High Serum Adipocyte Fatty Acid Binding Protein Is Associated with Metabolic Syndrome in Patients with Type 2 Diabetes

Adipocyte fatty acid binding protein (A-FABP) is a key mediator of obesity-related metabolic syndrome (MetS). The aim of this study was to evaluate the relationship between A-FABP concentration and MetS in type 2 diabetes mellitus (DM) patients. Fasting blood samples were obtained from 165 type 2 DM volunteers. MetS and its components were defined using diagnostic criteria from the International Diabetes Federation. Among 165 DM patients, 113 patients (68.5%) had MetS. Diabetic persons who had MetS had significantly higher A-FABP levels (P < 0.001) than those without MetS. Female DM persons had higher A-FABP level than man (P < 0.001). No statistically significant differences in A-FABP levels were found in use of statin, fibrate, or antidiabetic drugs. Multivariate forward stepwise linear regression analysis revealed that body fat mass (P < 0.001), logarithmically transformed creatinine (log-creatinine; P < 0.001), female DM patients (P < 0.001), and logarithmically transformed high sensitive C-reactive protein (log-hs-CRP; P = 0.013) were positively correlated, while albumin (P = 0.004) and glomerular filtration rate (GFR; P = 0.043) were negatively correlated with serum A-FABP levels in type 2 DM patients. In this study, higher serum A-FABP level was positively associated with MetS in type 2 DM patients.


Introduction
Metabolic syndrome (MetS) is a clustering of metabolic risk factors for atherosclerotic cardiovascular disease and diabetes mellitus (DM) [1]. There are more than 415 million people affected by DM worldwide and it is one of the most important public health challenges of the twenty-first century [2].
Adipocyte fatty acid binding protein (A-FABP) is one of the most abundant proteins in mature adipocytes, which is known for the ability to bind fatty acids and related compounds throughout various cellular compartments, including the peroxisomes, mitochondria, endoplasmic reticulum, lipid droplets, and nucleus [3,4]. A-FABP has been shown to affect insulin sensitivity, lipid metabolism, and lipolysis in animal studies [3]. Furthermore, studies also found that A-FABP is a key mediator for the obesity-related cardiovascular disease and is positively associated with MetS [3,5]. Our previous studies noted that A-FABP was associated with MetS in coronary artery disease and in hemodialysis patients [6,7]. The aim of this study was to investigate the relationship between fasting serum A-FABP level and the MetS among type 2 DM patients.  morning using standard mercury sphygmomanometers with appropriate cuff sizes after sitting for at least 10 minutes. Systolic BP (SBP) and diastolic BP (DBP) were taken 3 times at 5 min intervals and were averaged for analysis. Patients who were diagnosed with hypertension were defined as SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg or have received any antihypertensive medication in the past 2 weeks. Patients were excluded if they had an acute infection, acute myocardial infarction, heart failure, and malignancy at the time of blood sampling, or if they refused to provide informed consent for the study.

Anthropometric
Analysis. Body weight of participant was measured in light clothing and without shoes to the nearest 0.5 kilograms, and body height was measured to the nearest 0.5 cm. Waist circumference was measured using a tape measurement around the waist from the point between the lowest ribs and the hip bones with the hands on the hips. Body mass index (BMI) was calculated as the weight in kilograms divided by the height in meters squared. Bioimpedance measurements of fat mass were performed at the bedside according to the standard tetrapolar whole body (handfoot) technique, using a single-frequency (50 kHz) analyzer (Biodynamic-450, Biodynamics Corporation, Seattle, USA). Measurements were carried out by the same operator [6-8].

Results
Clinical characteristics of the 165 type 2 DM patients are presented in Table 1. One hundred thirteen DM persons (68.5%) had MetS, and 52 DM persons (31.5%) did not. Diabetic persons who had MetS had significantly higher serum fasting A-FABP levels than those without MetS ( < 0.001). Compared with DM patients without MetS, those with MetS showed a much higher proportion of females ( = 0.002) and as expected more hypertension ( = 0.001),  Clinical characteristics and serum A-FABP values for the 165 DM patients are presented in Table 2. A-FABP level was statistically significantly higher in female DM persons than male DM persons ( < 0.001). No statistically significant differences in A-FABP levels were found as a function of smoking; presence of hypertension; or use of statin, fibrate, or antidiabetic drugs.
Univariate linear analysis of clinical variables associated with fasting serum A-FABP levels in DM patients is presented in Table 3 (Table 4).

