Background: Inflammation has been recognized as a key feature of both type 2 diabetes mellitus ( T2DM) and atherosclerosis. However, the relationships between circulating levels of novel adipose tissue‑ derived inflammatory factors, including resistin, vaspin, and visfatin, and the severity of atherosclerosis have not been determined. Moreover, the associations between these inflammatory factors and obesity and insulin resistance in elderly patients remain to be clarified. Methods: A cross‑ sectional study of 256 elderly patients with T2DM admitted in our center was performed. Baseline circulating levels of resistin, vaspin and visfatin were measured with enzyme‑ linked immunosorbent assays. Ultrasonic evaluations of the carotid arteries of the patients were performed to reflect the severity of systemic atherosclerosis. Patients were classified as having mild, moderate, or severe atherosclerosis according to the results of carotid ultra‑ sonic examination. Circulating levels of the inflammatory factors listed above also were correlated with body mass index (BMI) and homeostasis model assessment of insulin resistance (HOMA‑ IR). Results: With more severe carotid atherosclerosis, circulating levels of resistin (mild: 2.01 ± 0.23; moderate: 2.89 ± 1.01; severe: 3.12 ± 1.12; p < 0.05) and visfatin (mild: 11.63 ± 7.48; moderate: 15.24 ± 2.19; severe: 17.54 ± 2.98; p < 0.05) gradually increased, while level of vaspin decreased (mild: 317 ± 23.12; moderate: 269 ± 32.12; severe: 229 ± 14.24; p < 0.05). Subsequent results of Pearson coefficient analyses indicated that all of the tested adipose tissue‑ derived inflammatory factors were positively correlated with the BMI and HOMA ‑ IR of the patients (all p < 0.05), even after adjustment for hs‑ CRP. Conclusions: The adipose tissue‑ derived inflammatory factors resistin, vaspin and visfatin may be involved in the pathogenesis of atherosclerosis in elderly T2DM patients. Keywords: Vaspin, Resistin, Visfatin, Diabetes mellitus, Atherosclerosis *Correspondence: email@example.com Department of Geriatric Medicine, Capital Medical University, Xuanwu Hospital, No. 45 Chang Chun Street, Beijing 100053, China Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yang et al. Cardiovasc Diabetol (2018) 17:75 Page 2 of 9 the recently published Canakinumab Anti-inflammatory Background Thrombosis Outcomes Study (CANTOS) showed that Atherosclerosis has been recognized as a fundamental anti-inflammatory treatment with Canakinumab target - pathologic change in many cardiovascular diseases , ing the interleukin-1β innate immunity pathway reduced and thus, represents an important threat to the health of the risk of recurrent cardiovascular events in patients the global population. Indeed, the primary pathophysio- with previous myocardial infarction . However, the logical feature of both coronary heart disease (CHD) and incidence of T2DM was not significantly affected , stroke is atherosclerosis, and these diseases have become indicating the importance of identifying novel inflam - major contributors to morbidity and mortality worldwide matory factors that mediate the association between [2, 3], particularly among the elderly population . Con- T2DM and CHD. Recent evidence suggests that in addi- ventionally, many risk factors have been identified for the tion to storing energy, adipose tissue may secrete sev- pathogenesis of atherosclerosis, including male gender, eral inflammatory factors, such as resistin, vaspin and family history of early incidence of cardiovascular dis- visfatin, which may be important mediators of obesity, eases, smoking, hypertension, dyslipidemia, obesity, and atherosclerosis, and DM [21, 22]. Resistin was initially diabetes mellitus (DM) . Atherosclerosis is now con- discovered as an adipocyte-secreted hormone mediat- sidered an inflammatory disease, because overactivated ing obesity and insulin resistance in animal studies, and a inflammation has been demonstrated to be a common recently published study in humans suggests its potential pathway that mediates the pathogenesis of atherosclero- role in the pathogenesis of atherosclerosis . Vaspin, a sis [6, 7]. Therefore, identification of key inflammatory visceral adipose tissue-derived serine protease