Abstract
Aims: Visceral fat accumulation is the central feature of metabolic syndrome and subsequent atherosclerotic cardiovascular disease. Soluble T-cadherin (sT-cad) has been identified in circulation, but its clinical significance in the general population remains unclear. We investigated the associations of circulating sT-cad levels with metabolic syndrome and its components in a population undergoing health checkups.
Methods: A total of 1321 Japanese participants (825 males and 496 females) undergoing health checkups were enrolled. Serum levels of sT-cad (130-kDa, 100-kDa, and 30-kDa), adiponectin (APN), and other clinical parameters were measured. Associations between sT-cad and metabolic risk factors were analyzed.
Results: Among the three sT-cad isoforms, serum 130-kDa sT-cad levels were significantly negatively correlated with waist circumference, blood pressure, Homeostatic Model Assessment for Insulin Resistance (HOMA-R), triglycerides, Alanine aminotransferase (ALT), uric acid, and high-sensitivity C-reactive protein (hsCRP), and positively correlated with high-density lipoprotein (HDL) cholesterol and APN. In multivariate analysis, high TG levels and/or HDL-C levels and hsCRP were independent negative determinants of 130-kDa sT-cad levels in both sexes. Furthermore, 130-kDa sT-cad levels decreased progressively with an increasing number of metabolic risk factors (P for trend ＜0.001).
Conclusion: Low serum 130-kDa sT-cad levels are associated with the presence and accumulation of metabolic syndrome-related abnormalities in a Japanese population undergoing health checkups. Inflammation and lipid abnormalities of metabolic syndrome (high TG and/or low HDL-C) may influence the serum 130-kDa sT-cad levels.
Keywords: Soluble T-cadherin, Adiponectin, Metabolic syndrome, Ankle–brachial index
See editorial vol. 33: 380-381
1. Introduction
Visceral fat accumulation is the central feature of metabolic syndrome and plays a pivotal role in its pathogenesis. Metabolic syndrome consists of a cluster of metabolic abnormalities, including impaired glucose tolerance, elevated blood pressure, and lipid abnormalities (high triglyceride (TG) levels and/or low high-density lipoprotein cholesterol (HDL-C) levels), and is strongly associated with an increased risk of atherosclerotic cardiovascular disease (CVD) 1 - 5) . Excess visceral fat promotes chronic inflammation and oxidative stress, leading to dysregulation of adipocytokine secretion, most notably hypoadiponectinemia 6) .
Adiponectin (APN) is an adipocyte-specific secretory protein, and its circulating levels are reduced in the presence of visceral fat accumulation 7) . APN exists as trimeric, hexameric, and high-molecular-weight (HMW) multimeric complexes in the blood. Low levels of HMW-APN have been associated with insulin resistance and coronary artery disease 8 , 9) . We and others have previously identified T-cadherin as a specific and high-affinity binding partner for HMW-APN 10 - 12) . T-cadherin is a glycosylphosphatidylinositol (GPI)-anchored membrane protein belonging to the cadherin superfamily 13) . We have shown that T-cadherin binding with HMW-APN is essential for the protective effects of APN in T-cadherin–expressing tissues, including the heart, skeletal muscle, and vascular endothelium 14 - 17) .
Membrane-bound T-cadherin in the heart, skeletal muscle, and vascular endothelial cells is expressed in two molecular forms: 130 kDa and 100 kDa 18) . Recently, we demonstrated the presence of soluble T-cadherin (sT-cad) in human circulation 19) . Circulating sT-cad exists stably in at least three isoforms (130-kDa, 100-kDa, and 30-kDa), with no interconversion among these isoforms under steady-state conditions. sT-cad exists in a monomeric form and does not bind to APN or other circulating proteins. Using tissue-specific knockout mice, we further demonstrated that a portion of circulating sT-cad is derived from vascular endothelial cells and skeletal muscle 20) . Furthermore, we have shown that sT-cad levels correlate with various clinical parameters, including the visceral fat area and serum APN level, in patients with type 2 diabetes 19) and with the area under the curve (AUC) of CK-MB in patients with acute myocardial infarction 21) . However, these findings were obtained from specific patient populations, and the clinical significance of sT-cad in the general population, including healthy individuals, remains unclear.
In this study, we investigated whether circulating sT-cad levels are associated with metabolic syndrome and the accumulation of its component risk factors in a population undergoing health checkups.
2. Methods
2.1 Participants
A total of 1348 examinees who underwent comprehensive health examinations at Sumitomo Hospital (Osaka, Japan) between June 2024 and August 2024 were enrolled. The majority of the participants were employees of various companies. Consent to participate in this study was obtained with an opt-out method. The health checkup data and residual serum of each patient were collected and irreversibly anonymized. This study was approved by the Human Ethics Committees of Osaka University Hospital (Approval no. 23437) and Sumitomo Hospital (Approval no. 23-19).
The inclusion and exclusion criteria of this study are shown in Fig.1 . From a total of 1348 consecutive examinees, 1322 individuals with available serum adiponectin (APN) measurements were selected for analysis. Twenty-six participants were excluded due to duplicate records, as the same individuals had registered in another health checkup program on the same day. Serum soluble T-cadherin (sT-cad) levels were subsequently measured, and one participant whose sT-cad level could not be determined due to a technical error was excluded. A total of 1321 participants (825 males and 496 females) were included in the subsequent analysis.
Fig.1.
Participants’inclusion and exclusion criteria in this study
Among the 1321 study participants, ABI data were available for 38 individuals (24 males and 14 females), who were included in the exploratory analysis of the relationship between sT-cad and ABI.
