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Lipopolysaccharide-binding protein is associated with arterial stiffness in patients with type 2 diabetes: a cross-sectional study

Cardiovascular Diabetology volume 16, Article number: 62 (2017) Cite this article

Abstract

Background

Lipopolysaccharide (LPS)-binding protein (LBP) is an acute-phase reactant that mediates immune responses triggered by LPS. Recent evidence indicates the association of circulating LBP levels with obesity, diabetes, and cardiovascular diseases. In this study, we aimed to investigate the relationship between serum LBP levels and arterial stiffness in patients with type 2 diabetes.

Methods

A total of 196 patients with type 2 diabetes, including 101 men and 95 women, were enrolled in this cross-sectional study. Fasting serum LBP levels were determined by enzyme-linked immunosorbent assay. Arterial stiffness was assessed by measuring the aortic pulse wave velocity (PWV).

Results

The mean values of serum LBP and aortic PWV were 18.2 μg/mL and 1194 cm/s, respectively. Serum LBP levels were positively correlated with body mass index, triglycerides, high-sensitivity C-reactive protein, and insulin resistance index and were negatively correlated with high-density lipoprotein cholesterol. They were, however, not significantly correlated with aortic PWV in univariate analyses. Multivariate analysis revealed that serum LBP levels were independently and positively associated with aortic PWV (β = 0.135, p = 0.026) after adjusting for age, sex, body mass index, albumin, high-sensitivity C-reactive protein, and other cardiovascular risk factors. Further analyses revealed that the impact of serum LBP levels on aortic PWV was modified by sex, and the association between serum LBP levels and aortic PWV was found to be significant only in men.

Conclusions

Serum LBP levels are associated with arterial stiffness, independent of obesity and traditional cardiovascular risk factors, especially in men with type 2 diabetes. This study indicates a potential role of the LPS/LBP-induced innate immunity in the development and progression of arterial stiffness in type 2 diabetes.

Background

The association of chronic inflammation with the pathogeneses of obesity, diabetes, and atherosclerosis is well recognized [1]. Accumulating evidence indicates a link between low-grade inflammation produced by common subclinical or chronic infections and the risk of atherosclerosis in humans [2, 3]. Lipopolysaccharide (LPS) derived from Gram-negative bacteria is known to play a critical role in triggering the immune and inflammatory responses in vascular cells, leading to atherosclerosis [4]. LPS-binding protein (LBP), an acute-phase reactant synthesized mainly in the liver, binds LPS and initiates the immune response by presenting LPS to cluster of differentiation (CD)14, which in turn interacts with toll-like receptor (TLR)4 on immune cells [5]. Since LBP is synthesized and released into circulation in the presence of LPS, with a relatively long half-life, LBP level is considered a surrogate biomarker for the activation of LPS-induced innate immune responses [6,7,8].

Several studies in humans recently demonstrated that serum LBP levels are closely associated with obesity, the metabolic syndrome, and type 2 diabetes [6, 8,9,10,11,12,13]. Furthermore, serum LBP levels were shown to be a predictor of prevalent coronary artery disease [7] and cardiovascular mortality [14], independent of established cardiovascular risk factors and markers of systemic inflammation. A recent study also showed that serum LBP levels were positively correlated with subclinical atherosclerosis, as assessed by carotid intima-media thickness, in healthy individuals, independent of body mass index (BMI) and high-sensitivity C-reactive protein (hs-CRP) level [15]. These studies collectively indicate that serum LBP level may be a biomarker for atherosclerotic cardiovascular disease and implicate a potential role of the innate immune mechanisms in the progression of atherosclerosis in humans.

To our knowledge, no previous study has investigated the relationship between LBP and arterial stiffness, a well-established surrogate marker for cardiovascular diseases [16], in human subjects. Moreover, no study has examined the impact of LBP on subclinical atherosclerosis in patients with comorbid cardiovascular risk factors, including diabetes. Therefore, in the present study, we investigated the association between serum LBP levels and arterial stiffness by measuring aortic pulse wave velocity (PWV) in patients with type 2 diabetes.

Methods

Study design and subjects

We consecutively enrolled 196 patients with type 2 diabetes, including 101 men and 95 women, who were admitted to the Diabetes Center of the Osaka City University Hospital for the purpose of glycemic control, education, and/or evaluation of diabetic complications between July 2013 and December 2015. Type 2 diabetes was diagnosed based on American Diabetes Association criteria [17]. Patients with type 1 diabetes or other types of diabetes were not included in the present study. The following patients were not included in this study: those with acute or chronic infection, chronic inflammatory disease, use of anti-inflammatory drugs including glucocorticoids, or hematologic or malignant disease, and those who underwent recent surgery within 1 month at the time of entry. A smoker was defined as a current smoker in our analyses.

