscle mass, strength AWGS BIA Insulin or oral 1090 52.3 236 35 854 96 14.8 sectional 7.2 and physical performance diabetic medication 13. Celiker (25) Turkey Cross- 60.9 ± 10.0 ± 7.3 Low muscle mass, strength EWGSOP BIA Diabetic Not reported 103 64.8 50 17 53 8 34 December 2021 | Volume 12 | Article 782391 Sectional 6.9 and physical performance nephropathy 14. Cheng (26) China Cross- 64.6 ± Not reported Low muscle mass AWGS DXA Diabetic foot Not reported 1105 42.8 120 42 985 162 35.3 Diabetes Mellitus and Risk of Sarcopenia Sectional 9.6 15. Fukuda (27) Japan Cross- 63.4 Low muscle mass, strength AWGS DXA Non-proliferative Insulin or oral 299 62.5 38 261 Sectional diabetic diabetic retinopathy medication 16. Fukuda (27) Japan Cross- 63.5 Low muscle mass, strength AWGS DXA Proliferative Insulin or oral 278 62.2 17 261 Sectional diabetic diabetic retinopathy medication 17. Yang (28) China Cross- 64.7 Low muscle mass Baumgartner DXA Diabetic foot Not reported 1361 42 257 91 1104 204 35.4 Sectional diagnostic criteria (Continued) Qiao et al. Diabetes Mellitus and Risk of Sarcopenia Prevalence of sarcopenia in exposure factor (%) Previous studies reported a harmful influence of diabetes on 20.5 24.7 sarcopenia, which was based on studies showing that muscle mass, strength, and performance were significantly lower in patients with diabetes than in non-diabetic controls (32–35). exposure factors However, few studies have examined whether there is a subjects without Sarcopeniain difference in the risk of sarcopenia among patients with (n) 41 8 diabetes, taking into account crucial variables such as the degree of glycemic control and the presence of long-term exposure factors Subjects without diabetic complications. Therefore, a novel contribution of this systematic review is its demonstration that poor glycemic 308 (n) 90 control, assessed by HbA1c level, is an additional risk factor for the development or progression of sarcopenia among patients exposure factors Sarcopenia in subjects with with diabetes. Although HbA1c reflects glycemic control in the 163 127 (n) previous 2–3 months (11), daily glycemic control is also very important. According to reports, large daily glycemic fluctuations also increased the risk of muscle loss (OR=1.045) exposure factors Subjects with (36), which suggests that both short-and long-term blood 796 512 (n) glycemic control should be emphasized. Whether poor glycemic control is related to both muscle loss, Females muscle strength, and performance remains an open question. 59.5 (%) Three studies (14–16) using either body mass index, skeletal Participants mass index (SMI), or appendicular skeletal muscle mass as 1104 602 (n) measurements of muscle mass, showed that poor glycemic control was closely associated with the loss of muscle mass Therapy of dia- rather than the loss of muscle strength and performance. In Insulin or oral Not reported betes medication contrast, in the Baltimore Longitudinal Study of Aging, knee diabetic extensor strength was lower across increasing quartiles of HbA1c (37). The differences in race, sample size, and assessment complications Diabetic methods can explain the divergent results. Therefore, larger neuropathy neuropathy Diabetic Diabetic studies using uniform methods to evaluate muscle morphology and function are needed. measuring Method of skeletal muscle mass Muscle mass and prediabetes are likely to have bidirectional DXA BIA relationships. In a cross-sectional analysis of the National Health and Nutrition Examination Survey from the United States, after Sarcopenia diagnostic Baumgartner criteria diagnostic EWGSOP adjusting for multiple confounding factors, each 10% increase in criteria SMI was associated with a 12% relative reduction in prediabetes prevalence (95% CI, 1%—21%) (38). These results suggest that Low muscle mass, strength Definition of sarcopenia muscle mass is inversely proportional to the risk of prediabetes. Low muscle mass Since glucose levels are only slightly impaired in the prediabetic stage, it could be postulated that the pathways activated by insulin resistance, rather than those activated by chronic hyperglycemia, are meaningful in the development of sarcopenia. HbA1c level (%) A clear influence of diabetic complications was found on the risk of sarcopenia. In this regard, we would like to emphasize that Diabetes duration (years) diabetic retinopathy and diabetic nephropathy tend to coexist and can synergistically increase the risk of sarcopenia. In 64.35 ± (years) 60.2 ± Mean addition, although previous studies (39–41) have mostly 9.32 10.6 age analyzed the association between one or two complications of Sectional Sectional design Study diabetes and sarcopenia, compared with patients without Cross- Cross- diabetic complications, each type of complication will TABLE 1 | Continued Country significantly increase the risk of sarcopenia which is consistent Turkey China with our findings. NA, not applicable. First author, In the age-based subgroup analysis (< 60 years group and ≥60 publication Yasemin (29) Year of Yang (28) years group), the results indicated that the risk of sarcopenia in patients with diabetes aged < 60 years (OR: 3.21, 95% CI: 1.77— 18. 