2.2 Clinical Examination
The health checkup was conducted in the morning after an overnight fast. Height and body weight were measured, and body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Waist circumference (WC) was measured at the umbilical level in the standing position. Blood pressure (BP) was measured in the sitting position using an automated sphygmomanometer. Blood samples were collected for measuring glucose levels, lipid profiles (total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG)), liver enzymes, renal function, and other biochemical markers. Abdominal ultrasonography was performed using a standardized protocol by trained sonographers, and the results were reviewed by experienced physicians. The ankle–brachial index (ABI) was measured using an automated oscillometric device with participants in the supine position. Systolic blood pressure was simultaneously recorded at both brachial arteries and both posterior tibial arteries. The ABI was calculated as the lower value of the ratio of ankle systolic pressure to ipsilateral brachial systolic pressure. FIB-4 index was calculated by the formula: (age [years] × AST [U/L]) / (platelet [10^9/L] x (ALT [U/L])^1/2), according to the EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease 22) .
2.3 Definition of Visceral Fat Accumulation and Risk Factors for Metabolic Syndrome, Diabetes Mellitus, Hypertension, Dyslipidemia, and Fatty Liver
To analyze metabolic syndrome and its components ( Table 1 , 2 , 3 , 4 , Figs.2 , 3 ) , we used the Japanese criteria for metabolic syndrome ( Fig.2 ) 23) . Visceral fat accumulation was defined as WC of ≥ 85 cm for males and ≥ 90 cm for females. Hyperglycemia was defined as fasting plasma glucose ≥ 110mg/dL. Elevated blood pressure was defined as systolic BP ≥ 130mmHg and/or diastolic BP ≥ 85mmHg. High TG/low HDL-C was defined as TG ≥ 150mg/dL and/or HDL-C ＜40mg/dL. Participants receiving antidiabetic and/or antihypertensive and/or antidyslipidemic medications were considered positive for each abnormality. Individuals without visceral fat accumulation and any metabolic abnormalities (i.e., normal glucose tolerance, normal blood pressure, and normal lipid profile) were defined as “metabolically healthy” and designated as the control group (Group I). This group was compared with those with only visceral fat accumulation (Group II), pre-metabolic syndrome (Group III), and metabolic syndrome (Group IV).
Table 1. Characteristics of participants.
| Total (N = 1321) | Male (N = 825) | Female (N = 496) | P value | |
|---|---|---|---|---|
| Age (years) | 55.83±11.09 | 56.81±11.05 | 54.19±10.96 | ＜0.001＊ |
| BMI | 23.07±3.59 | 24.11±3.34 | 21.34±3.31 | ＜0.001＊ |
| WC (cm) | 82.95±10.08 | 86.34±8.92 | 77.28±9.33 | ＜0.001＊ |
| Systolic BP (mmHg) | 118.87±16.37 | 120.86±15.49 | 115.55±17.23 | ＜0.001＊ |
| Diastolic BP (mmHg) | 71.95±11.87 | 73.90±11.59 | 68.70±11.62 | ＜0.001＊ |
| FPG (mg/dL) | 101.99±14.90 | 105.07±15.59 | 96.86±12.04 | ＜0.001＊ |
| HbA1c (%) | 5.69±0.52 | 5.72±0.54 | 5.65±0.49 | 0.023＊ |
| HOMA-R | 1.52 [0.16-13.13] | 1.71 [0.16-13.13] | 1.3 [0.26-9.78] | ＜0.001＊＊ |
| AST (U/L) | 22.74±7.99 | 23.93±8.71 | 20.74±6.13 | ＜0.001＊ |
| ALT (U/L) | 23.63±14.38 | 26.57±15.52 | 18.72±10.57 | ＜0.001＊ |
| eGFR | 70.14±14.08 | 68.7±13.00 | 72.54±15.44 | ＜0.001＊ |
| UA (mg/dL) | 5.65±1.37 | 6.22±1.19 | 4.69±1.08 | ＜0.001＊ |
| TG (mg/dL) | 89 [20-938] | 99 [29-938] | 76 [20-738] | ＜0.001＊＊ |
| HDL-C (mg/dL) | 67.96±17.96 | 62.49±15.72 | 77.06±17.79 | ＜0.001＊ |
| LDL-C (mg/dL) | 122.73±29.99 | 121.82±30.05 | 124.26±29.84 | 0.152＊ |
| hsCRP (mg/dL) | 0.05 [0-5.27] | 0.06 [0-5.27] | 0.05 [0-1.41] | ＜0.001＊＊ |
| Platelet (x104/μL) | 231.9±52.8 | 227.3±50.1 | 239.5±56.1 | ＜0.001＊ |
| FIB-4 index | 1.14 [0.33-11.0] | 1.16 [0.33-11.0] | 1.11 [0.34-4.73] | 0.024＊＊ |
| Hyperglycemia (%) | 262 (20%) | 207 (25%) | 55 (11%) | ＜0.001 + |
| on medication (%) | 76 (5.8%) | 60 (7.3%) | 16 (3.2%) | ＜0.001 + |
| Elevated BP (%) | 542 (41%) | 395 (48%) | 147 (30%) | ＜0.001 + |
| on medication (%) | 316 (24%) | 244 (30%) | 72 (15%) | ＜0.001 + |
| High TG/low HDL-C (%) | 452 (34%) | 348 (42%) | 104 (21%) | ＜0.001 + |
| on medication (%) | 308 (23%) | 229 (28%) | 79 (16%) | ＜0.001 + |
| Fatty Liver (%) | 409 (31%) | 331 (40%) | 78 (16%) | ＜0.001 + |
| APN (μg/mL) | 9.1 [1.9-44.2] | 7.8 [2.2-39.2] | 12.25 [1.9-44.2] | ＜0.001＊＊ |
| 130-kDa sT-cad (pmol/L) | 380.7±127.0 | 365.5±120.4 | 405.9±133.6 | ＜0.001＊ |
| 100-kDa sT-cad (pmol/L) | 1021.9±292.2 | 1028.2±291.2 | 1011.5±294.0 | 0.317＊ |
| 30-kDa sT-cad (pmol/L) | 753.9±314.8 | 791.9±336.9 | 690.6±262.3 | ＜0.001＊ |
Data are shown as the mean±standard deviation for normally distributed parameters or median [minimum–maximum] for skewed parameters. BMI; body mass index, WC; waist circumference, BP; blood pressure, FPG; fasting plasma glucose, HOMA-R; homeostasis model assessment of insulin resistance, AST; aspartate aminotransferase, ALT; alanine aminotransferase, eGFR; estimated glomerular filtration rate, UA; uric acid, TG; triglycerides, HDL-C; high-density lipoprotein cholesterol, LDL-C; low-density lipoprotein cholesterol, hsCRP; high-sensitivity C-reactive protein, APN; adiponectin, sT-cad; soluble T-cadherin. Statistical analysis was performed with ＊; Student’s t test, +; chi-square test, or ＊＊; Wilcoxon test.