inhibitor mediators involved in the initiation and progression of that is upregulated in animal models of obesity and insu- atherosclerosis may be of important clinical significance lin resistance, has also been hypothesized to participate for the prevention and treatment of atherosclerosis- in the development of atherosclerosis . Moreover, vis- related cardiovascular diseases . fatin, also known as the enzyme nicotinamide phospho- Type 2 DM (T2DM) is characterized by insulin resist- ribosyltransferase (Nampt), which was initially identified ance and has been confirmed to be a strong risk factor as a molecule with insulin-like properties in 2005, also for the pathogenesis of atherosclerosis . More than has been suggested to be involved in the pathogenesis 400 million people globally are estimated to DM, and of atherosclerosis primarily by mediating the inflamma - data from a recent epidemiological study suggest that the tory response [25, 26]. However, the circulating levels of age-standardized prevalence of total DM is nearly 10% these inflammatory factors in T2DM patients according and the prevalence in people over 60 years old exceeds to the severity of atherosclerosis have not been deter- 20% . Development of vascular disease has become a mined. More importantly, the associations between these major cause of morbidity and mortality in patients with adipose-derived inflammatory factors and the severity T2DM. Indeed, a previous collaborative meta-analysis of atherosclerosis in elderly patients with T2DM have of 102 prospective studies showed that compared with not been reported. The aim of the current retrospective controls without T2DM, patients with T2DM have a cohort study was to compare the levels of resistin, vaspin, 73% increased risk for total vascular diseases, including and visfatin in T2DM patients according to the severity a 100% increased risk for CHD, a 127% increased risk of carotid atherosclerosis and to explore the potential for ischemic stroke, and a 54% increased risk for hemor- relationships of these factors and the conventional risk rhagic stroke . However, the potential mechanisms factors for T2DM and atherosclerosis, such as body mass underlying the association between T2DM and athero- index (BMI) and indicators of insulin resistance. sclerosis have not been fully determined, and the acti- vated inflammatory response has been considered an important common pathophysiological feature of both diseases [12, 13]. Indeed, classical inflammatory fac - Methods tors, such as the high-sensitivity C-reactive protein (hs- This retrospective cross-sectional study included 256 CRP) and tumor necrosis factor alpha are involved in the elderly patients (> 60 years) with T2DM who were admit- pathogenesis of both T2DM and CHD [14, 15]. Moreover, ted to the Department of Geriatrics or Department adiponectin, an inflammatory peptide secreted by adi - of Endocrinology of Xuanwu Hospital affiliated to the pocytes, and neutrophil gelatinase-associated lipocalin Capital Medical University between July 2013 and July (NGAL), an acute phase protein released by neutrophils, 2017. Written informed consent was obtained from each are involved in the interrelationship between T2DM and included patient before enrollment. The study protocol CHD [16, 17]. These findings raised the hypothesis that was approved by the Ethics Committee of Xuanwu Hos- anti-inflammatory treatment may be effective for the pital affiliated to the Capital Medical University before prevention of both T2DM and CHD . Importantly, the performance of the study. Yang et al. Cardiovasc Diabetol (2018) 17:75 Page 3 of 9 Inclusion and exclusion criteria of the patients Measurement of blood biochemical parameters Patients were included if they were > 60 years and diag- We obtained blood samples from all included patients nosed with T2DM according to the criteria of 2013 between 6 a.m. and 10 a.m. at the admission of the Chinese Guidelines for the Management of Diabetes patients after fasting for more than 12 h. The blood sam - . Specifically, patients were diagnosed with T2DM ples were centrifuged immediately for further analyses if they met either of the following criteria: (1) presented of the blood biochemical parameters of lipids and glu- with