Background
Sarcopenia was defined as a muscle disease rooted in adverse muscle changes that accrue across a lifetime by The European Working Group on Sarcopenia in Older People 2 (EWGSOP2) in 2019 [
1], which means it is becoming a global health problem. Sarcopenia is characterized by decreased muscle strength and physical conditions, which lead to an increased risk of falls, fractures and mortality [
2].
The prevalence of sarcopenia varies widely among studies because of the controversy definition of sarcopenia [
3]. A study of community dwelling older adults (average age of 67 years) in UK found the prevalence of sarcopenia was 4.6% in men and 7.9% in women according to EWGSOP definition [
4]. In a community-dwelling elderly Japanese population, the prevalence of sarcopenia ranged from 2.5 to 98.0% in men and 2.3 to 88.0% in women based on different sarcopenia definitions [
5]. In Turkey, sarcopenia was diagnosed in 73.3% of the nursing home residents [
6], while the prevalence of sarcopenia defined by EWGSOP was 0.8% (1.3% in men and 0.6% in women) in community-dwelling outpatient older adults [
7]. Other studies also reported the prevalence of sarcopenia differed among different populations, ages, sex as well as living settings (community or nursing homes) [
8‐
10].
Epidemiological evidence has shown that the prevalence of diabetes is 12.8% among adults living in China and the prevalence of diabetes is even higher among adults aged 50 [
11]. Numerous studies have reported that the possibility of sarcopenia is much higher in type 2 diabetes mellitus (T2DM) [
12,
13]. Wang et al. demonstrated that the prevalence of sarcopenia was significantly higher in patients with diabetes than in healthy subjects (14.8% vs. 11.2%), the patients with T2DM were 1.56-fold likely to exhibit sarcopenia compared to healthy controls [
14].
Reportedly, sarcopenia is associated with a 1.5–2-fold increased risk of falls and fractures, especially in older adults [
15], and diabetes is also correlated with a higher risk of fractures independently of bone mineral density [
16]. Thus, sarcopenia may be associated with an increased risk of diabetes-related fractures [
17] and it is crucial to identify subjects with sarcopenia in patients with T2DM. Importantly, despite the attention given to the diagnosis of sarcopenia, poor management is still performed, mainly related to physical therapy [
18]. Searching for key biomarkers can assist with further comprehension of the pathophysiological disease processes, which can help with the early detection of sarcopenia and the selection of the optimal pharmacologic agents for interventions. Previous experimental data have suggested that the pathogenesis of sarcopenia might be attributed to decreases in hormone levels, neuromuscular dysfunction and inflammation [
19]. Chronic inflammation is considered as a hazardous factor for sarcopenia [
19]. Visser et al. reported a negative association of inflammatory indicators with handgrip strength [
20]. A meta-analysis compared inflammatory markers in participants with and without sarcopenia, and found that high-sensitivity C-reactive protein (hs-CRP) demonstrated a significantly positive correlation with sarcopenia [
19]. Furthermore, homocysteine, an indicator closely related to inflammation, plays an important role in many age-correlated diseases, including cardiovascular diseases and sarcopenia [
21]. Whether these correlations could apply to older Chinese adults with T2DM or nor, and what’s the pathophysiological roles that hs-CRP and homocysteine play in the development of sarcopenia remain unknown. In the present study, based on a well-characterized T2DM cohort, we aimed to explore the prevalence of sarcopenia and examined the associations of homocysteine and inflammatory cytokines with sarcopenia and its components.
Discussion
Sarcopenia is a generalized, progressive muscle disease [
1]. In the current study, we identified an 8.9% prevalence of sarcopenia in an older Chinese T2DM cohort. Additionally, we demonstrated a positive correlation of homocysteine (OR: 2.829; 95% CI, 1.064–7.525) and hs-CRP (OR: 1.021; 95% CI, 1.001–1.042) with the components of sarcopenia, and the relationship remained significant after adjustment for age, sex, BMI and HbA1c. Importantly, hs-CRP and homocysteine may serve as new biomarkers of sarcopenia and contribute to the development of sarcopenia.
