Association between Changes in Physical Activity and Incident Depression among Patients with Newly Diagnosed Type 2 Diabetes Mellitus
Article information
Abstract
Background
This study aimed to investigate the relationship between changes in physical activity patterns following a new diagnosis of type 2 diabetes mellitus (T2DM) and the risk of developing depression.
Methods
This study used comprehensive diabetes data from the National Health Insurance Service of South Korea. From this dataset, we included 254,619 individuals newly diagnosed with T2DM between 2009 and 2015 who had health examination data within 2 years before and after their diagnosis date and no prior history of depression. Physical activity levels were quantified using the metabolic equivalent of task (MET) method.
Results
Compared with individuals with 0 MET-min/wk of physical activity before a new T2DM diagnosis, those who increased their activity levels to 500–999 MET-min/wk after diagnosis showed a 23% reduction in the risk of depression, while an increase to ≥1,000 MET-min/wk was associated with a 25% reduction in depression risk. Conversely, individuals with 1–499 MET-min/wk before diagnosis who became inactive after diagnosis experienced a 25% increased risk of depression. A similar trend toward increased depression risk was observed among those who reduced their physical activity from 500–999 or ≥1,000 MET-min/wk.
Conclusion
Changes in physical activity levels before and after a new diagnosis of T2DM significantly influence the risk of developing depression, with increased activity reducing the risk and decreased activity elevating it. This finding underscores the importance of encouraging physical activity to support mental health in patients with newly diagnosed T2DM.
Highlights
• Using the Korean NHIS cohort, changes in PA after a new T2DM diagnosis were analyzed.
• PA levels, based on MET-min/wk were assessed from two consecutive health screenings.
• Changes in PA after diabetes diagnosis were associated with incident depression.
• Increasing PA lowered depression risk, while decreased PA raised it.
• Increasing PA may be helpful for mental health in patients with newly diagnosed T2DM.
INTRODUCTION
Type 2 diabetes mellitus (T2DM) has numerous comorbidities, including physical conditions such as cardiovascular disease as well as psychiatric disorders [1,2]. Depression is the most common psychiatric comorbidity of diabetes, affecting 16.5% of patients with T2DM [3], who are prone to mood disorders due to the emotional burden of managing a lifelong condition and persistent social stigma surrounding metabolic disorders [4,5]. Depression in patients with T2DM leads to negative health outcomes such as poor adherence to treatment and inadequate glycemic control [6–8]. In addition, depression decreases quality of life (QoL) in patients with T2DM, independently of the lower QoL caused by diabetes itself [9,10]. Therefore, efforts are needed to treat and prevent depression in people with T2DM, and prevention activities should include identifying modifiable risk factors.
Physical inactivity is one of the key risk factors for depression, and numerous studies in the general population have shown that engaging in regular physical activity (PA) has a protective effect against depression, regardless of age, sex, or global region [11,12]. Increasing PA compared with baseline levels also lowers the risk of incident depression in the general population [13,14]. Considering that 54% of people with diabetes have no or insufficient physical activity [15], a significant number of patients with T2DM would benefit from increasing their amount of exercise. A few studies have reported that PA is associated with fewer depressive symptoms in the diabetic population [16,17]. Similarly, a meta-analysis by Narita et al. [18] revealed that PA interventions are effective in treating diabetes-related depression. However, only limited evidence is available on whether PA is also effective in preventing depression in patients with T2DM. To our knowledge, no prior research has suggested that changes in PA, rather than baseline activity, are associated with the risk of incident depression in patients with T2DM and no previous history of depression.
Thus, this nationwide population-based cohort study aimed to evaluate the association between changes in physical activity and the risk of incident depression in participants with newly diagnosed T2DM.
METHODS
Participants
Our study used a nationwide, population-based dataset from the National Health Insurance Service (NHIS) of Korea, comprising randomly sampled data from approximately 2.2 million patients diagnosed with T2DM. From this database, we identified 319,125 individuals who were newly diagnosed with T2DM between 2009 and 2015 and completed two consecutive health examinations: one within 2 years before their T2DM diagnosis and the other within 2 years after diagnosis. Among these, we first excluded 2,766 individuals because of missing data related to PA or covariates. We subsequently excluded an additional 61,740 participants who had been diagnosed with depression before the index date. Ultimately, as shown in Fig. 1, our final population included 254,619 patients who met the inclusion criteria, having undergone both health check-ups with complete PA data and no prior history of depression. Approval for this study was obtained from the Seoul National University Hospital Institutional Review Board (E-2204-038-1314). Additionally, the NHIS Big Data Steering Department provided approval with research management number NHIS-2023-1-695. The requirement for informed consent from individual participants was waived because the NHIS database consists of strictly anonymized clinical data, with access limited to authorized individuals in compliance with the Personal Information Protection Act guidelines.