symptoms of hyperglycemia (dry mouth, poly- cose metabolism, and the serum samples were stored dipsia, polyuria, and weight loss) and random plasma at − 80 °C for measurements of adipose tissue-derived glucose ≥ 11.1 mmol/L; or (2) fasting plasma glucose inflammatory factors, including resistin, vaspin, and vis - (FPG) ≥ 7.0 mmol/L; or (3) 2-h postprandial plasma fatin. A standardized OGTT with a 75-g oral glucose load glucose (2 h-PPG) ≥ 11.1 mmol/L on standardized oral was performed for each patient to measure the 2 h-PPG. glucose tolerance test (OGTT). Patients were excluded Briefly, FPG and 2 h-PPG were measured with a glucose if they had any of the following clinical conditions: type oxidase procedure. Glycosylated hemoglobin (HbA1c) 1 DM; comorbidities of acute complications of T2DM; was measured with a Cobas Integra 800 automated bio- other acute clinical conditions or severe diseases such chemistry analyzer (Roche, Basel, Switzerland) according as severe hepatic or renal dysfunction, severe infection, to the manufacturer’s instruction. We used the radioim- sepsis, or malignancies; other endocrine or autoimmune munoassay analysis method (Ray Bio, Norcross, GA) to diseases that may affect the systemic levels of adipose measure the fasting serum insulin (FSI) concentration, tissue-derived inflammatory factors; or taking hormonal and an enzyme-linked immunosorbent assay (ELISA) preparations or immune inhibitors with the potential to was applied for the measurement of hs-CRP. Parameters affect the systemic levels of inflammatory factors, such for the indexes of lipid metabolism, including total cho- as glucocorticoid, cyclosporine A, or tacrolimus etc. at lesterol (TC), triglyceride (TG), low-density lipoprotein enrollment. (LDL-C), and high-density lipoprotein (HLD-C), were measured with a Hitachi 7600 automatic biochemi- cal analyzer following the instructions of the manufac- turer. To represent the extent of insulin resistance of Definitions of clinical parameters each included patient, we calculated the parameter of Clinical parameters, including demographic data (age, insulin resistance index (homeostasis model assessment gender, body weight, and height), BMI, duration of of insulin resistance, HOMA-IR) according to the fol- T2DM, waist to hip circumference ratio (WHR), systolic lowing equation: HOMA-IR = FPG (mmol/L) × FINS blood pressure (SBP), diastolic blood pressure (DBP), (μU/L)/22.5. and blood biochemical parameters of lipids and glucose metabolism, were obtained from individual patients at admission. Briefly, BMI was calculated by dividing the Determination of circulating resistin, vaspin and visfatin weight (kg) by the square of the height (m ). For each levels patient, we measured waist and hip circumferences twice A partial blood sample for each patient was used for with an inextensible tape. The patients were instructed to measurements of circulating vaspin, resistin, and vis- stand erect with arms relaxed at both sides and feet close fatin levels. Briefly, the serum of the blood sample was together. To measure the waist circumference, the tape obtained after centrifugation at 3500 rpm for 5 min was placed just above the uppermost lateral border of the within 2 h after blood collection. The serum levels of right iliac crest in a horizontal plane around the abdo- resistin, vaspin, and visfatin were measured with com- men, and the measurement was performed at the end of mercially available ELISA kits in an automatic multifunc- a normal expiration. To measure the hip circumference, tional enzymatic standard instrument (Thermo MK3, the tape was placed at the level of the greater trochanter, USA). which indicated the position of the middle part of the hip in a horizontal plane. During the measurements, the tape Ultrasonic evaluation of the carotid arteries was placed at a horizontal level parallel to the floor. The All of the included patients underwent ultrasonic eval- measurements were recorded in centimeters (cm) to the uation of the carotid arteries to determine the extent nearest 0.1 cm. Information regarding the prescription of of systemic atherosclerosis. The ultrasonic evalua- medications for the primary prevention of cardiovascu- tion of the carotid arteries was performed by