19. 5.85) was higher than that in patients with diabetes that are aged ID Frontiers in Endocrinology | www.frontiersin.org 6 December 2021 | Volume 12 | Article 782391 Qiao et al. Diabetes Mellitus and Risk of Sarcopenia FIGURE 2 | (A) Meta-analysis of the association between diabetes and the risk of sarcopenia. (B) Subgroup analysis of the association between diabetes and the risk of sarcopenia according to age. (C) Subgroup analysis of the association between diabetes complications and the risk of sarcopenia according to diabetic vascular disease. (D) Subgroup analysis of the association between diabetes complications and the risk of sarcopenia according to different diabetic complications. OR, odds ratio; CI, confidence interval. Where I2 is the variation in effect estimates attributable to heterogeneity, overall is the pooled random/fixed effect estimate of all studies. subtotal is the pooled random effects estimate of sub-group analysis studies. Weights are from random-effects analysis. %Weight is the weight assigned to each study, based on the inverse of the within- and between-study variance. The size of the grey boxes around the point estimates reflects the weight assigned to each study. ≥60 years (OR: 1.69, 95% CI: 1.03—2.78). However, this does not participants with diabetes aged ≥ 60 years (108 males and 105 mean that as age increases, patients with diabetes have a lower risk females), the prevalence of sarcopenia was 19.2% and the risk of of sarcopenia. First, age is a common risk factor for diabetes and sarcopenia increased with longer duration of diabetes in women sarcopenia. With age, insulin resistance becomes more common (OR = 1.43) (45). Finally, few studies on patients with diabetes (9) and the ability of insulin to stimulate protein synthesis aged <60 years were included, which may have induced bias. gradually weakens (42). Ageing is accompanied by major The mechanisms involved in the association between diabetes changes in body composition, including a gradual decrease in and the risk of sarcopenia need to be fully elucidated, but some muscle mass, strength, and performance, which can markedly pathophysiological explanations have been provided. First, affect the daily activities of older adults (43, 44). Second, older age insulin resistance, through inhibition of the mTOR pathway tends to be accompanied by a longer duration of diabetes, (46), activation of autophagy (46), activation of the ubiquitin- although this is not absolute. In a study from Japan on proteasome proteolytic pathway (47), and accelerated muscle protein degradation may cause sarcopenia. Second, poor blood glucose control causes many metabolic abnormalities (10), such TABLE 2 | The OR values and 95%CI of diabetic complications. as the activation of apoptosis triggered by TNF-a (48) and Types of diabetic complications OR value and 95%CI impaired muscle mitochondrial oxidative capacity (49), thereby contributing to muscle cell damage (10). Third, repeated Diabetic microangiopathic complications 2.08 (1.48-2.92) episodes of ischemia-reperfusion caused by vascular Diabetic macroangiopathic complications 2.11 (1.44-3.10) complications are a common pathway for muscle loss (50). Diabetic nephropathy 2.89 (1.11-7.52) Diabetic foot 2.11 (1.44-3.10) Finally, in diabetic neuropathy, loss of motor neurons (51) or Diabetic retinopathy 4.88 (1.85-12.86) imbalance between denervation and reinnervation (51) can Diabetic neuropathy 1.71 (1.16-2.53) induce loss of muscle mass and strength. Frontiers in Endocrinology | www.frontiersin.org 7 December 2021 | Volume 12 | Article 782391 Qiao et al. Diabetes Mellitus and Risk of Sarcopenia In this study, some clinical issues were worthy of attention. In DATA AVAILABILITY STATEMENT the prediabetes stage, it is crucial to reduce the risk of impaired glucose tolerance (IGT) progressing towards overt diabetes; The original contributions presented in the study are included in therefore, lifestyle interventions are strongly recommended. In the article/Supplementary Material. Further inquiries can be this regard, a clinical trial conducted in the U.S. (2.8 years of directed to the corresponding author. follow-up) showed that lifestyle intervention reduced the incidence of diabetes by 58% (95% CI: 48%—66%) in comparison with placebo (52). In addition, treatment with ETHICS STATEMENT metformin and acarbose has a positive effect on reducing the risk of conversion from IGT to diabetes (52, 53). In patients with This article does not contain any studies with human diabetes and sarcopenia, tight control of blood glucose levels is participants or animals performed by any of the authors. recommended, and for this reason, monitoring HbA1c levels and blood glucose monitoring should be