Study flow diagram. T2DM, type 2 diabetes mellitus.
Assessment of PA change
PA levels were assessed using self-administered questionnaires based on a 7-day recall method, a validated approach for population-level PA monitoring [19]. In addition, this questionnaire has been used in previous population-based studies and its reliability and validity have been evaluated in Korean settings. For example, the Korean version of the Global Physical Activity Questionnaire demonstrated test–retest reliability (κ or correlation coefficients approximately 0.60 to 0.70 for recreational PA) and a modest but significant correlation with accelerometer-based measurements (r=0.30–0.40) [20,21]. The PA questionnaires were self-administered by participants as part of the standardized NHIS health screening program and collected under the supervision of trained medical staff at examination centers. Questionnaires were administered at routine national health examinations conducted within 2 years before and 2 years after the diagnosis of T2DM. Using data from the two health examinations closest to the T2DM diagnosis date one within 2 years before diagnosis and the other within 2 years after diagnosis we calculated PA levels. Participants indicated how often they engaged each week in light (≥30 minutes/day; e.g., casual walking and light exercise), moderate (≥30 minutes/day; e.g., fast walking and easy biking), and vigorous (≥20 minutes/day; e.g., jogging, aerobic workouts, intense cycling, and hiking) PA. Light, moderate, and vigorous PA were assigned metabolic equivalent of task (MET) scores of 2.9, 4.0, and 7.0, respectively, according to prior literature [22,23]. Total energy spent on PA per week (in MET-min/wk) was calculated by multiplying frequency, duration, and MET value for each PA level and summing the results. Based on total MET-min/wk, individuals were grouped into four categories: 0, 1–499, 500–999 (aligning with recommended PA levels), and ≥1,000. PA change was determined by subtracting the pre-diagnosis MET-min/wk value from the post-diagnosis value. Additionally, we conducted comparative analyses across 16 subgroups defined by MET categories at both health examinations. Four separate analyses were performed, each stratified by baseline PA level measured during the first examination. The first analysis included individuals with 0 MET-min/wk at baseline, comparing those who maintained 0 MET-min/wk at the second examination with those whose MET-min/wk increased. The second analysis involved participants initially categorized as 1–499 MET-min/wk, comparing those who maintained their MET category with those who experienced MET changes at the second examination. Similarly, the third analysis assessed participants initially within the 500–999 MET-min/wk range, and the fourth analysis included individuals initially classified as having ≥1,000 MET-min/wk, focusing on comparative changes, particularly MET reductions, during the second examination period.
Follow-up for new-onset depression
The onset of depression was defined using, the International Classification of Diseases, 10th Revision (ICD-10) codes and antidepressant prescriptions. Among the ICD-10 codes, patients diagnosed with F32 or F33 who were prescribed antidepressants at the same time and had at least two hospital visits were defined having depression [24,25]. Because F33 is a code for recurrent depressive disorders, it was difficult to determine when the first depressive episode occurred in some patients; however, this code was used to identify additional patients because of limitations in the data accessibility range. To determine the effect of exercise on the onset of depression, patients with depression before the new diabetes diagnosis were removed; thus, only depression newly diagnosed after the new diabetes diagnosis date was included.