Physical and laboratory measurements

Blood pressure was determined using an automatic sphygmomanometer with a conventional cuff after the subject had rested for at least 5 min. Waist circumference was measured to the nearest centimeter at the level of the umbilicus in a standing position at the end of gentle expiration. Blood was drawn after an overnight fast and biochemical parameters were analyzed using a standard laboratory method at the Central Clinical Laboratory of the Osaka City University Hospital [18, 19]. The estimated glomerular filtration rate (eGFR) was calculated using the Japanese eGFR equation [20]. Immunoreactive insulin levels were measured for subjects not receiving insulin therapy (n = 144) by electro-chemiluminescence immunoassay [Cobas 8000 (502/602), Roche Diagnostics] at the Central Clinical Laboratory. Homeostasis model assessment of insulin resistance (HOMA-R) was calculated according to the following formula: fasting insulin (μU/mL) × fasting glucose (mg/dL)/405 [21]. Frozen serum samples were shipped to SRL Inc. (Tokyo, Japan) and hs-CRP concentrations were measured by means of particle-enhanced immunonephelometry with the Behring nephelometer using N Latex CRP mono reagent.

Serum levels of LBP were measured using a commercial enzyme-linked immunosorbent assay (HK315-02, HyCult Biotech Inc., Uden, the Netherlands) as per manufacturer’s instructions. The intra- and inter-assay coefficients of LBP variation were <5 and <10%, respectively.

Measurement of arterial stiffness

Arterial stiffness was evaluated by measuring PWV in the heart-femoral segment using an automatic waveform analyzer (Model BP-203RPE; Omron Colin Co., Ltd., Tokyo, Japan) as described previously [22, 23]. Reproducibility in the measurements of arterial stiffness was confirmed in our previous study, in which the coefficients of variation were less than 5% for heart-femoral PWV [22].

Statistical analysis

Data are expressed as the number (%), mean ± standard deviation (SD), or median (interquartile range) as appropriate. For comparisons between men and women, χ2-test, unpaired t-test, or Wilcoxon rank-sum test, was performed as appropriate. Skewed parameters, such as HOMA-R, triglycerides, and hs-CRP were logarithmically transformed before regression analysis. Simple linear regression analyses were performed to evaluate the relationship between serum LBP levels or aortic PWV and various clinical variables, including cardiovascular risk factors. To explore the association between LBP and aortic PWV, multiple linear regression analyses were performed after adjustment for age, sex, BMI, systolic blood pressure, albumin, eGFR, high-density lipoprotein (HDL) cholesterol level, log [hs-CRP], serum LBP level, treatment with statins, treatment with inhibitors of the renin-angiotensin system (RAS inhibitors), treatment with calcium-channel blockers, and smoking status. To assess whether the effect of serum LBP levels on aortic PWV is modified by sex, the interaction term between LBP and sex was inserted into the multiple regression model. A p value of <0.20 was considered significant for interaction effects, as has been used in a previous study [24], and a p value of <0.05 was considered significant for all other analyses. Statistical analyses were performed by using the JMP 10 software program (SAS Institute Inc., Cary, NC, USA).

Results

Clinical characteristics, serum LBP levels, and aortic PWV of the subjects

The clinical characteristics of the total population, as well as of men and women, are shown in Table 1. The subjects had a mean age of 61 years, median duration of diabetes of 10 years, and mean BMI of 27.1 kg/m2. One hundred sixty-eight subjects (85.7%) were receiving any antihyperglycemic agents. Eighty (40.8%) subjects were treated with statins for dyslipidemia, 72 (36.7%) with RAS inhibitors, and 74 (37.8%) with calcium-channel blockers for hypertension. There were significantly more male smokers than female smokers. Serum creatinine levels, but not eGFR, were significantly different between men and women. Parameters of obesity and insulin resistance, such as BMI, waist circumference, and HOMA-R, were not significantly different between men and women. Triglycerides levels and diastolic blood pressure were higher, and HDL-cholesterol levels were lower in men than in women.

Table 1 Clinical characteristics, serum LBP levels, and aortic PWV in all subjects as well as in men and women with type 2 diabetes
Full size table

Mean ± SD value for serum LBP levels of all subjects was 18.2 ± 6.3 μg/mL (range 2.1–36.2 μg/mL). Mean ± SD value for the aortic PWV was 1194 ± 346 cm/s (range 610–2500 cm/s). Serum LBP levels and aortic PWV were not significantly different between men and women.

Association between serum LBP levels and cardiovascular risk factors

We first examined the association of serum LBP levels with the parameters related to obesity, insulin resistance, and other cardiovascular risk factors by simple linear regression analyses (Table 2). Serum LBP levels were significantly correlated with measures of obesity including BMI (r = 0.279, p < 0.001) and waist circumference (r = 0.295, p < 0.001) and with parameters related to insulin resistance including HOMA-R (r = 0.257, p = 0.002), triglycerides (r = 0.234, p < 0.001), and HDL-cholesterol levels (r = −0.163, p = 0.020). In addition, serum LBP levels were correlated with inflammatory factors such as hs-CRP (r = 0.575, p < 0.001) and serum albumin levels (r = −0.156, p = 0.029) (Table 2).