an expe- lar diseases and treatment of T2DM was also recorded, rienced physician for each included patient on the such as the use of aspirin, statins, probucol, metformin, first day of their admission. The patients were clas- acarbose, sulfonylureas (SUs), thiazolidone (TZDs), and sified according to the severity of atherosclerosis as insulin. Yang et al. Cardiovasc Diabetol (2018) 17:75 Page 4 of 9 reflected by the findings of the ultrasonic evaluation Results of the carotid arteries: (1) mild group: thickening of Characteristics of the patients according to the severity the intima-media or plaque formation in the carotid of carotid atherosclerosis artery; (2) moderate group: arterial stenosis of < 50% in Overall, our study included 256 elderly patients with the carotid artery of either side; and (3) severe group: T2DM who were admitted in our hospital, of which 87, arterial occlusion or arterial stenosis of ≥ 50% in the 105, and 64 patients were allocated to the mild, moder- carotid artery of either side. ate, and severe atherosclerosis groups according to the findings of ultrasonic examination of the carotid arteries. The demographic characteristics and the clinical param - Statistical analyses eters of the included T2DM patients according to the We used SPSS for Windows Software, Version 18.0 severity of atherosclerosis are presented in Tables 1 and (SPSS Inc., Chicago, IL, USA) for statistical analyses. 2. No significant differences were detected regarding age, Data are presented as mean ± standard deviation (SD) gender, duration of BMI, or DBP among patients allo- if they were normally distributed. For data that were cated to the above three groups (all p > 0.05). However, not normally distributed, logarithmical transformation compared with those with mild to moderate atheroscle- was performed to achieve normal distribution. We rosis, elderly T2DM patients with severe atherosclerosis applied single factor analysis of variance to compare were more likely to have a higher BMI, WHR, SBP, and the quantitative data among multiple groups. T test TG, as well as lower HDL, indicating that severe athero- was applied to compare the quantitative data between sclerosis is more likely to be complicated by conventional two groups. Fisher’s exact test was applied for the anal- risk factors of atherosclerosis, such as obesity, hyperten- ysis of categorical variables. Single factor correlation sion, and dyslipidemia. Moreover, higher levels of FINS between two independent variables was analyzed with and HOMA-IR were noticed in patients with severe ath- Pearson coefficient analysis. Moreover, correlations erosclerosis, although HbA1c did not differ significantly between the three adipose tissue-derived inflamma- among the patients of the three groups. These results sug - tory factors and metabolic parameters were also ana- gest that elderly T2DM patients with severe atherosclero- lyzed after adjustment for hs-CPR levels. A p value less sis have more significant insulin resistance, although the than 0.05 was considered statistically significant. statuses of management of T2DM across the groups did Table 1 Baseline characteristics of patients according to the severity of carotid atherosclerosis Mild group Moderate group Severe group F value/χ p (n = 87) (n = 105) (n = 64) Gender (M/F) 55/32 64/44 40/24 0.653 > 0.05 Age (years) 75.52 ± 3.32 76.21 ± 7.21 76.01 ± 5.21 0.487 > 0.05 DM duration (years) 23.89 ± 2.32 23.28 ± 1.26 24.79 ± 3.43 0.563 > 0.05 BMI (kg/m ) 25.13 ± 2.54 26.40 ± 5.24 28.24 ± 5.14* 8.324 < 0.05 WHR 0.83 ± 0.13 0.86 ± 0.24 0.98 ± 0.65* 11.324 < 0.01 SBP (mmHg) 135 ± 6 141 ± 13 148 ± 12* 4.213 < 0.05 DBP (mmHg) 69 ± 4 67 ± 7 72 ± 9 0.672 > 0.05 Medications, n (%) Aspirin 26 (29.8%) 54 (51.4%) 48 (75%) 6.324 < 0.05 Statins 34 (39%) 55 (52%) 50 (78.1%) 7.324 < 0.01 Probucol 10 (11.4%) 25 (23.8%) 40 (62.5%) 5.234 < 0.05 Metformin 35 (40.2%) 74 (70.4%) 55 (85.9%) 5.341 < 0.05 Acarbose 55 (63.2%) 76 (72.3%) 55 (85.9%) 0.985 > 0.05 SUs 15 (17.2%) 27 (25.7%) 16 (17.8%) 0.765 > 0.05 TZDs 35 (40.2%) 57 (54.2%) 48 (75%) 2.543 < 0.05 Insulin 22 (25.2%) 46 (43.8%) 45 (70.3%) 4.324 < 0.05 Italic values indicates that, the proportions of patients that received aspirin and probucol were significantly larger in