Table 2. Correlations between serum concentrations of 130-kDa, 100-kDa, and 30-kDa soluble T-cadherin (sT-cad) and clinical parameters in male participants.
| Male (N = 825) | vs. 130-kDa sT-cad | vs. 100-kDa sT-cad | vs. 30-kDa sT-cad | |||
|---|---|---|---|---|---|---|
| r | P | r | P | r | P | |
| Age (years) | -0.02 | 0.652 | 0.06 | 0.094 | 0.21 | ＜0.001 |
| BMI | -0.18 | ＜0.001 | 0.03 | 0.366 | 0.04 | 0.222 |
| WC (cm) | -0.19 | ＜0.001 | 0.02 | 0.506 | 0.03 | 0.329 |
| Systolic BP (mmHg) | -0.11 | ＜0.001 | 0 | 0.939 | -0.06 | 0.085 |
| Diastolic BP (mmHg) | -0.1 | 0.005 | 0 | 0.984 | -0.12 | ＜0.001 |
| FPG (mg/dL) | -0.04 | 0.211 | 0.04 | 0.272 | 0.05 | 0.171 |
| HbA1c (%) | -0.07 | 0.036 | 0.04 | 0.244 | 0.04 | 0.207 |
| HOMA-R | -0.18 | ＜0.001 | 0.03 | 0.353 | 0.10 | 0.003 |
| AST (U/L) | -0.01 | 0.86 | 0.1 | 0.003 | 0 | 0.995 |
| ALT (U/L) | -0.09 | 0.012 | 0.07 | 0.045 | -0.05 | 0.156 |
| eGFR | 0.03 | 0.45 | -0.12 | ＜0.001 | -0.44 | ＜0.001 |
| UA (mg/dL) | -0.12 | ＜0.001 | 0.03 | 0.411 | 0.06 | 0.107 |
| Log TG (mg/dL) | -0.23 | ＜0.001 | -0.07 | 0.058 | 0.05 | 0.164 |
| HDL-C (mg/dL) | 0.18 | ＜0.001 | 0.05 | 0.127 | -0.1 | 0.006 |
| LDL-C (mg/dL) | 0.01 | 0.704 | 0.08 | 0.018 | -0.03 | 0.342 |
| hsCRP (mg/dL) | -0.12 | ＜0.001 | -0.07 | 0.062 | -0.02 | 0.516 |
| Platelet (x104/μL) | -0.11 | ＜0.001 | -0.10 | ＜0.001 | -0.12 | ＜0.001 |
| FIB-4 Index | 0.12 | ＜0.001 | 0.14 | ＜0.001 | 0.20 | ＜0.001 |
| Log APN (μg/mL) | 0.18 | ＜0.001 | -0.09 | 0.01 | 0.05 | 0.19 |
Pearson’s correlation coefficients (r) and probability values (P) are shown. Values with |r|＜0.15 (with certain levels of correlation) and P＜0.05 (with statistical significance) are presented in bold font. T-cad; T-cadherin, BMI; body mass index, WC; waist circumference, BP; blood pressure, FPG; fasting plasma glucose, HOMA-R; homeostasis model assessment of insulin resistance, AST; aspartate aminotransferase, ALT; alanine aminotransferase, eGFR; estimated glomerular filtration rate, UA; uric acid, TG; triglycerides, HDL-C; high-density lipoprotein cholesterol, LDL-C; low-density lipoprotein cholesterol, hsCRP; high-sensitivity C-reactive protein, APN; adiponectin.
Table 3. Correlations between serum concentrations of 130-kDa, 100-kDa, and 30-kDa soluble T-cadherin (sT-cad) and clinical parameters in female participants.