strengthened. The strength of this meta-analysis is that many factors associated with the risk of sarcopenia were considered, thus providing a more AUTHOR CONTRIBUTIONS comprehensive analysis of the factors affecting sarcopenia. YQ contributed the interpretation of data, and drafting the However, this study has certain limitations. First, due to the report. ZZ contributed to statistical analysis, interpretation of statistical difference in age and duration of diabetes between data. YC and HG contributed the re-analysis, interpretation of groups in some included studies, we cannot adequately consider data. J-BZ and RS contributed to study design and review. CS these two variables, as they may cause bias in the results of this study. revised the manuscript. J-BZ is the guarantor of this work and, as Second, data in some studies did not consider the influence of such, had full access to all the data in the study and takes confounding factors, such as the severity of diabetes complications responsibility for the integrity of the data and the accuracy of the and the ranges of HbA1c and interactions among diabetes data analysis. All authors contributed to the article and approved complications, which may have led to an overestimation of the the submitted version. study results. Third, although it had been meta-analyzed using multiple sarcopenia diagnostic criteria (AWGS, EWGSOP, FNIH criteria), the diagnostic criteria for sarcopenia also included observational studies measured by BIA. Fourth, the number of FUNDING studies included in the subgroup analysis was relatively small, which may have caused false-negative results. Finally, the participants in This work was supported by the National Natural Science many studies were not from the community but from the hospital, Foundation of China (No. 82070851, 81870556), Beijing which may have resulted in lack of representativeness. In the future, Municipal Administration of Hospitals’ Youth Program more studies should be conducted to address these shortcomings. (QML20170204), Excellent Talents in Dongcheng District In conclusion, high HbA1c levels, prediabetes, diabetes, and of Beijing. diabetes complications were significantly associated with an increased risk of sarcopenia. Whether these associations are further affected by age, sex and duration of diabetes complications needs to be SUPPLEMENTARY MATERIAL tested in more prospective cohort studies. Meanwhile, therapeutic strategies aimed at avoiding the conversion of IGT to diabetes and The Supplementary Material for this article can be found online at: optimizing glycemic control seem to be the best way to prevent or https://www.frontiersin.org/articles/10.3389/fendo.2021.782391/ arrest sarcopenia in the diabetic population. full#supplementary-material 5. Waters DL, Baumgartner RN. Sarcopenia and Obesity. Clinics Geriatric Med REFERENCES (2011) 27(3):401–21. doi: 10.1016/j.cger.2011.03.007 1. Woo J, Leung J, Morley JE. Defining Sarcopenia in Terms of Incident Adverse 6. Dodson S, Baracos VE, Jatoi A, Evans WJ, Cella D, Dalton JT, et al. Muscle Outcomes. J Am Med Directors Assoc (2015) 16(3):247–52. doi: 10.1016/ Wasting in Cancer Cachexia: Clinical Implications, Diagnosis, and Emerging j.jamda.2014.11.013 Treatment Strategies. Annu Rev Med (2011) 62:265–79. doi: 10.1146/ 2. Beaudart C, Zaaria M, Pasleau F, Reginster JY, Bruyère O. 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Skeletal Muscle Insulin Resistance Is the Primary and do not necessarily represent those of their affiliated organizations, or those of Defect in Type 2 Diabetes. Diabetes Care (2009) 32(Suppl 2):S157–63. the publisher, the editors and the reviewers. Any product that may be evaluated in doi: 10.2337/dc09-S302 this article, or claim that may be made by its manufacturer, is not guaranteed or 50. Buford TW, Anton SD, Judge AR, Marzetti E, Wohlgemuth SE, Carter CS, endorsed by the publisher. et al. Models of Accelerated Sarcopenia: Critical Pieces for Solving the Puzzle of Age-Related Muscle Atrophy. Ageing Res Rev (2010) 9(4):369–83. Copyright © 2021 Qiao, Chai, Gong, Zhuldyz, Stehouwer, Zhou and Simo.́ This is an doi: 10.1016/j.arr.2010.04.004 open-access article distributed under the terms of the Creative Commons Attribution 51. Campbell MJ, McComas AJ, Petito F. Physiological Changes in Ageing License (CC BY). The use, distribution or reproduction in other forums is permitted, Muscles. J Neurol Neurosurg Psychiatry (1973) 36(2):174–82. doi: 10.1136/ provided the original author(s) and the copyright owner(s) are credited and that the jnnp.36.2.174 original publication in this journal is cited, in accordance with accepted academic 52. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker practice. No use, distribution or reproduction is permitted which does not comply with EA, et al. Reduction in the Incidence of Type 2 Diabetes With Lifestyle these terms. Frontiers in Endocrinology | www.frontiersin.org 10 December 2021 | Volume 12 | Article 782391