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The adipose tissue, predominantly visceral adipose tissue (VAT), produces and secretes a variety of bioactive adipocytokines. However, VAT accumulation induces adipocytes dysfunction, including oversecretion of interleukin-6, tumor necrosis factor-α, plasminogen activator inhibitor-11 and visfatin,2 and hyposecretion of adiponectin,3 which were supposed to be involved in the pathogenesis of insulin resistance and abnormal glucose metabolism.
Vaspin (a visceral adipose tissue-derived serine protease inhibitor) is a novel adipocytokine that was reported to be specifically expressed in VAT of Otsuka Long-Evans Tokushima Fatty (OLETF) rats.4,5 In OLETF rats, the mRNA expression of vaspin in VAT increased with the increment of body fat and insulin level.5 Vaspin was proved to have an insulin-sensitizing effect, which may act through normalizing the altered expression of genes relevant to insulin resistance in diet-induced obese mice.5 Treatment with insulin or insulin-sensitizing agent, pioglitazone, in OLETF rats would normalize serum vaspin level. In human beings, vaspin mRNA or serum concentration was reported to be associated with blood glucose concentration,6,7 insulin sensitivity,7,8 and body mass index (BMI) or percent body fat.8,9 Taken together, vaspin may play a role in obesity and obesity-related disorders.
However, the pathophysiological role of vaspin in humans remains largely unknown. Our study aimed to investigate the relationships of serum vaspin level with body fat indexes, insulin resistance, and the markers of glucose metabolism in Chinese adults.
METHODS
Subjects
A total of 123 subjects aged 33–78 years old were enrolled, including 39 diagnosed diabetic patients from out-patient department, and 84 subjects with normal glucose tolerance (NGT) from those who underwent regular health medical check-up in Shanghai Clinical Center for Diabetes. The exclusion criteria included known cardiovascular diseases, acute or chronic inflammatory diseases, and systemic corticosteroid treatment. The study was approved by the Ethics Committee of Shanghai Jiao Tong University Affiliated Sixth People′s Hospital, and signed informed consents were obtained from the participants.
Methods
After an overnight fast for 10–12 hours, blood samples were drawn. The subjects without a validated history of diabetes underwent a 75 g oral glucose tolerance test (OGTT). Plasma glucose concentration, hemoglobin A1c (HbA1c), and serum insulin concentration were assayed. Fasting serum lipid profile, including total cholesterol, triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), and low density lipoprotein cholesterol (LDL-c) were assessed. Serum vaspin level was measured with a commercial ELISA kit (Wuhan USCN Science Co., Ltd., China) according to the manufacturers′ instructions. The intra-assay and inter-assay coefficients of variation were 7.3%–7.8% and 7.6%–8.0%, respectively. Homeostatic model assessment of insulin resistance (HOMA-IR) was calculated as fasting insulin concentration (FINS) (mU/L)×fasting plasma glucose (FPG) (mmol/L)/22.5. HOMA β-cell function (HOMA-β) was calculated as FINS (mU/L) × 20/(FPG (mmol/L)–3.5).10
BMI was calculated by weight (kg) divided by height squared (m2). Waist and hip circumferences were measured, and waist-hip ratio (WHR) was calculated. The areas of subcutaneous abdominal adipose tissue (SAT) and VAT were measured at the abdominal level between L4 and L5 vertebras by magnetic resonance imaging (MRI) scan (MR Signa, GE Medical Systems, Milwaukee).11
NGT was defined as FPG <6.1 mmol/L and 2-hour post-load plasma glucose (PG2h) <7.8 mmol/L during OGTT; while diabetes was diagnosed if subjects had medical records of diabetes and were using hypoglycemic medication or insulin, or FPG ≥7.0 mmol/L and/or PG2h ≥11.1 mmol/L based on OGTT.12 Overweight or obesity was defined as BMI ≥25 kg/m2,13 and visceral obesity was defined as VAT ≥80 cm2.11
Statistical analysis
Data were expressed as mean ± standard deviation (SD), median (interquartile range) or percentage (%). The Student′s t test or analysis of variance (ANOVA) was used to compare statistical differences of normal variables among different groups; for skewed variables, Mann-Whitney U test or Kruskal-Wallis H test was used. To evaluate the relationships between vaspin and the other variables, univariate and stepwise multivariate linear regression analyses were performed. A 2-tailed P value less than 0.05 was considered statistically significant. For statistical analyses, SPSS version 11.5 (SPSS Inc., USA) was used.
RESULTS
Clinical characteristics
General characteristics
FPG, PG2h, HbA1c, FINS, 2-hour post-load insulin concentration (INS2h), and HOMA-IR were significantly higher in diabetes group than in NGT group in men. FPG, PG2h, hemoglobin A1c (HbA1c), HOMA-IR, VAT and the proportion of visceral obesity were higher in diabetes group than those in NGT group in women.
Compared with men, women had lower WHR, higher SAT, and HDL-c in both NGT and diabetes groups; and higher total cholesterol (TC) level in diabetes group. Age, waist circumference, BMI, and the proportion of overweight/obesity were similar among these 4 groups.