| Female (N = 496) | vs. 130-kDa sT-cad | vs. 100-kDa sT-cad | vs. 30-kDa sT-cad | |||
|---|---|---|---|---|---|---|
| r | P | r | P | r | P | |
| Age (years) | 0.03 | 0.55 | 0.22 | ＜0.001 | 0.23 | ＜0.001 |
| BMI | -0.24 | ＜0.001 | 0.01 | 0.805 | 0.02 | 0.727 |
| WC (cm) | -0.22 | ＜0.001 | 0.05 | 0.255 | 0.08 | 0.06 |
| Systolic BP (mmHg) | -0.03 | 0.463 | 0.06 | 0.198 | 0.07 | 0.122 |
| Diastolic BP (mmHg) | -0.03 | 0.525 | 0.00 | 0.926 | 0.06 | 0.152 |
| FPG (mg/dL) | -0.17 | ＜0.001 | -0.01 | 0.74 | -0.01 | 0.764 |
| HbA1c (%) | -0.13 | 0.004 | 0.02 | 0.698 | 0.00 | 0.932 |
| HOMA-R | -0.28 | ＜0.001 | -0.04 | 0.33 | -0.02 | 0.724 |
| AST (U/L) | 0.04 | 0.386 | 0.11 | 0.019 | 0.05 | 0.311 |
| ALT (U/L) | -0.12 | 0.008 | 0.02 | 0.663 | 0 | 0.987 |
| eGFR | -0.13 | 0.004 | -0.24 | ＜0.001 | -0.35 | ＜0.001 |
| UA (mg/dL) | -0.15 | ＜0.001 | 0.03 | 0.54 | 0.16 | ＜0.001 |
| Log TG (mg/dL) | -0.20 | ＜0.001 | 0.03 | 0.534 | -0.01 | 0.804 |
| HDL-C (mg/dL) | 0.27 | ＜0.001 | 0.04 | 0.374 | 0.05 | 0.237 |
| LDL-C (mg/dL) | 0.00 | 0.981 | 0.07 | 0.099 | -0.02 | 0.594 |
| hsCRP (mg/dL) | -0.18 | ＜0.001 | -0.06 | 0.197 | -0.09 | 0.041 |
| Platelet (x104/μL) | -0.10 | 0.020 | -0.07 | 0.123 | -0.13 | ＜0.001 |
| FIB-4 Index | 0.14 | ＜0.001 | 0.19 | ＜0.001 | 0.21 | ＜0.001 |
| Log APN (μg/mL) | 0.26 | ＜0.001 | -0.04 | 0.378 | 0.04 | 0.371 |
(See the legend of Table 2.)
Table 4. Multiple regression analysis for serum concentration of 130-kDa soluble T-cadherin (sT-cad) in male and female participants.
| for 130-kDa sT-cad | Males | Females | ||||
|---|---|---|---|---|---|---|
| Stdβ | VIF | P | Stdβ | VIF | P | |
| Age (years) | 0.019 | 1.300 | 0.625 | 0.067 | 1.422 | 0.182 |
| WC (cm) | -0.057 | 1.569 | 0.179 | 0.000 | 1.633 | 0.993 |
| Log (APN (μg/mL)) | 0.065 | 1.371 | 0.098 | 0.126 | 1.345 | 0.010 |
| Hyperglycemia | 0.039 | 1.205 | 0.288 | -0.052 | 1.175 | 0.252 |
| Elevated BP | -0.044 | 1.249 | 0.239 | 0.027 | 1.283 | 0.579 |
| High TG/low HDL-C | -0.148 | 1.234 | ＜0.001 | -0.140 | 1.304 | 0.004 |
| Fatty Liver | -0.069 | 1.570 | 0.101 | -0.121 | 1.607 | 0.024 |
| Uric acid | -0.049 | 1.116 | 0.166 | -0.060 | 1.202 | 0.199 |
| Log (hsCRP (mg/dL)) | -0.085 | 1.172 | 0.020 | -0.129 | 1.271 | 0.007 |
Pearson’s correlation standardized beta coefficient (Stdβ), variance inflation factor (VIF), and probability value (P) are shown. Values with P＜0.05 are presented in bold font. WC; waist circumference, APN; adiponectin, BP; blood pressure, hsCRP; high-sensitivity C-reactive protein.
Fig.2. Definitions of “metabolically healthy” and metabolic syndrome in this study.
FPG; fasting plasma glucose, DM; diabetes mellitus, SBP; systolic blood pressure, DBP; diastolic blood pressure, HT; hypertension, TG; triglycerides, HDL-C; high-density lipoprotein cholesterol, DLp; dyslipidemia
Fig.3. Changes in 130-kDa soluble T-cadherin (sT-cad) and adiponectin levels in response to metabolic syndrome in males (A, B) and females (C, D).
Data are shown as box-and-whisker plots. Steel test (vs Group I) was performed, and the P values were represented above the plots. Jonckheere–Terpstra trend test was performed, and the P values were represented at the bottom of the figure. I: “metabolically healthy” group, II: visceral fat accumulated group, III: pre-Metabolic syndrome group, IV: Metabolic syndrome group.
In Supplemental Tables 3 and 4 , diabetes mellitus was defined as fasting plasma glucose ≥ 126 mg/dL and HbA1c ≥ 6.5%. Hypertension was defined as systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg. Dyslipidemia (as disease criteria) was defined as TG ≥ 150 mg/dL and/or HDL-C ＜40 mg/dL and/or LDL-C ≥ 140 mg/dL, according to the guideline for each disease 24 - 26) . Participants receiving antidiabetic and/or antihypertensive and/or antidyslipidemic medications were considered positive for each disease. Fatty liver was diagnosed based on characteristic echogenic findings, such as increased hepatic echogenicity compared with the renal cortex, attenuation of the ultrasound beam, and poor visualization of intrahepatic vessels 27) .