patients with severe atherosclerosis as compared with those in patients with mild atherosclerosis; while the proportions of patients were significantly different among the three groups. As for the hypoglycemic, the proportions of patients that received metformin, thiazolidones and insulin injection were significantly larger as compared with those in patients with mild atherosclerosis DM diabetes mellitus, BMI body mass index, WHR waist hip ratio, SBP systolic blood pressure, DBP diastolic blood pressure, SUs sulfonylureas, TZDs thiazolidone * p < 0.05 compared with the mild group; p < 0.05 compared with the moderate group Yang et al. Cardiovasc Diabetol (2018) 17:75 Page 5 of 9 Table 2 Circulating levels of vaspin, resistin, and visfatin and other parameters related to metabolism and inflammation according to the severity of carotid atherosclerosis Mild group (n = 87) Moderate group Severe group (n = 64) F value/χ p value (n = 105) Δ# TG (mmol/L) 1.50 ± 0.69 1.64 ± 1.24 2.34 ± 1.41 7.745 < 0.05 TC (mmol/L) 4.76 ± 0.23 4.61 ± 0.54 4.75 ± 2.09 0.876 > 0.05 LDL‑ C (mmol/L) 2.62 ± 0.93 2.61 ± 0.75 2.59 ± 1.17 0.654 > 0.05 Δ# HDL‑ C (mmol/L) 1.79 ± 0.59 1.58 ± 0.45 1.37 ± 0.50 5.567 < 0.05 FPG (mmol/L) 7.11 ± 1.20 7.76 ± 3.16 8.76 ± 2.20 0.532 > 0.05 FINS (mIU/L) 21.73 ± 5.2 22.78 ± 11.72 26.89 ± 13.12 4.543 < 0.05 Δ Δ# HOMA‑IR 7.41 ± 2.72 9.44 ± 21.18 13.17 ± 6.62 7.324 < 0.05 HbA1C (%) 7.58 ± 0.41 8.07 ± 1.97 8.42 ± 2.17 0.432 > 0.05 Vaspin (pg/mL) 317 ± 23.12 269 ± 32.12 229 ± 14.24 9.511 < 0.05 Resistin (ng/mL) 2.01 ± 0.23 2.89 ± 1.01 3.12 ± 1.12 7.271 < 0.05 Δ Δ Visfatin (µg/mL) 11.63 ± 7.48 15.24 ± 2.19 17.54 ± 2.98 6.876 < 0.05 Δ# hs‑ CRP (mg/L) 2.78 ± 3.84 3.12 ± 4.30 5.02 ± 3.54 5.321 < 0.05 TG triglyceride, TC total cholesterol, LDL-C low-density lipoprotein cholesterol, HLD-C high-density lipoprotein cholesterol, FPG fasting plasma glucose, FINS fasting insulin, HOMA-IR homeostasis model assessment of insulin resistance, HbA1C glycosylated hemoglobin, hs-CRP high-sensitivity C-reactive protein Δ # p < 0.05 compared with the mild group; p < 0.05 compared with the moderate group not significantly differ. More importantly, we found that visfatin were significantly correlated in these patients (R circulating levels of the adipose tissue-derived inflamma - linear = 4.356, p = 0.043), whereas neither of resistin nor tory factors resistin and visfatin were significantly higher visfatin levels were significantly correlated with the level in patients with severe atherosclerosis; however, the of vaspin (both p > 0.05). level of vaspin was significantly lower in these patients. These results, together with the finding of a significantly Correlations of circulating vaspin, resistin, and visfatin increased level of hs-CRP, a classical inflammatory fac - levels with BMI and HOMA‑IR tor involved in atherosclerosis, demonstrated that over- To further clarify the significance of changes in levels of activated systemic inflammation, including changes in adipose tissue-derived inflammatory factors in elderly adipose tissue-derived inflammatory factors, may be patients with T2DM, Pearson coefficient analyses were involved in the pathogenesis of microvascular complica- performed to elucidate the association between adipose tions in elderly patients with T2DM. tissue-derived inflammatory factors and conventional risk factors for atherosclerosis. We found that fast- ing serum vaspin was positively correlated with gen- Correlations between circulating vaspin, resistin, der and TG, but not with other variables including age, and visfatin levels duration of T2DM, WHR, TC, LDL-C, FPG, HbA1c, or To further clarify the relationships of the levels of the hs-CRP (Table 3). Similarly, fasting serum resistin was three adipose tissue-derived inflammatory factors in positively correlated with TG, but not with gender, age, elderly patients with T2DM, Pearson coefficient analy - duration of T2DM, WHR, TC, LDL-C, FPG, HbA1c, or ses were performed. We found that levels of resistin and hs-CRP (Table 3). Moreover, fasting serum visfatin was Table 3 Correlations between circulating vaspin, resistin, and visfatin levels and the other parameters related to metabolism and inflammation in elderly patients with T2DM Statistic Gender TG WHR