Statistical analysis
In this study, we employed a moving index date approach to define the follow-up period, beginning from the second health examination conducted after the initial diagnosis of T2DM, rather than from a fixed baseline date. Participants were followed up for a mean duration of 7.765 years. Follow-up was concluded at the earliest occurrence among newly diagnosed depression, death, or December 31, 2022. Participants who did not experience any event during the study period were followed until December 31, 2022. Baseline characteristics were described according to sex, incorporating socioeconomic data from the year of T2DM diagnosis and health examination results from the second post-diagnosis assessment. Cox proportional hazards models were used for survival analyses. The first Cox regression model adjusted only for age and sex. The second model further adjusted for socioeconomic variables, including household income, and additional health screening variables, including body mass index (BMI), fasting blood glucose (FBG), total cholesterol (TCHO), systolic blood pressure (SBP), alcohol intake, smoking status, and the Charlson comorbidity index (CCI). Variables such as sex, PA, household income, alcohol intake, smoking status, and CCI were categorized, while BMI, FBG, TCHO, SBP, and age were treated as continuous variables. In the primary analysis, the association between continuous changes in MET-min/wk and the risk of depression was evaluated for the entire cohort using restricted cubic spline curves, with knots placed at 200-unit intervals of MET-min/wk change. In the secondary analysis, participants were stratified based on baseline MET-min/wk levels obtained from the initial health examination, and the risk of depression associated with changes in MET-min/wk by the second examination was assessed through survival analysis. All analyses were performed using SAS software version 9.4 (SAS Institute, Cary, NC, USA), and statistical significance was determined using a two-sided P value <0.05.
Additional analyses
Two additional analyses were conducted: first, depression risk was evaluated based solely on MET-min/wk status at the initial pre-diagnosis health examination; second, depression risk was analyzed based solely on MET-min/wk status at the post-diagnosis health examination.
Subgroup analyses
To explore potential heterogeneity in the association between changes in PA and incident depression, subgroup analyses were performed by age group (<65 years vs. ≥65 years), sex, BMI (<25 kg/m2 vs. ≥25 kg/m2), smoking status (current vs. non-current), alcohol intake (none vs. mild-to-heavy), and CCI (<2 vs. ≥2). Participants were stratified by baseline PA level (0 or ≥1,000 MET-min/wk) at the pre-diagnosis health examination. Within each stratum, the association between changes in PA and incident depression was re-estimated. Interaction was tested by including an interaction term between the PA change group and the subgroup variable in Cox proportional hazards models with the same adjustment variables as in the main analysis. A two-sided P value for trend and interaction <0.05 was considered statistically significant. These subgroup analyses were exploratory in nature.
RESULTS
Baseline characteristics
A total of 254,619 participants were included in this study, with a mean±standard deviation age of 56.6±12.0 years. Of these participants, 130,309 were men, accounting for approximately 51.2% of the total cohort. Before the diagnosis of T2DM, 22.9% of participants reported no PA (0 MET-min/wk); this proportion was higher among women (26.5%) than among men (19.5%). Conversely, 19.7% of participants had higher PA levels (≥1,000 MET-min/wk), with a higher proportion observed among men (22.5%) than among women (16.8%). Similar patterns were observed at the second health screening after the diagnosis of T2DM. Detailed baseline characteristics by sex are presented in Table 1.
Descriptive statistics of the study population at the inception of the study according to the change in physical activity based on the second (after diagnosed with T2DM) National Health Insurance Service National Health Screening Cohort
Changes in PA (MET-min/wk) after a new diagnosis of T2DM and the risk of depression
Fig. 2 illustrates the association between changes in MET-min/wk, treated as a continuous variable, and the risk of new-onset depression using restricted cubic spline curves. In the overall cohort, greater increases in PA from the pre-diagnosis to post-diagnosis period were significantly associated with a lower risk of depression, whereas greater decreases in PA were significantly associated with a higher depression risk. These trends were statistically significant when the confidence intervals (CIs) were considered.
Association between changes in physical activity (metabolic equivalent of task [MET]-min/wk) after a new diagnosis of type 2 diabetes mellitus and the risk of depression. A restricted cubic spline curve was constructed to examine the non-linear association between changes in physical activity, defined as the difference in MET-min/wk after versus before type 2 diabetes mellitus diagnosis, and the risk of depression. The solid line represents the adjusted hazard ratio, and the shaded area indicates the 95% confidence interval derived from Cox proportional hazards regression models. Changes in physical activity were modeled as a continuous variable. A change of 0 MET-min/wk represents no difference in physical activity levels before and after type 2 diabetes mellitus diagnosis. The restricted cubic spline curve was generated using knots placed at intervals of 200 MET-min/wk. The model was adjusted for age, sex, household income, body mass index, systolic and diastolic blood pressure, fasting serum glucose, total cholesterol, alcohol intake, and Charlson comorbidity index.