Sarcopenia is an age-related disease with reduced muscle mass and function, and its prevalence has risen rapidly in recent years [
2]. There is a significant variability about the prevalence of sarcopenia [
3]. In older healthy people (≥ 60 years old), the prevalence of sarctaopenia varies from 5% to 50%, which has resulted in a significant reduction in the quality of life of elderly individuals [
18]. The prevalence of sarcopenia in Europe is between 11% and 20% in healthy men and women aged over 60 years in 2016 [
24]. Among Japanese residents (≥ 65 years old), the prevalence of sarcopenia is 11.5% in men and 16.7% in women [
25]. Importantly, the prevalence of sarcopenia in elderly Japanese diabetes patients is even higher, about 18.7% [
26]. A systematic review and meta-analysis from 20 studies including over 50,000 participants demonstrated that individuals with diabetes had greater likelihood of having sarcopenia [
27]. A report from the Korean Sarcopenic Obesity Study, in which sarcopenia was defined using the skeletal muscle index only, found the prevalence of sarcopenia in patients with T2DM is much higher than the controls (15.7% vs. 6.9%) [
12]. Similarly, Çeliker et al. [
28] reported a higher prevalence of sarcopenia in T2DM individuals (21.4%) compared with those without T2DM (15.1%) in Turkey. In our study, we reported that the prevalence of sarcopenia in older adults with T2DM was 8.9% (mean 67.6 years). Our results were similar to the data from Mori H et al. in Japanese patients with T2DM (7.2%, with mean age of 63.2) [
29]. However, our results were lower than 24% from Singapore diabetic patients with a mean age of 68.3 [
30] and 28.5% from Malaysian in older T2DM patients [
31]. The shortage of established diagnostic criteria for low SMI and the age deviation may explain these differences. In addition, studies have shown that the association between sarcopenia and T2DM varies with different adjustment methods of skeletal muscle mass [
32]. Bahat et al. [
33] reported that the association between muscle mass and functionality is better when skeletal muscle mass was adjusted by BMI rather than height
2. Thus, the prevalence of sarcopenia in T2DM individuals may depend on different sarcopenia definitions, ethnicity, living settings as well as age, sex, BMI and comorbidities [
34].
Additionally, hyperglycemia is extremely detrimental to muscle health and function and numerous studies have reported that patients with T2DM had a high risk of sarcopenia [
12‐
14]. A longitudinal Korean study has reported that poor glycemic control (HbA1c above 8.5%) is harmful to muscle performance [
35]. Also, we found that the patients with sarcopenia showed worse glucose control (9.2 ± 2.2 vs. 8.4 ± 1.8%,
P = 0.008), which was confirmed by several other observations [
36,
37], therefore, leading to the poor prognosis of diabetes. The hypothesized mechanism is the myosin glycation and mitochondrial dysfunction [
37]. Clinically, screening T2DM patients who have sarcopenia and then giving targeted treatment and intervention may provide a more positive impact on the prognosis of both diseases.
Additionally, we found a negative correlation between the proinflammatory cytokines hs-CRP, IL-6, and SMI. In line with our results, recent studies of T2DM adults in Indonesians [
38], the United Kingdom [
39], and Korean [
40] also showed an inverse correlation between SMI and hs-CRP. A large-scale meta-analysis of morbid participants also illustrated particularly higher concentrations of hs-CRP in subjects with sarcopenia. The relationships between IL-6 and sarcopenia differs in different studies. Grosicki et al. [
41] and Visser et al. [
20] reported the close correlation of low skeletal muscle mass with high serum levels of IL-6. The potential mechanism is the enhanced muscle catabolism caused by the chronic inflammation [
10]. Importantly, protein synthesis in skeletal muscle demonstrates an inverse association with CRP and IL-6 [
42]. However, Bano et al. [
43] reported that patients with sarcopenia experienced significantly higher levels of CRP, whilst no significant differences emerged for IL-6, which is consistent with our study. It has previously been shown that the sole action of IL-6 is not enough to induce muscle wasting, the catabolic effect of IL-6 is dependent on the synergistic interaction with other factors mediating the inflammatory response. The correlation between interleukin-6 and sarcopenia remains to be further explored. A series of studies have revealed the causal relationship between inflammatory markers and decreased muscle mass [
20,
44]. In a study of rats, it was found that the infusion of inflammatory factors can result in the atrophy of skeletal muscle [
45]. To summarize, chronic inflammation plays a vital role in the progression of sarcopenia.
