Correlation between sarcopenia-related traits and type 2 diabetes mellitus

To the Editor: Sarcopenia, age-associated wasting of skeletal muscle mass (SMM) and function, is an independent medical condition according to the International Classification of Diseases. The prevalence of sarcopenia varies from 5% to 50% owing to different definitions and populations and is expected to significantly increase over the next 30 years owing to the progressive increase in life expectancy. Sarcopenia is associated with a high risk of postoperative complications, low survival rate, longer hospital stays, dysphagia, and physical disability at hospital discharge. Existing research on the causal relationship between sarcopenia and type 2 diabetes mellitus (T2DM) has yielded conflicting outcomes. First, the results of studies that included hemoglobin A1c (HbA1c), an important tool for assessing glycemic control, remain inconsistent.[1,2] Second, when exploring the relationship between sarcopenia and T2DM, potential confounding factors should be considered as comprehensively as possible. In addition to physical activity, whether smoking status, socioeconomic status, or education play a role in the relationship remains unknown. Third, it is difficult to determine the relationship through observational studies due to inevitably confounding factors and reverse causation. Most studies have focused on the causal relationship between sarcopenia and T2DM, while sarcopenia-related traits have been poorly investigated. Given the paucity of effective medical treatment and poor outcomes of sarcopenia, assessing the causal relationship between sarcopenia-related traits and T2DM may help in developing new techniques for T2DM prevention, diagnosis, and treatment. This study aimed to (1) identify the potential correlations between sarcopenia-related traits and the incidence of T2DM within the UK Biobank (UKB); and (2) explore the underlying mechanisms through mediation analysis. The study data were derived from the UKB. This study was conducted using the UKB resource under application number 106397. Fifteen possible risk factors that are associated with both sarcopenia and T2DM have been previously reported by preliminary statistical analysis. Supplementary Figure 1, https://links.lww.com/CM9/C399 presents a flowchart of the study. Overall, 427,810 participants were included. After excluding participants without T2DM and HbA1c ≥6.5% in the baseline, 427,138 participants were included in the principal analysis. For the secondary analysis of the relationship between sarcopenia-related traits and T2DM, we excluded participants without T2DM history and HbA1c between 5.7% and 6.4% at baseline. Participants included in the secondary analysis were followed up until the T2DM event. When no T2DM was reported, a follow-up was censored at the data extraction date (November 2nd, 2023). The European Working Group on Sarcopenia in Older People criteria[3] were applied to classify the participants into four subgroups: non-sarcopenic group (normal handgrip strength [HGS], normal skeletal muscle index [SMI]), low HGS group (low HGS and normal SMI), low SMI group (normal HGS and low SMI), and group with sarcopenia (low HGS and SMI). Cox regression analysis was used to determine the relationship between sarcopenia-related traits and T2DM. For Cox regression, Model a was not adjusted. Model b was adjusted for sociodemographic factors and socioeconomic status, and Model c included all variables in Model b and lifestyle (body mass index [BMI], smoking status, physical activity, cereal intake, protein intake). Model d included all variables in Model c, high-density lipoprotein cholesterol (HDL), and triglyceride (TG). Additionally, mediation analysis was used to assess the mediation effect of BMI and Townsend deprivation index (TDI) on the relationship. Statistical analyses were performed using SPSS (version 27.0, SPSS Inc., Chicago, USA), and forest plots were constructed using GraphPad Prism (version 8.0, GraphPad, San Diego, CA, USA). All tests were two-sided, and statistical significance was set at P <0.05. The characteristics of the study population are summarized in Supplementary Table 1, https://links.lww.com/CM9/C399. The prevalence of low HGS, low SMI, and sarcopenia among participants with T2DM and without T2DM at baseline was 9.9% (2183/21,985) and 6.6% (26,867/405,825), respectively. Patients with T2DM at follow-up were more prone to be with poor HGS, low SMI, and sarcopenia at baseline. Supplementary Figure 2, https://links.lww.com/CM9/C399 shows the forest plots of the subgroup analysis between the risk factors and sarcopenia-related traits. Poor lifestyle, female, old age, low education, low household income, and high deprivation index were associated with sarcopenia-related traits. The significant confounders were further analyzed through Cox regression. We excluded 21,985/427,810 (5.1%) patients with previously diagnosed diabetes and 68,793/427,810 (16.1%) patients with prediabetes. Over a median follow-up of 15.0 years, 6577 participants were newly diagnosed with T2DM. The participants with T2DM at the follow-up had a moderately higher muscle mass at baseline than those without T2DM (8.50 [1.57] Kg/m2vs. 7.72 [1.52] Kg/m2). After adjusting for potential confounders, the hazard ratios (HR) of T2DM incidence for low HGS, decreased SMI, and sarcopenia in Model d were 1.39 (95% confidence interval [CI], 1.26–1.53), 1.40 (95% CI, 1.11–1.75), and 1.73 (95% CI, 1.04–2.87), respectively [Figure 1]. Participants with sarcopenia were nearly twice as likely to develop T2DM as those without sarcopenia.Figure 1: Relationship between sarcopenia-related traits and T2DM. a: Model a was not adjusted; b: Model b was adjusted for age, sex, average total house