Increased PA and depression
Table 2 shows the results of subgroup analyses based on PA levels at the initial health screening. Compared with participants who remained physically inactive (0 MET-min/wk), patients who increased their PA to 500–999 MET-min/wk had a significantly reduced incidence of depression (incidence rate per 10,000 person-years [PY], 12.95; hazard ratio [HR], 0.77; 95% CI, 0.62 to 0.95). Similarly, patients who increased their PA to ≥1,000 MET-min/wk also showed a significantly lower incidence of depression (10.92 per 10,000 PY; HR, 0.75; 95% CI, 0.57 to 0.997). A clear gradient in risk corresponding to increasing exposure levels was identified (P for trend=0.0056), indicating that greater increases in PA were correlated with greater reductions in depression risk. Table 2 also shows that among participants initially categorized as moderately active (1–499 or 500–999 MET-min/wk), reductions in PA were significantly associated with increased depression risk. Both groups displayed statistically significant dose-response trends (P for trend=0.0173 and 0.0232, respectively), supporting the relationship between PA changes and depression risk.
Association between changes in physical activity before and after a new diagnosis of type 2 diabetes mellitus and the risk of depression
Decreased PA and depression
As shown in Table 2, participants initially engaging in ≥1,000 MET-min/wk who decreased their MET-min/wk demonstrated a non-significant increase in depression risk compared with those who maintained higher PA levels. Specifically, the incidence rates and HRs for those decreasing to 500–999 MET-min/wk (incidence rate per 10,000 PY, 10.59; HR, 1.12; 95% CI, 0.89 to 1.43), 1–499 MET-min/wk (12.48 per 10,000 PY; HR, 1.26; 95% CI, 0.96 to 1.66), and becoming inactive (14.13 per 10,000 PY; HR, 1.33; 95% CI, 0.97 to 1.81) indicated a trend towards an increased risk of depression with reduced PA. Despite non-significant CIs, a meaningful trend indicating a progressive association with rising exposure levels was detected (P for trend=0.0342). Among participants initially categorized as moderately active (1–499 or 500–999 MET-min/wk), increases in PA initially showed marginal increases in depression risk, followed by a non-significant trend towards risk reduction with larger activity increases.
Additional analyses
As shown in Supplementary Table 1, among initially inactive participants (0 MET-min/wk), higher PA levels prior to diabetes diagnosis significantly reduced depression risk. Specifically, participants with ≥1,000 MET-min/wk had significantly lower depression incidence (10.66 per 10,000 PY; HR, 0.79; 95% CI, 0.63 to 0.98), confirming a significant dose-response relationship (P for trend=0.0274). Additionally, as shown in Supplementary Table 2, analyses based on post-diagnosis PA showed significantly lower depression risk for all groups with increased PA compared with inactive participants (1–499 MET-min/wk: 11.49 per 10,000 PY; HR, 0.88; 95% CI, 0.79 to 0.98; 500–999 MET-min/wk: 10.10 per 10,000 PY; HR, 0.79; 95% CI, 0.71 to 0.89; ≥1,000 MET-min/wk: 9.07 per 10,000 PY; HR, 0.74; 95% CI, 0.65 to 0.84). All groups demonstrated significant dose-response relationships (P for trend <0.0001).
Subgroup analyses
To further explore potential heterogeneity in our findings, additional stratified analyses were conducted according to baseline PA levels before diabetes diagnosis. Supplementary Tables 3 and 4 report both the P values for trend and the P values for interaction. Among participants who reported no PA (0 MET-min/wk) at the pre-diagnosis examination, an increase in MET-min/wk at the second screening was consistently associated with a lower risk of incident depression, showing a graded inverse relationship (P for trend <0.05 in several subgroups). The protective association of increasing PA was generally observed across most strata including age, sex, BMI, smoking status, alcohol intake, and comorbidity level while the overall direction and magnitude of the associations were concordant with those in the main analysis. Conversely, among individuals who were physically active (≥1,000 MET-min/wk) before diabetes diagnosis, a reduction in PA was associated with a higher risk of developing depression, again consistent with the primary findings. Although a few subgroup-specific estimates (e.g., older adults and non-smokers) showed borderline statistical significance, the overall trend suggested that maintaining or increasing PA was associated with a lower depression risk among patients with newly diagnosed T2DM. Collectively, these supplementary analyses reaffirmed the robustness of the main results and supported the inverse dose-response relationship between changes in PA and subsequent depression risk. Although subgroup-specific point estimates for the trend differed, the formal test for interaction was not statistically significant (P for interaction >0.05), indicating that we found no evidence that subgroup characteristics modified the effect of PA change on depression risk. To further evaluate whether the impact of decreased PA differed according to baseline PA level, we additionally conducted subgroup analyses restricted to participants with low (1–499 MET-min/wk) and moderate (500–999 MET-min/wk) baseline activity. In both subgroups, decreases in PA were associated with an increased risk of incident depression, consistent with the direction of the main findings (Supplementary Tables 5 and 6).