Supplemental Table 3. Characteristics of 38 participants with ABI/PWV data.
| Total (N = 38) | Male (N = 24) | Female (N = 14) | |
|---|---|---|---|
| Age (years) | 63.29±9.83 | 64.33±10.18 | 61.50±9.30 |
| BMI | 24.55±3.63 | 25.45±3.58 | 23.01±3.29 |
| WC (cm) | 86.45±8.94 | 88.5±7.95 | 82.93±9.72 |
| ABI | 1.17±0.07 | 1.18±0.07 | 1.14±0.06 |
| hsCRP (mg/dL) | 0.07 [0.02–0.52] | 0.075 [0.02–0.52] | 0.05 [0.02–0.33] |
| APN (μg/mL) | 8.1 [3–27] | 6.35 [3–27] | 11.7 [7.4–20.8] |
| 130-kDa sT-cad (pmol/L) | 371.48±131.19 | 353.58±131.75 | 402.15±129.12 |
| Diabetes (N) | 5 | 5 | 0 |
| Hypertension (N) | 18 | 13 | 5 |
| Dyslipidemia (N) | 23 | 14 | 9 |
| Smoking (Current/Former/Never) | 5/7/26 | 3/5/16 | 2/2/10 |
Data are shown as the mean±standard deviation, median[minimum–maximum], or number of participants. BMI; body mass index, WC; waist circumference, ABI; ankle–brachial index, hsCRP; high-sensitivity C-reactive protein, APN; adiponectin, sT-cad; soluble T-cadherin.
Supplemental Table 4. Single and multiple regression analyses between ankle–brachial Index (ABI) and clinical parameters in 38 participants.
| Single regression model | Multiple regression model | |||||
|---|---|---|---|---|---|---|
| vs. ABI | Model 1 | Model 2 | ||||
| r | P | std β | P | std β | P | |
| 130-kDa sT-cad (pmol/L) | 0.373 | 0.021 | 0.479 | 0.002 | 0.428 | 0.007 |
| Age (years) | 0.048 | 0.773 | - | - | - | - |
| Sex (Female) | NA | 0.035 | -0.304 | 0.058 | -0.413 | 0.011 |
| Visceral fat accumulation (Yes) | NA | 0.076 | - | - | - | - |
| Diabetes (Yes) | NA | 0.465 | - | - | 0.006 | 0.967 |
| Hypertension (Yes) | NA | 0.702 | - | - | - | - |
| Dyslipidemia (Yes) | NA | 0.650 | - | - | - | - |
| Smoker (Current/Former) | NA | 0.206 | - | - | -0.111 | 0.454 |
| log (APN (μg/mL)) | -0.321 | 0.049 | -0.270 | 0.091 | - | - |
| log (hsCRP (mg/dL)) | 0.166 | 0.321 | - | - | - | - |
Pearson’s correlation coefficient (r), standardized beta coefficient (stdβ), and probability value (P) are shown. Values with P＜0.05 are presented in bold font. Model 1 is adjusted for 130-kDa sT-cad, sex, and log(APN). Model 2 is adjusted for the 130-kDa sT-cad, sex, diabetes, and smoking status. sT-cad; soluble T-cadherin, APN; adiponectin, hsCRP; high-sensitivity C-reactive protein, NA; not applicable.
2.4 Measurement of Adiponectin and Soluble T-cadherin
Serum adiponectin levels were measured by latex particle-enhanced turbidimetric immunoassay (Human Adiponectin Latex Kit; Otsuka Pharmaceutical Co., Tokyo, Japan) at Sumitomo Hospital. Serum soluble T-cadherin levels were measured by Human T-cadherin (130K) Assay kit, Human T-cadherin (100K+130K) Assay kit, and Human T-cadherin (30K+130K) Assay kit (Immuno-Biological Laboratories Co., Ltd.), as reported previously 19) . Serum samples were stored at −30℃ until analysis.
2.5 Statistical Analysis
All statistical analyses were performed using JMP(R) Student Edition 18.2.1 software (JMP Statistical Discovery LLC, Cary, NC, USA). Probability (P) values ＜0.05 were considered to indicate statistical significance.
3. Results
3.1 Characteristics of Participants
The clinical characteristics of these 1321 participants are shown in Table 1 . Various clinical parameters, especially age, BMI, and the frequency of factors associated with metabolic syndrome (such as hyperglycemia, elevated blood pressure, high TG/low HDL-C, and fatty liver), significantly differed between males and females. Serum APN, 130-kDa sT-cad, and 30-kDa sT-cad levels were significantly lower in males than in females, although 100-kDa sT-cad levels did not significantly differ between the two groups.
3.2 Correlations between sT-cad Levels and Clinical Parameters
We first examined the correlations between each form of sT-cad and clinical parameters. In males ( Table 2 ) , 130-kDa sT-cad was significantly negatively correlated with body mass index (BMI), waist circumference, blood pressure, HbA1c, HOMA-R, ALT, uric acid, triglycerides, platelets, and high-sensitivity C-reactive protein (hsCRP) and significantly positively correlated with high-density lipoprotein cholesterol (HDL-C) and APN. Among these, the correlation coefficients with BMI, waist circumference, HOMA-R, triglycerides, HDL-C, FIB-4 index, and APN were slightly greater (|r| ＞0.15) than those with the other parameters. In contrast, 100-kDa and 30-kDa sT-cad were negatively correlated only with the estimated glomerular filtration rate (eGFR), with a comparatively higher correlation coefficient (r = -0.44 at 30-kDa). Similar correlation patterns were observed in females ( Table 3 ) ; however, 130-kDa sT-cad was not significantly correlated with blood pressure but was negatively correlated with fasting plasma glucose and the eGFR.
Among the three sT-cad isoforms, the 130-kDa form correlated with the greatest number of clinical parameters. We subsequently investigated which parameters influenced 130-kDa sT-cad levels using multivariable regression analysis ( Table 4 ) . In both males and females, high TG/low HDL-C and hsCRP were significant negative explanatory factors for 130-kDa sT-cad after age adjustment. Additionally, in females, APN and fatty liver were also significant, with similar trends observed in males.