BMI HOMA‑IR Vaspin R value 0.855 0.857 0.88 0.776 p value 0.014 0.023 0.029 0.032 Resistin R value 0.963 0.812 0.724 p value 0.024 0.041 0.047 Visfatin R value 0.814 0.898 0.821 p value 0.041 0.037 0.039 TG triglyceride, HOMA-IR homeostasis model assessment of insulin resistance, BMI body mass index, WHR waist hip ratio Yang et al. Cardiovasc Diabetol (2018) 17:75 Page 6 of 9 Fig. 1 Correlations of circulating vaspin, resistin, and visfatin levels with BMI in elderly patients with T2DM Fig. 2 Correlations of circulating vaspin, resistin, and visfatin levels with HOMA‑IR in elderly patients with T2DM positively correlated with WHR, but not with gender, Table 4 Correlations between circulating vaspin, age, duration of T2DM, TG, TC, LDL-C, FPG, HbA1c, resistin, and visfatin levels and other parameters related to metabolism and inflammation in elderly patients or hs-CRP (Table 3). Importantly, all of the above adi- with T2DM after adjustment for hs-CRP pose tissue-derived inflammatory factors showed posi - tive correlations with BMI and HOMA-IR (Figs. 1, 2), Statistic TG WHR BMI HOMA‑IR suggesting that activated inflammation in elderly patients Vaspin R value 0.731 0.786 0.721 with T2DM may be associated with obesity and insulin p value 0.033 0.039 0.036 resistance in these patients. Subsequent analyses after Resistin R value 0.863 0.712 0.714 adjustment for hs-CRP showed similar results (Table 4), p value 0.029 0.043 0.048 suggesting the correlations of the above adipose tissue- Visfatin R value 0.772 0.828 0.842 derived inflammatory factors with BMI and HOMA-IR p value 0.045 0.039 0.032 were independent of the systematic inflammation index. TG triglyceride, HOMA-IR homeostasis model assessment of insulin resistance, BMI body mass index, WHR waist-to-hip ratio Discussion In this cross-sectional study of elderly patients with T2DM, we found that circulating levels of novel adi- tissue-derived inflammatory factors were positively cor - pose tissue-derived inflammatory factors showed a related with the BMI and HOMA-IR of the patients, even trend of significant change according to the severity of after adjustment for hs-CRP. These results suggest that systemic atherosclerosis. Specifically, with the worsen - resistin and visfatin, both as the proinflammatory factors, ing of carotid atherosclerosis, circulating levels of resis- may exert a synergetic effect during the pathogenesis tin and visfatin gradually increased, while the level of of atherosclerosis in these patients, and the circulating vaspin decreased. Subsequent results of Pearson coef- levels of resistin, vaspin, and visfatin may parallel the ficient analyses indicated that levels of resistin and vis - severity of systemic atherosclerosis, despite their roles fatin were positively correlated, and all the above adipose as indicators of the extent of insulin resistance. Based on Yang et al. Cardiovasc Diabetol (2018) 17:75 Page 7 of 9 above findings, we hypothesize that resistin, vaspin and segment elevated myocardial infarction suggested that visfatin may be involved in the pathogenesis of athero- the circulating level of visfatin in these patients can inde- sclerosis in elderly patients with T2DM. pendently predict mortality risk . The results of our Resistin was initially identified in white adipocytes study showed that circulating resistin and visfatin were of mice , and the serum level of resistin was found positively associated with the severity of atherosclerosis to be more remarkable in animal models of obesity and in elderly diabetes patients. Interestingly, some recent insulin resistance . Subsequent experimental stud- prospective cohort studies also indicated that higher ies showed that resistin may be a mediator of insulin resistin and visfatin levels at baseline are associated with resistance, likely via a decrease in the phosphorylation an increased risk of major cardiovascular adverse events of 5′ adenosine monophosphate-activated protein kinase (MACEs). In a prospective cohort study of 150 patients (AMPK) in the liver . This is consistent with our with diabetic nephropathy, increased resistin and visfatin results, which showed a positive correlation between levels at baseline were found to be independent predic- the circulating