DISCUSSION
This nationwide population-based cohort study demonstrated that changes in PA before and after T2DM diagnosis had a significant effect on the risk of new-onset depression. The association was evident in both directions of change: an increase in MET-min/wk was linked to a decrease in depression, whereas a decrease in MET-min/wk was associated with an increased risk of depression. Furthermore, this trend was consistent regardless of whether individuals had no, moderate, or high levels of previous exercise. In addition, engaging in PA, even at mild levels, had a protective effect against developing depression compared with being inactive, whether before or after a T2DM diagnosis.
A few studies have shown that changes in metabolic risk factors can help prevent depression in the diabetic population, although none have focused on changes in PA level alone. A cohort study by Kim et al. [26] showed that both increases and decreases in body weight were associated with a higher risk of incident depression in patients with T2DM. Another cohort study by An et al. [27] showed that variability in FBG, BMI, blood pressure, and TCHO affects the risk of incident depression in participants with T2DM. Our study demonstrated findings in line with this prior research by focusing on changes in PA.
Because PA is a factor that is amenable to structured intervention in healthcare settings [28,29], some previous studies have suggested that exercise programs can improve mental health indicators such as depressive symptom scores in patients with T2DM [30–32]. Our findings are consistent with these studies, but we focused more on preventive intervention than on the therapeutic effects of PA by completely excluding depression before the time of T2DM diagnosis.
Several mechanisms support the protective effect of exercise against depression in individuals newly diagnosed with T2DM. One such mechanism involves apelin, which regulates glucose and lipid metabolism and has been suggested as a novel therapeutic agent for diabetes [33,34]. Apelin can also explain the antidepressant effects of exercise because it inhibits neuroinflammation and is associated with hippocampal neuroplasticity [35,36]. Another mechanism involves the hypothalamic-pituitary-adrenal (HPA) axis, which affects cognition and behavior in general by regulating the stress response. Dysregulation of the HPA axis due to chronic stress contributes to the development of depression [37]. Patients with T2DM have subclinical hypercortisolism and abnormalities in the diurnal rhythm of cortisol, which may explain their vulnerability to depression [38,39]. Exercise stabilizes the HPA axis by reducing stress reactivity in both acute and habitual settings, which may support mental health in the diabetic population [40,41]. Glucose metabolism and inflammation may also serve as mechanisms linking diabetes, exercise, and depression [42–45]. Psychosocial stress is also relevant, given that diabetes has a detrimental effect on body image in affected individuals [46], and this stress may be alleviated by engaging in PA [47].
The strength of this study is that it obtained a large study population from a national database, which increases the generalizability of the results; the definitions of T2DM and depression were based on diagnostic codes, which reflect real-world clinical practice; and both the direction and magnitude of MET-min/wk change were considered. We classified participants into four PA groups and demonstrated a dose-response relationship between changes in PA and depression.
Clinical implications
It should also be noted that PA was assessed only at two time points, before and after diabetes diagnosis, which limited our ability to capture long-term behavioral trajectories. Nevertheless, this approach was intentionally chosen to focus on early behavioral changes occurring around the time of diagnosis, a period when patients are most likely to modify their lifestyle. By leveraging both pre- and post-diagnosis examinations, our study provides unique insights into the dynamic impact of PA changes on mental health in newly diagnosed patients. This study has implications for both clinical practice and public health policy. Given that changes in exercise behavior before and after a T2DM diagnosis have been shown to affect psychological well-being, clinicians should encourage appropriate changes in exercise levels among patients with newly diagnosed T2DM. Individuals who have not been exercising regularly can be encouraged to start some activity, and those who have been mildly physically active can be encouraged to increase their amount of exercise. Our results also suggest that maintaining existing exercise levels is crucial, as decreased PA was associated with adverse mental health outcomes. Furthermore, our findings indicate that the greater the increase in MET-min/wk among previously inactive individuals, the larger the reduction in the HR for depression, which could provide a rationale for health policy interventions targeting populations with newly diagnosed T2DM.