3.3 Association between sT-cad and Metabolic Syndrome
Both univariate ( Tables 2 and 3 ) and multivariate analyses ( Table 4 ) revealed that serum 130-kDa sT-cad levels were associated not only with APN but also with key components of metabolic syndrome, including high TG/low HDL-C, hsCRP, and fatty liver. Moreover, the absolute values of the standardized β coefficients (Stdβ) for these factors were comparable to or even greater than those of APN in both sexes, suggesting that these factors related to metabolic syndrome may influence 130-kDa sT-cad levels independently.
Fig.2 shows the classification of the study participants according to the Japanese criteria for metabolic syndrome. The clinical characteristics of each group are shown in Supplemental Tables 1 and 2 . As shown in Fig.3 , serum 130-kDa sT-cad levels in males significantly decreased linearly with increasing numbers of metabolic risk factors (P for trend ＜0.001; Fig.3(A) ). Although serum APN levels also tended to significantly decrease, the pattern differed from that of 130-kDa sT-cad; a marked decrease was observed between Group I and Group II (without or with visceral fat accumulation in Fig.3(B) , P＜0.001), whereas changes from Group II to Group IV were relatively modest (Fig.3(B)) . Similar trends were observed in females (Fig.3(C)–(D)) . In contrast, serum 100-kDa and 30-kDa sT-cad levels showed no significant changes in either sex ( Supplemental Fig.1 ) .
Supplemental Table 1. Characteristics of male participants divided by the criteria for metabolic syndrome are shown in Fig. 3.
| Male (N=825) |
I “metabolically healthy” |
II visceral fat accumulated |
III pre-Metabolic syndrome |
IV Metabolic syndrome |
|---|---|---|---|---|
| N | 152 | 96 | 144 | 219 |
| Age (years) | 51.5±11 | 51.7±9.3 | 57.1±10.4 | 61.8±10.1 |
| BMI | 21.2±2 | 25.1±2.3 | 25.5±2.5 | 26.7±3.4 |
| WC (cm) | 77.5±4.9 | 90±4.9 | 91.4±5.5 | 94.1±7.5 |
| SBP (mmHg) | 112.3±12.7 | 114.2±8.8 | 124.9±14 | 127.7±16.1 |
| DBP (mmHg) | 68.2±10.4 | 69.2±7.9 | 77.4±10.7 | 77.3±11.8 |
| FPG (mg/dL) | 98±7.2 | 97.8±5.9 | 103.3±9.9 | 115±20.7 |
| HbA1c (%) | 5.5±0.2 | 5.5±0.3 | 5.6±0.3 | 6±0.7 |
| HOMA-R | 1.11 [0.37–3.43] | 1.63 [0.16–4.76] | 1.95 [0.34–8.99] | 2.57 [0.63–13.13] |
| AST (U/L) | 21.3±5.3 | 22.2±6.7 | 23.7±7.1 | 26.8±11.3 |
| ALT (U/L) | 20.3±8.3 | 25.4±15.7 | 28.3±12.8 | 31.8±20.9 |
| eGFR | 73.6±12.1 | 71.4±12.9 | 68.6±11.4 | 63.6±13.5 |
| UA (mg/dL) | 5.9±1.1 | 6.2±1.2 | 6.4±1.2 | 6.5±1.2 |
| HDL-C (mg/dL) | 70.4±15.6 | 61.5±12.3 | 62.4±14.5 | 55.5±14.4 |
| TG (mg/dL) | 69.5 [33–146] | 90.5 [29–143] | 104 [48–353] | 137 [35–938] |
| LDL-C (mg/dL) | 110.8±19.2 | 133.4±27.5 | 127.5±29.3 | 117.3±32 |
| hsCRP (mg/dL) | 0.04 [0–3.42] | 0.065 [0.02–0.48] | 0.07 [0–3.48] | 0.10 [0–5.27] |
| APN (μg/mL) | 10.1 [2.4–39.2] | 7.8 [3.3–30.3] | 7.2 [3–19.8] | 6.4 [2.2–30.2] |
| 130-kDa sT-cad (pM) | 404.8±125.3 | 381.9±119.9 | 353.4±106.9 | 334.6±122.1 |
| 100-kDa sT-cad (pM) | 1001.2±284.6 | 1042.4±263.7 | 1074.3±320.9 | 1028.8±308.4 |
| 30-kDa sT-cad (pM) | 774.2±215.9 | 755.9±246.3 | 763.3±295.2 | 851.6±456.5 |
Data are shown as the mean±S.D. for normally distributed parameters or median [minimum–maximum] for skewed parameters. BMI; body mass index, WC; waist circumference, SBP; systolic blood pressure, DBP; diastolic blood pressure, FPG; fasting plasma glucose, eGFR; estimated glomerular filtration rate, UA; uric acid, HDL-C; high-density lipoprotein cholesterol, TG; triglycerides, LDL-C; low-density lipoprotein cholesterol, APN; adiponectin, sT-cad; soluble T-cadherin.