size, education, and deprivation; c: Model c was ajusted for factors included all variables in model b and life style (BMI, smoking status, physical activity, cereal intake, protein intake); d: Model d included all variables in model c, high-density lipoprotein cholesterol (HDL) and triglyceride (TG). BMI: Body mass index; HGS: Handgrip strength; SMI: Skeletal muscle index; TDI: Townsend deprivation index; T2DM: Type 2 diabetes mellitus.TDI and BMI were found to be associated with the risk of T2DM and were further studied for their mediation effects. Mediation analysis revealed that the links between sarcopenia-related traits and T2DM are partially mediated by the TDI and BMI [Figure 1]. BMI management could prevent patients with low HGS or low SMI from developing T2DM. In the subgroup analyses and sensitivity analyses, similar conclusions regarding the causal relationship between sarcopenia-related traits and T2DM were drawn among 184,644 women [Supplementary Figure 3A, https://links.lww.com/CM9/C399] and 336,137 participants after excluding the cases in the first two years [Supplementary Figure 3B, https://links.lww.com/CM9/C399]. This study explored the causal relationships between sarcopenia-related traits and T2DM in a sizeable, credible, and complex cohort. We reported significant positive associations between sarcopenia-related traits and T2DM. Even after adjusting for sociodemographic factors, socioeconomic status factors, and lifestyles, the associations were still significant. Individuals with low HGS, low SMI, and sarcopenia exhibited a 1.39-, 1.40-, and 1.73-fold increased risk of T2DM, respectively. This result was similar to that of meta-analyses that showed that sarcopenia was associated with two-fold higher risk of having diabetes.[4] With alterations in glucose tolerance, elevated blood insulin levels, and localized inflammation, sarcopenia has become a causal risk factor for T2DM.[5] When exploring the relationship between sarcopenia and T2DM, potential confounding factors have been considered. Physical exercise, BMI, age, and sex are well-known factors and have been previously reported. The impact of HbA1c level on the relationship between sarcopenia and T2DM was inconsistent in previous studies. Most studies evaluated the impact of HbA1c level on sarcopenia, and the results are inconsistent. In a multicenter study, poor glycemic control in patients with T2DM without obesity was associated with decreased muscle mass rather than weak grip strength.[1] In a Korean longitudinal study, HbA1c ≥8.5% was associated with poor lower limb muscle strength and physical performance in men aged ≥65 years with T2DM.[2] This study showed that HbA1c level could influence the causal relationship between sarcopenia and T2DM. When individuals with prediabetes were included in the prospective study, the causal relationship between sarcopenia and T2DM disappeared. The first reason for this discrepancy may be the limited number of patients with sarcopenia in previous studies. Second, the prevalence of sarcopenia among the patients with T2DM in this study was lower than the reported 15.7–29.3% in older adults. Third, physical activity, which plays an important role in the relationship between HbA1c and sarcopenia, was not fully considered in previous studies. In the prediabetic stage, other factors may play a more important role in the development of T2DM than sarcopenia, such as BMI. Previous studies have evaluated the influence of BMI on T2DM. Previous studies suggested that BMI is a potential overadjustment in the causal relationship. Our findings from the mediation analysis suggested that BMI has mediating effects on the relationship between different sarcopenia-related traits and T2DM. More efforts should be devoted to BMI management to prevent patients with different sarcopenia-related traits from developing T2DM. Compared with individuals without T2DM in the follow-up period, those prone to developing T2DM had a higher muscle mass at baseline. Muscle metabolic disorders may exist in individuals prone to T2DM even before abnormal glucose metabolism. Myosteatosis may be a key reason for higher appendicular muscle mass at baseline in participants with T2DM during follow-up. Early assessment of systemic body muscle strength and mass could help identify high-risk healthy individuals prone to developing T2DM. Further research is required to obtain additional mechanistic insights into the intermuscular adipose tissue and insulin resistance. This study has a few limitations. First, we did not evaluate whether patients with T2DM are more likely to develop sarcopenia in this prospective study because sarcopenia was not defined according to the International Classification of Diseases-10 in the UKB. Second, the mean age of the study population was much lower than that in previous studies. Third, the participants of the UKB included in this study were mostly white people. Given the inclusion of only white participants, these results must be interpreted with caution in other races, such as Asians and black people. These findings have several important public health implications. Clinicians and national policymakers should emphasize the importance of different management strategies for physical activity, glycemic control, and BMI to prevent sarcopenia. Future studies should be conducted using elderly, prospective cohorts. Adults with sarcopenia may have an increased risk of developing T2DM. Assessing muscle strength and mass in all participants may be useful in identifying sarcopenia and preventing high-risk comorbidities. Funding This study was supported by grants from the Beijing Natural Science Foundation (No. 7232165), and Basic Research Project of Shanghai Sixth People’s Hospital (No. ynms202408). Conflicts of interests None.