Expression of serum vaspin
The median (interquartile range) of serum vaspin level was 441 (296–590) pg/ml (range 143–1789 pg/ml). Serum vaspin level was significantly higher in diabetic patients than that in NGT subjects (592 (438–695) pg/ml vs 380 (294–517) pg/ml, P=0.020) in women. Although in men, diabetic patients had higher vaspin level than NGT subjects, the difference was not statistically significant (476 (320–771) pg/ml vs 362 (258–580) pg/ml, P=0.162). There was no significant difference in serum vaspin level between men and women either in NGT group (P=0.320) or in diabetes group (P=0.295) (Table 1).
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Table 1. Clinical characteristics of the study subjects |
We further investigated the relationships between serum vaspin level and body fat indexes in total subjects. Serum vaspin level did not differ either between the subjects with normal weight (n=47) and those with overweight/obesity (n=76) (445 (273–615) pg/ml vs 399 (293–573) pg/ml, P=0.958), or between the subjects with and without visceral obesity (n=84, 449 (288–590) pg/ml vs n=39, 414 (284–588) pg/ml, P=0.923).
Clinical parameters changed with serum vaspin tertiles (Table 2)
Mean age, FPG, PG2h, HbA1c, and HDL-c increased significantly with the elevation of vaspin concentration. After adjusting for age, the dose-response associations of vaspin level with glucose concentrations and HDL-c remained significant (all P <0.01).
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Table 2. Clinical characteristics of total study subjects by tertiles of serum vaspin level |
Association between serum vaspin concentration with other parameters
In univariate linear regression analyses, serum vaspin was only significantly correlated with age (β=0.340, P=0.002) in NGT subjects. In diabetic patients, vaspin was positively associated with PG2h (β=0.526, P=0.001), HbA1c (β=0.388, P=0.016), FPG (β=0.365, P=0.023), and HDL-c (β=0.353, P=0.027), and negatively with HOMA-β (β=–0.361, P=0.016) (Table 3). Vaspin was not correlated with body fat indexes, including BMI, waist circumference, WHR, SAT, and VAT, in either NGT subjects or diabetic patients (Table 3). Further stepwise multivariate regression analyses revealed that age in NGT subjects (β=0.327, P=0.037), and PG2h in diabetic patients (β=0.528, P=0.001) were independently associated with serum vaspin level.
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Table 3. Linear regression analyses in subjects with normal glucose tolerance and in diabetic patients |
DISCUSSION
Vaspin is a new adipocytokine linking adipose tissue related to systemic insulin resistance and thereby, likely contributing to the pathogenesis of diabetes. However, the relationship between vaspin and diabetes is still controversial. In Caucasians, Klöting et al9 reported that vaspin mRNA expression was not detected in all of the study subjects, and was more detectable in diabetic patients than in NGT subjects. However, no difference was found in serum vaspin level between diabetic patients and NGT subjects in other studies.7,8,14
In the present study, we have found that serum vaspin level was increased in diabetic patients, and significantly associated with glucose concentrations, especially with PG2h. It was inferred that there was a causal relationship between vaspin and diabetes. Serum vaspin level was found to be associated with HbA1c in diabetic Turkish women, and was higher in those with HbA1c over 7% than in those with HbA1c less than 7%.7 Besides, Tan et al6 showed that mRNA expression and protein levels of vaspin in omental adipose tissue, and its serum vaspin level were significantly associated with glucose concentrations in obese polycystic ovary syndrome (PCOS) women.
Metformin therapy in diabetic women7 or in PCOS patients6 significantly reduced serum vaspin level, and the reduction in glucose concentration was predictive of the change in serum vaspin level (β=0.572, P=0.014).6 Further in primary explant culture experiments, the production and secretion of vaspin were dose-dependently increased from the omental adipose tissues that were cultured with the addition of glucose, but not from those with the addition of insulin.6 These data implied that elevated glucose concentration might be an important factor to increase vaspin level.
In the current study, we demonstrate that age is an independent predictor of vaspin concentration in NGT subjects, which is in agreement with the report from Seeger et al14 that age was positively and independently associated with vaspin level in subjects with normal glomerular filtration rate.
As an adipocytokine, vaspin was supposed to be associated with obesity. However, until now, the relationships between vaspin level and body fat indexes remain controversial.5,7-9,14 Klöting et al9 showed that vaspin mRNA expression in visceral fat was independently and positively associated with percent body fat. Youn et al8 have reported that vaspin was positively correlated with BMI in NGT subjects, while in diabetic patients, this correlation was not confirmed. However, in a 4-week intensive exercise training, reduced BMI was an independent predictor of increased vaspin concentration. In other studies,7,14 including our study, no significant associations were detected between vaspin level and body fat indexes, including VAT and SAT measured by MRI.
In conclusion, serum vaspin level is significantly higher in diabetic patients than that in NGT subjects in women. Ageing increases vaspin concentration in NGT subjects, and PG2h is independently associated with vaspin level in diabetic patients.
Acknowledgments: We thank Dr. QIAO Rui-hua in the Department of Radiology, Shanghai Jiao Tong University Affiliated Sixth People′s Hospital. The colleagues in Shanghai Diabetes Institute gave their help on the measurement of the clinical parameters.
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