Supplemental Table 2. Characteristics of female participants divided by the criteria for metabolic syndrome are shown in Fig. 3.
| Female (N = 496) |
I “metabolically healthy” |
II visceral fat accumulated |
III pre-Metabolic syndrome |
IV Metabolic syndrome |
|---|---|---|---|---|
| N | 217 | 10 | 18 | 18 |
| Age (years) | 49.7±9.6 | 50.5±8.1 | 56.4±12.5 | 57.8±8.2 |
| BMI | 20.2±2.3 | 24.7±1.6 | 27.3±3.1 | 28.8±3.1 |
| WC (cm) | 73.7±6.9 | 92.4±2 | 98.2±5.9 | 98.5±7.6 |
| SBP (mmHg) | 108.9±13.3 | 108.8±9.5 | 120.7±18.1 | 131.9±12.5 |
| DBP (mmHg) | 64.8±9.9 | 66.1±6.6 | 72.9±13.3 | 81.1±8.6 |
| FPG (mg/dL) | 92.8±7.3 | 98.7±7.9 | 93.3±6.4 | 116.5±22.1 |
| HbA1c (%) | 5.5±0.3 | 5.6±0.3 | 5.7±0.3 | 6.3±0.8 |
| HOMA-R | 1.08 [0.26–3.71] | 2.215 [1.15–3.63] | 2.065 [0.8–4.74] | 3.53 [1.3–9.78] |
| AST (U/L) | 19.8±4.6 | 25.8±21 | 20.8±7.6 | 24.4±7 |
| ALT (U/L) | 16.6±7.2 | 26.7±34.4 | 21.4±14 | 30.9±16.3 |
| eGFR | 75.9±13.8 | 62.7±18.3 | 72.6±20.1 | 75.9±39.6 |
| UA (mg/dL) | 4.3±0.9 | 6.5±1.6 | 5.4±1.4 | 5.5±0.9 |
| HDL-C (mg/dL) | 79.5±16.5 | 76.1±26.6 | 70.5±12 | 53.5±10.8 |
| TG (mg/dL) | 64 [20–144] | 103.5 [57–127] | 102.5 [34–187] | 123 [84–622] |
| LDL-C (mg/dL) | 108.8±20.5 | 142.3±28.2 | 125.3±25.2 | 132.6±31.1 |
| hsCRP (mg/dL) | 0.04 [0–1.41] | 0.10 [0.04–0.46] | 0.17 [0.02–1.3] | 0.14 [0.03–0.98] |
| APN (μg/mL) | 12.5 [1.9–44.2] | 11.55 [5.5–13.3] | 10.55 [6.1–21] | 7.7 [4.8–14.7] |
| 130-kDa sT-cad (pM) | 424.1±129.9 | 363.6±140.9 | 376.6±155.2 | 281.7±86.7 |
| 100-kDa sT-cad (pM) | 997.8±283.9 | 1020.8±174.2 | 1022.2±362.5 | 934.4±229.9 |
| 30-kDa sT-cad (pM) | 678.8±233 | 877±817.3 | 737.5±244 | 705.3±210.8 |
Data are shown as the mean±S.D. for normally distributed parameters or median [minimum–maximum] for skewed parameters. BMI; body mass index, WC; waist circumference, SBP; systolic blood pressure, DBP; diastolic blood pressure, FPG; fasting plasma glucose, eGFR; estimated glomerular filtration rate, UA; uric acid, HDL-C; high-density lipoprotein cholesterol, TG; triglycerides, LDL-C; low-density lipoprotein cholesterol, APN; adiponectin, sT-cad; soluble T-cadherin.
Supplemental Fig.1. Changes in 100-kDa and 30-kDa soluble T-cadherin (sT-cad) levels towards metabolic syndrome in males (A, B) and females (C, D).
Data are shown as box-and-whisker plots. Jonckheere–Terpstra trend test was performed. I: “metabolically healthy” group, II: visceral fat accumulated group, III: pre-Metabolic syndrome group, IV: Metabolic syndrome group.
3.4 Exploratory Analysis: Association between sT-cad and the Ankle–brachial Index
Based on the findings described above, an association between 130-kDa sT-cad and metabolic syndrome has been shown. To further explore its relevance to atherosclerosis—a clinical consequence of metabolic syndrome—we conducted an exploratory analysis in a subset of participants for whom the ankle–brachial index (ABI) was available. Supplemental Table 3 shows the characteristics of 38 individuals who have ABI data. As shown in Supplemental Table 4 , univariate analysis revealed a significant positive correlation between 130-kDa sT-cad and the ABI (r = 0.373, P = 0.021). Multivariate analyses revealed that the 130-kDa sT-cad remained a significant positive explanatory factor for ABI even after adjustment for factors significantly correlated with the ABI in a single regression model (Model 1, P = 0.002) and for the well-known risk factors for PAD, such as age, diabetes, and smoking habit (Model 2, P = 0.007).
4. Discussion
In the present study, we investigated serum concentrations of soluble T-cadherin (sT-cad) in a cohort of participants undergoing health checkups, including healthy individuals. Our key findings are as follows:
(1) Serum 130-kDa sT-cad levels were significantly correlated not only with APN but also with BMI, waist circumference, impaired glucose metabolism (fasting plasma glucose, HbA1c, and/or HOMA-R), ALT, uric acid, TG, HDL-C, FIB-4 index, platelets, and hsCRP in both males and females ( Tables 2 and 3 ) . Among these factors related to metabolic syndrome, high TG/low HDL-C and hsCRP were significantly negatively correlated with the 130-kDa sT-cad form ( Table 4 ) .
(2) The more metabolic syndrome risk factors accumulated, the lower the serum levels of 130-kDa sT-cad ( Fig.3 ) .
We previously reported correlations between the 130-kDa form of sT-cad and BMI, waist circumference, HDL-C, hsCRP, and APN in patients with type 2 diabetes 19) . The results of the current study, conducted in a larger cohort including healthy individuals and patients with diseases other than diabetes (e.g., hypertension and dyslipidemia), confirmed that the 130-kDa sT-cad is significantly correlated with these metabolic syndrome-related factors. For the 100-kDa and 30-kDa forms of sT-cad, a relatively strong correlation was observed only with renal function (eGFR), which is consistent with our previous report 19) . In this study, we identified for the first time a significant positive correlation between the FIB-4 index and sT-cad. Among the components of the FIB-4 index (age, AST, ALT, and platelet count), platelet count seemed to be the main contributor to the correlation with sT-cad. Further investigation will be needed to clarify the physiological significance of the relationships between sT-cad, FIB-4 index, and/or platelets.