Discussion
Our study showed that fasting A-FABP levels were higher in type 2 DM patents with MetS, and body fat mass, creatinine, female, albumin, hs-CRP, and GFR were independent predictors of serum A-FABP levels in type 2 DM patients.
MetS is defined by the presence of central obesity, hyperglycemia, type 2 DM, hypertension, and dyslipidemia [11]. The prevalence of MetS was 46.9% for males and 65.1% for females in type 2 DM patients in a Korean study [13] and 78.6% in type 2 DM patients in Brazil [14]. In this study, the prevalence of MetS in type 2 DM patients is 68.5%. MetS is strongly associated with insulin resistance and inflammation [11]. Patients with type 2 DM and MetS showed significantly higher blood CRP and insulin resistance than type 2 DM without MetS [13]. Our study noted that diabetic persons who had MetS had significantly higher in-body fat mass, HbA1c level, hs-CRP, insulin level, and HOMA-IR than those diabetic persons without MetS. Females are at greater risk of obesity and central adiposity due to their increased propensity to gain fat [15]. Our results found that diabetic persons who had MetS had higher trend in female gender. MetS and its components are associated with the development of chronic kidney disease and microalbuminuria or overt proteinuria [16]. Type 2 DM patients with MetS are associated with the reduction of GFR [14]. Our study also noted that MetS in patients with type 2 DM had higher serum BUN level and lower GFR.
Studies in A-FABP knockout mice and A-FABP inhibitor treated animals suggest that A-FABP has an important role in lipolysis and regulating insulin sensitivity [3,5,17,18]. Recent studies also demonstrated A-FABP expression in macrophages and modulate inflammatory responses and cholesterol ester accumulation [3,5,19]. All of these results indicate that A-FABP has an important role in the development of major components of the MetS through its distinct Table 4: Multivariable stepwise linear regression analysis of gender, height, body mass index, waist circumference, body fat mass, systolic blood pressure, diastolic blood pressure, albumin, total cholesterol, log-triglyceride, log-HbA1c, log-BUN, log-creatinine, glomerular filtration rate, log-CRP, log-insulin, and log-HOMA-IR: correlation to fasting serum adipocyte fatty acid binding protein level among 165 diabetic patients.

Items
Beta  [24]. Our study also noted that female diabetic patients had higher A-FABP levels than man. In type 2 DM patients, A-FABP levels were positively correlated with BMI, TG, TCH, SBP, waist circumference, IL-6, TNF-, and hs-CRP [23,25]. Furthermore, A-FABP levels were positively correlated with plasma TG, apolipoprotein C-III, and all the components of TG-rich lipoproteins in type 2 diabetic subjects [26]. A-FABP levels positively correlated with BMI, glucose, insulin levels, HOMA-IR, and CRP in morbidly obese women [27]. Subjects in the highest A-FABP tertile at baseline exhibited higher values for BMI, body fat mass, blood pressure, fasting glucose, TCH, TG, LDL-C, insulin, and HOMA-IR in a total of 465 participants in a Korean study [21]. A-FABP was independently associated with body fat mass in a cohort of Chinese women without DM [28]. Serum A-FABP concentrations were positively associated with serum creatinine and albumin and predict a worse hospital outcome in critically ill patients with sepsis [29]. Since serum creatinine is a component of the GFR estimation. Studies also noted serum A-FABP4 levels correlated positively with serum creatinine and negatively with GFR in type 2 DM patients [30,31]. Serum A-FABP level was independently associated with macrovascular complications in type 2 DM patients [31]. We also noted that BMI, body fat mass, SBP, DBP, TCH, log-TG, log-creatinine, log-HbA1c, log-hs-CRP, log-insulin, and log-HOMA-IR were positively correlated with A-FABP levels, while height, albumin, and GFR were negatively correlated with A-FABP levels in our DM subjects. After adjustment for a variety of confounders in multivariable forward stepwise linear regression analysis, body fat mass, log-creatinine, female DM patients, and loghs-CRP remained to be positively associated, while serum albumin level and GFR negatively associated with A-FABP level.
Our study had some limitations. First, this study had a cross-sectional design without a control group with a limited number of participants enrolled and the possibility of bias cannot be excluded. Second, pharmacological interventions have been shown to influence serum A-FABP in humans. Thiazolidinedione increases plasma A-FABP concentrations in type 2 DM subjects [23]. Another study noted that canagliflozin increases serum A-FABP levels in diabetic patients [32]. Our patients did not use any the sodium/glucose cotransporter 2 (SGLT2) inhibitor. Our results did not show a relationship between thiazolidinedione, stains, fibrates or other antidiabetic drugs, and serum A-FABP in the diabetic patients studied. Further studies are required to elucidate the relationship between medication and A-FABP in type 2 DM patients.

Conclusion
In summary, the present study showed that serum A-FABP level was positively associated with MetS in the type 2 DM patients. In addition, body fat mass, log-creatinine, female DM patients, and log-hs-CRP are positively correlated, while serum albumin and GFR are negatively correlated with A-FABP level.