Limitations
This study has several limitations. First, because of its retrospective design, the possibility of reverse causation cannot be fully excluded. However, this issue was minimized by clearly separating the exposure assessment period (newly diagnosis of T2DM) from the outcome follow-up period (incident depression) and by excluding participants with prior depression. Second, the definition of depression relied on ICD-10 codes F32 and F33, which may not have captured all clinically relevant cases, such as those treated under different diagnostic codes. Nevertheless, the use of claim-based codes enabled the identification of patients with physician-diagnosed depression while minimizing the inclusion of subclinical symptoms [48]. Third, we did not differentiate between those requiring insulin and those treated with oral agents, nor did we assess the effect of this factor on glycemic control or comorbidity reduction. We attempted to mitigate this limitation by adjusting for key demographic, clinical, and comorbidity variables. Fourth, this study focused solely on depression as a mental health outcome. Other psychiatric disorders such as anxiety, bipolar disorder, or schizophrenia were not separately identified or excluded. Because depression is the most common psychiatric comorbidity among patients with diabetes, we prioritized it for analytic clarity. Nevertheless, unmeasured comorbid psychiatric conditions may have influenced our findings, and this potential residual confounding should be considered in interpretation. Fifth, PA was measured only twice, within 2 years before and after diabetes diagnosis, limiting the evaluation of long-term or time-varying patterns during the average 7.76-year follow-up. This may have introduced some exposure misclassification. However, focusing on early behavioral changes after diagnosis remains clinically meaningful, and the questionnaire used has demonstrated acceptable reliability and validity in Korean populations, supporting the robustness of this measurement despite temporal limitations. Sixth, subgroup analyses were exploratory in nature and should be interpreted with caution. Nevertheless, they provide additional context for understanding how the proposed associations may vary across different patient characteristics.
Conclusions
This research suggests that changes in PA among patients with newly diagnosed T2DM are associated with the risk of incident depression, regardless of previous exercise levels. Even mild exercise is protective for mental health in the T2DM population, and increasing PA levels is also helpful, whereas decreased activity elevates the risk of depression. These findings indicate that interventions to increase or at least maintain PA levels would benefit the mental health of individuals with newly diagnosed T2DM.
SUPPLEMENTARY MATERIALS
Supplementary materials related to this article can be found online at https://doi.org/10.4093/dmj.2025.0766.
Association between physical activity levels immediately before a new diagnosis of type 2 diabetes mellitus and the risk of depression
Association between physical activity levels immediately after a new diagnosis of type 2 diabetes mellitus and the risk of depression
Subgroup analysis of the association of increase in physical activity with incident depression among patients with newly diagnosed type 2 diabetes mellitus who reported 0 MET-min/wk at the pre-diagnosis health examination
Subgroup analysis of the association of decrease in physical activity with incident depression among patients with newly diagnosed type 2 diabetes mellitus who reported ≥1,000 MET-min/wk at the pre-diagnosis health examination
Subgroup analysis of the association of decrease in physical activity with incident depression among patients with newly diagnosed type 2 diabetes mellitus who reported 1–499 MET-min/wk at the pre-diagnosis health examination
Subgroup analysis of the association of decrease in physical activity with incident depression among patients with newly diagnosed type 2 diabetes mellitus who reported 500–999 MET-min/wk at the pre-diagnosis health examination
Notes
CONFLICTS OF INTEREST
Dae Ho Lee has served as an international editorial board member of Diabetes & Metabolism Journal since 2023 but was not involved in the review process for this manuscript. The author declares no competing interests related to this work.
AUTHOR CONTRIBUTIONS
Conception or design: S.P., B.K., S.J., S.M.P., D.H.L., S.J.C.
Acquisition, analysis, or interpretation of data: S.P., B.K., H.J.K., S.J.P., J.S., J.C.
Project administration and supervision: S.J., S.M.P., D.H.L., S.J.C.
Writing the original draft: all authors.
ACKNOWLEDGMENTS
Sangwoo Park, Hye Jun Kim, Sun Jae Park, Jihun Song, and Jina Chung received a BK21 FOUR education program scholarship. It was offered by the National Research Foundation of Korea.
FUNDING
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (RS-2024-00440371 to Seogsong Jeong and NRF-2021R1A5A 2030333, to Dae Ho Lee). Also, this work was supported by the Gachon University Gil Medical Center (FRD2023-20 to Soo Jung Choi).