In this study, the levels of both 130-kDa sT-cad ( Figs.3A and 3C ) and APN ( Figs.3B and 3D ) decreased significantly in association with an increasing number of metabolic syndrome components. APN is an adipocyte-specific secretory protein, and its circulating levels decrease with excessive accumulation of visceral fat 7) . APN binds to membrane-anchored T-cadherin expressed in the vascular endothelium, skeletal muscle, and myocardium, positively regulating the abundance of this protein, especially the 130-kDa form 18) . Assuming that circulating sT-cad reflects the amount of tissue membrane-anchored T-cad, a reduction in serum APN with visceral fat accumulation would decrease membrane-anchored T-cad in these tissues, thereby lowering circulating sT-cad levels. Indeed, the expected changes were observed between Group I (metabolically healthy) and Group II (visceral fat accumulated).
Interestingly, 130-kDa sT-cad levels continued to decline stepwise, particularly in males, even between Groups II and IV ( Fig.3A ) , where the decrease in APN levels was relatively modest ( Fig.3B ) . We recently reported that endoplasmic reticulum (ER) stress reduces T-cad mRNA levels 28) . In metabolic syndrome, obesity-related hyperglycemia, elevated BP, high TG/low HDL-C, chronic inflammation, and adipocytokine dysregulation are thought to induce ER stress 29 - 32) , which can suppress the expression of membrane-anchored T-cad in the vascular endothelium, skeletal muscle, and myocardium, leading to reduced sT-cad levels in serum. Furthermore, even after adjustment for waist circumference and serum APN, high TG/low HDL-C and hsCRP in men and high TG/low HDL-C, fatty liver, and hsCRP in women, remained significant determinants of the 130-kDa sT-cad level ( Table 4 ) . These findings suggest that while serum APN levels are influenced predominantly by visceral fat accumulation, 130-kDa sT-cad levels are affected not only by APN but also by various metabolic abnormalities, which may account for the differences in their declining patterns.
Inflammation is strongly associated with the development of atherosclerosis and plays a central role in plaque formation, progression, and destabilization 33) . Chronic inflammation is linked to ER stress in vascular endothelial cells 31) , which may reduce the levels of membrane-bound T-cadherin in the endothelium 28) and thereby attenuate organ-protective effects. Hence, soluble T-cadherin, particularly the 130-kDa form, may serve as a marker reflecting the amount of membrane-bound T-cadherin in the tissue. Indeed, hsCRP was identified as a significant negative explanatory factor for 130-kDa soluble T-cadherin ( Table 4 ) . Furthermore, our exploratory analysis ( Supplemental Tables 3 and 4 ) suggested a significant positive correlation between the 130-kDa sT-cad and the ABI. Furthermore, this correlation remained significant after adjustment for well-known risk factors for PAD, including sex, diabetes, and smoking habit ( Supplemental Table 4 , Model 2). The range of ABI values in our study (1.03–1.29) is generally considered to be within the normal range. However, Aboyans et al. reported that the hazard ratio for all-cause mortality was significantly greater in the group with an ABI of 1.01–1.10 than in the reference group with an ABI of 1.11–1.20 34) . Similarly, Wassel et al. investigated a cohort with a mean ABI of 1.10±0.11 and argued that even subtle differences in ABI within the normal range may help identify subclinical PAD 35) . Thus, low levels of the 130-kDa sT-cad might serve as a potential biomarker or therapeutic target for PAD.
This study has several limitations. Its single-center, cross-sectional design precludes any conclusions about causality. The assessment of visceral fat accumulation was based on waist circumference rather than direct measurement of visceral fat area. Given that the number of female participants with visceral fat accumulation and metabolic syndrome was small, potential sex differences were not fully elucidated. Further validation in cohorts including patients with more advanced atherosclerosis is needed to determine whether low 130-kDa sT-cad levels in metabolic syndrome contribute to the development of atherosclerosis.
In conclusion, low serum levels of 130-kDa soluble T-cadherin are associated with metabolic syndrome in Japanese participants undergoing health checkups. Further studies are needed to establish whether the 130-kDa sT-cad can serve as a novel biomarker reflecting metabolic abnormalities.
Acknowledgements
We thank the medical staff of Sumitomo Hospital Physical Checkup Center and Sumitomo Hospital for recruiting participants and collecting blood samples. We also thank all members of the Third Laboratory (Adiposcience Laboratory), Department of Metabolic Medicine, Osaka University, for helpful discussion of the project.
Funding
This work was supported in part by Grants-in-Aid for Scientific Research [T23K080060 to HNi, T24K025040 to IS, T24K116750 to YF], Grant-in-Aid for Early Career Scientists [T24K192890 to SF, T24K193050 to HNa], AMED-CREST [to IS], Grants from the Manpei Suzuki Diabetes Foundation [to SF, to HNa], Lotte Research Promotion Grant (to HNa), the MSD Life Science Foundation, Public Interest Incorporated Foundation [to SF, to HNa], Japan Diabetes Society Junior Scientist Development Grant supported by Novo Nordisk Pharma Ltd. [to SF], Research Grants from Kowa Life Science Foundation [to SF], Joint Research Grants with Kowa Pharmaceutical [to IS], and Uehara Memorial Foundation [to IS]. The funding agencies had no role in the study design, data collection and analysis, decision to publish, or preparation of the article.
Conflicts of Interest
The authors declare no relationships or activities to disclose that might bias this work.
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