As a sulphur-containing amino acid, homocysteine is an important intermediate in the metabolism of methionine and cysteine [
46]. The increased serum homocysteine contributes to tissue damage by oxidative stress, thus resulting in age-correlated diseases, notably cardiovascular disease, bone and glucose metabolism, and muscle function [
21]. Herein, we found that serum homocysteine served as a positive predictor of sarcopenia, and the correlation remained even after adjustment for HbA1c. The results coincide with those from Lee et al., who observed the positive correlation of sarcopenia and homocysteine in healthy older residents [
47]. Moreover, an early study with a large sample size from the United States also found an inverse association between homocysteine and gait speed, and quadriceps strength [
48]. The mechanism of hyperhomocysteinemia and sarcopenia is still unclear. The general perception is that the hyperhomocysteinemia may mediate the imbalance of enzymatic and non-enzymatic cross-linking of collagen [
48]. Veeranki et al. [
49] established a rodent model to explore the pathophysiological mechanisms of homocysteine and sarcopenia and suggested that the impaired muscle fiber regeneration and energy production disorders caused by mitochondrial dysfunction were the reasons for the development of sarcopenia. Recently, a potential crosstalk between renin-angiotensin system (RAS) and homocysteine has been suggested [
50]. It has been reported that the RAS was involved in the development of insulin resistance in skeletal muscle and the increase of angiotensin II (Ang II) levels was approved to induce skeletal fiber wasting through enhanced protein degradation and apoptosis as well as decreased protein synthesis [
51‐
53]. However, although homocysteine is still an independent risk factor for sarcopenia in our study after adjusting for several confounders, adding homocysteine to the ROC improves the fit slightly. Thus, we speculate that homocysteine may play a minor role in diagnosing sarcopenia. Further basic and clinical studies should be carried out to reveal the mechanisms underlying sarcopenia and high serum levels of homocysteinemia considering the quickly increasing prevalence of sarcopenia, and it is ineffective treatment.
Growing attention has been given to the advantage of reversing sarcopenia by reducing the level of inflammatory markers and homocysteine. In a model of aged rats, Rieu et al. [
54] discovered that the muscle protein synthesis was restored by non-steroidal anti-inflammatory drugs (NSAIDs) which was used to suppress low-level inflammation. Furthermore, the beneficial effect of NSAIDs in muscle dysfunction was also confirmed in older people [
55]. For homocysteine, it is well known that the supplementation with vitamin B12 and folic acid can correct hyperhomocysteinemia to reverse its adverse effects [
56]. A previous nutrition intervention study from Japan demonstrated that vitamin B12 and folic acid could reduce the probability of fracture incidence [
57], thus improving the strength and function of muscle [
58]. However, a large review on the intervention of vitamin B12 to reduce the concentrations of homocysteine showed no differences in adverse outcomes [
57]. Since there is not enough information about the therapeutic effect of these medicines, further in-depth research is particularly warranted. In addition, when we compared the sarcopenia group to the non-sarcopenic group, patients with sarcopenia showed a higher proportion of male subjects and had significantly lower mean BMI values. Our outcomes were consistent with several other observational studies [
59‐
62]. Hormone differences may be the main reason for these outcomes. Although this study adds much information to the field of sarcopenia, there are still several limitations involved in the present study. First, this study was a cross-sectional study, and causal relationships therefore could not be determined. Second, our results come from Chinese adults with T2DM, which may not be applicable to other ethnic groups without replication. Thirdly, the information about drugs patients were taking for diabetes and the parameters such as creatine phosphokinase (CPK) and vitamin B12 is missing in our study, which may cause bias. Fourthly, we included the most common inflammatory markers such as hs-CRP and IL-6, although many others (TNF-α, IL-10, etc.) that have been implicated in sarcopenia. Finally, the exclusion criterion was designed to exclude patients who have neurological disease or sequelae of cerebrovascular disease. The criterion may lead to the omission of some patients with sarcopenia, and ultimately cause the deviation of the results. Besides, according to the recommendation from EWGSOP2, SARC-F questionnaire stands as one of the best tools to evaluate sarcopenia [
63‐
65]. Without screening for SARC-F in this study is of course a lacking, we will definitely consider validation of SARC-F in our future research.
Nonetheless, this study enriches our knowledge of the prevalence of sarcopenia in older Chinese adults with T2DM, and reveals the relationship and intrinsic connection of inflammatory markers and homocysteine with sarcopenia and its components.
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