resistin level and the indicator of insulin tors of cardiovascular mortality . Moreover, the pro- resistance HOMA-IR in elderly patients with T2DM. spective association between baseline circulating resistin Moreover, some evidence from experimental studies also and the risk of MACEs has also been indicated in recent suggests that resistin may accelerate the pathogenesis of large cohort studies and a meta-analysis, particularly in atherosclerosis by promoting endothelial dysfunction, T2DM patients [38, 39]. In summary, the inflammation- vascular smooth muscle cell proliferation, arterial inflam - inducing efficacy of resistin and visfatin may be impor - mation, and the formation of foam cells . Indeed, tant for the development of atherosclerosis in patients accumulating evidence from human epidemiological with T2DM. studies indicates that an increased circulating level of As a visceral adipose tissue-derived serine protease resistin may be related to increased risks of many car- inhibitor, vaspin is also confirmed to be upregulated diovascular diseases, including CHD and stroke . A in animal models of obesity and insulin resistance . recently published prospective cohort study showed that Although the potential mechanisms underlying the effect higher resistin is a significant predictor of cardiovascu - of vaspin on insulin resistance remain to be determined, lar diseases independent of conventional risk factors in it has been suggested that the circulating level of vaspin individuals over 70 years . However, the predictive correlates with the extent of insulin resistance in certain efficacy of resistin for cardiovascular risk was signifi - populations, such as overweight female patients with cantly attenuated by adjustment for inflammation . polycystic ovary syndrome . However, no correlation We extended these findings by showing that the circulat - between the circulating level of vaspin and HOMA-IR ing resistin level increased in parallel with the severity of was observed in 108 subjects with normal glucose toler- systemic atherosclerosis in elderly patients with T2DM, ance . Our results were consistent with the previous indicating that resistin may be an important contributor study in that the circulating level of vaspin was correlated to vascular complication in these patients. In addition, with HOMA-IR in elderly patients with T2DM. The dis - visfatin/Nampt was initially identified as a substance with crepancy of the other results may be explained by the insulin-like properties in mice in 2005 . Subsequent different study population included. However, whether studies revealed that an important role of visfatin/Nampt other potential factors exist that confound the asso- is the regulation of the inflammatory response, likely via ciation between the level of vaspin and extent of insulin induction of other inflammatory factors, including inter - resistance deserves further investigation. Moreover, we leukin-1, tumor necrosis factor alpha, interleukin-6, etc. found that the circulating level of vaspin decreased sig- . The pro-inflammation efficacy of visfatin/Nampt has nificantly in elderly T2DM patients increasing severity been considered to be the major mechanism underlying of atherosclerosis. This is inconsistent with the majority the induction of insulin resistance by visfatin. This was of previous findings, which showed that the circulating further confirmed by our findings, which showed a posi - level of vaspin was positively associated with the severity tive correlation between circulating visfatin and HOMA- of coronary stenosis in females with metabolic syndrome IR. Interestingly, recently published studies in patients  and positively associated with the severity of carotid with T2DM showed that circulating visfatin is corre- atherosclerosis in patients who underwent carotid endar- lated with an increased intima-media thickness (IMT) terectomy . Also, vaspin was shown to correlate with of carotid arteries . These findings were extended CAD in T2DM . However, a previous cross-sec- by our study, which showed that the circulating visfatin tional study of T2DM patients showed an inverse asso- level increased gradually with the increasing severity of ciation between serum vaspin and the presence of carotid carotid atherosclerosis in elderly patients with T2DM. plaque, which is similar to our findings . Again, dif - Moreover, a recent study in high-risk patients with ST ferences in the populations studied may contribute to Yang et al. Cardiovasc Diabetol (2018) 17:75 Page 8 of 9 high‑ density lipoprotein; AMPK: adenosine monophosphate‑activated protein the heterogeneity of the results, although other factors kinase. that may confound the association between the circulat- ing level of vaspin and severity of atherosclerosis deserve Authors’ contributions WY and LW designed the study. RH and YL collected and analysed the data. investigation in future studies. JYW advised on histological staining and analysis. RH contributed samples The strengths of our study include enrollment of elderly collection and intellectual input. WY drafted and wrote the manuscript. LW patients with T2DM who had rarely participated in pre- revised the manuscript critically for intellectual content. All authors gave intel‑ lectual input to the study. All authors read and approved the final manuscript. vious similar studies. Moreover, we analyzed the changes in circulating levels of three novel adipose tissue-derived Author details inflammatory factors to comprehensively evaluate their Department of Geriatric Medicine, Capital Medical University, Xuanwu Hos‑ pital, No. 45 Chang Chun Street, Beijing 100053, China. Department of Endo‑ association with the severity of atherosclerosis in these crine, Capital Medical University, Xuanwu Hospital, Beijing 100053, China. elderly patients. Despite the above strengths, our study also has limitations that should be considered when Acknowledgements Not applicable. interpreting the results. First, as a cross-sectional study, we could not examine the causative relationships of resis- Competing interests tin, vaspin and visfatin with atherosclerosis or insulin The authors declare that they have no competing interests. resistance. Moreover, we did not perform multivariate Consent for publication adjusted analyses for the potential associations of resis- All data published here are under the consent for publication. tin, vaspin and visfatin with atherosclerosis or insulin Availability of data and materials resistance. Therefore, we cannot not exclude the possibil - All data generated or analyzed during this study are included within the ity that confounding factors, such as differences in life - article. style or medication used in the included patients, may Ethics approval and consent to participate affect the associations. In addition, the sample size of The study protocol was approved by the Ethics Committee of Xuanwu Hospi‑ the study was relatively small. Due to the small number tal affiliated to the Capital Medical University before the performance of the of patients included in the groups with differing severity study. All procedures performed in studies that involved human participants were in accordance with the ethical standards of the institutional and national of atherosclerosis, the study may be statistically under- research committee and the 1964 Helsinki declaration and its later amend‑ powered to evaluate the correlations in the three differ - ments or comparable ethical standards. ent groups according to the severity of atherosclerosis. Funding Therefore, the correlations of the three adipose tissue- This study was supported by a grant from the National Natural Science Foun‑ derived inflammatory factors with the parameters of obe - dation of China (Grant reference number: 81,470,541). sity, insulin resistance, etc. were not evaluated. Finally, as a single-center study, the generalizing of the conclusion Publisher’s Note to patients from other centers should be done cautiously. Springer Nature remains neutral with regard to jurisdictional claims in pub‑ lished maps and institutional affiliations. Conclusions Received: 12 March 2018 Accepted: 23 May 2018 In conclusion, we found that circulating levels of novel adipose tissue-derived inflammatory factors, including resistin, vaspin and visfatin, may change according to the References severity of atherosclerosis in elderly patients of T2DM, 1. Hansson GK. 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Published: May 30, 2018