Table 2 Correlation between serum LBP levels or aortic PWV and cardiovascular risk factors
Full size table

Association of aortic PWV with cardiovascular risk factors and serum LBP levels

Next, we examined the association of aortic PWV with cardiovascular risk factors and serum LBP levels by simple linear regression analyses (Table 2). Aortic PWV was well correlated with age (r = 0.568, p < 0.001), systolic blood pressure (r = 0.498, p < 0.001), and eGFR (r = −0.473, p < 0.001). In addition, aortic PWV was found to be negatively correlated with obesity-related parameters, such as BMI (r = −0.312, p < 0.001), waist circumference (r = −0.216, p = 0.003), and HOMA-R (r = −0.279, p < 0.001). Among inflammation-related parameters, serum albumin levels were negatively correlated (r = −0.210, p = 0.003), while neither hs-CRP (r = −0.053, p = 0.462) nor serum LBP levels (r = 0.065, p = 0.364) were significantly correlated with aortic PWV in univariate analyses (Table 2).

Multivariate analyses of the factors associated with aortic PWV

To explore whether serum LBP levels have an independent association with arterial stiffness, we performed multiple regression analyses after adjusting for age; sex; BMI; systolic blood pressure; albumin; eGFR; log [triglycerides]; HDL-cholesterol; log [hs-CRP]; use of statins; use of RAS inhibitors; use of calcium-channel blockers; and smoking status (Model 1, Table 3). Aside from age (β = 0.344, p < 0.001), BMI (β = −0.233, p = 0.001), systolic blood pressure (β = 0.382, p < 0.001), and use of RAS inhibitors (β = −0.130, p = 0.025), serum LBP levels were found to be independently and positively associated with aortic PWV (β = 0.135, p = 0.026). On the other hand, hs-CRP levels were not found to be an independent determinant of aortic PWV (β = 0.024, p = 0.733) (Model 1, Table 3). Unlike RAS inhibitors, use of calcium-channel blockers was not significantly associated with aortic PWV (β = 0.049, p = 0.412). The association between serum LBP levels and aortic PWV remained nearly significant (β = 0.125, p = 0.083) after further adjustment for log [HOMA-R] (Model 2, Table 3).

Table 3 Multiple regression analysis of the determinants for aortic PWV
Full size table

Separate correlations between serum LBP levels and aortic PWV in men and women

Additionally, we performed an interaction analysis to assess whether sex modified the relationship between serum LBP levels and aortic PWV. The analysis indicated a potential effect modification by sex on the association between serum LBP levels and aortic PWV (β = −0.137, p for interaction = 0.065). Then, we examined the association between serum LBP levels and aortic PWV in men (n = 101) and women (n = 95) separately. Serum LBP levels were found to be positively correlated with aortic PWV in men (r = 0.242, p = 0.015), and the correlation remained significant (β = 0.209, p = 0.011) after adjusting for age; BMI; systolic blood pressure; albumin; eGFR; log [triglycerides]; HDL-cholesterol; log [hs-CRP]; use of statins; use of RAS inhibitors; use of calcium-channel blockers, and smoking status. On the contrary, no significant correlation was found between serum LBP levels and aortic PWV in women (β = 0.028, p = 0.768). Although not statistically significant, the impact of serum LBP levels on aortic PWV was greater in men (β = 0.146, p = 0.140) than in women (β = −0.020, p = 0.874), after further adjustment for log [HOMA-R].

Discussion

The present study demonstrated that serum LBP levels are positively associated with arterial stiffness, as assessed by aortic PWV, in patients with type 2 diabetes. Serum LBP levels were positively correlated with the parameters of obesity, insulin resistance, and inflammation in our diabetic subjects, which is in agreement with observations from previous studies of non-diabetic populations [9, 12, 15]. However, it is noteworthy that the association between serum LBP levels and aortic PWV was independent of obesity, inflammation, and other traditional cardiovascular risk factors. The results further revealed that the association between serum LBP levels and aortic PWV was observed in men, but not in women. To our knowledge, this is the first report to demonstrate the clinical implications of circulating LBP in the increased arterial stiffness in type 2 diabetes.

Clinical association between serum LBP levels and arterial stiffness

This study clearly demonstrated that serum LBP levels are independently and positively associated with aortic PWV in patients with type 2 diabetes. Two previous studies showed that serum LBP levels were a significant predictor of prevalent coronary artery disease [7] and cardiovascular mortality [14], independent of established cardiovascular risk factors and inflammatory markers, in hospital-based cohort studies. Recently, serum LBP levels have been shown to be independently associated with carotid intima-media thickness, the most established morphological surrogate marker for cardiovascular morbidity and mortality [25, 26], after adjusting for age, sex, BMI, and hs-CRP levels, in healthy subjects [15]. Aortic PWV has also been established as an independent predictor of future cardiovascular events and mortality [27, 28]. Recent studies have shown a close association between blood pressure and arterial stiffness as evaluated by brachial-ankle PWV [29] in patients with type 2 diabetes, and a predictive value of brachial-ankle PWV on the progression of coronary artery calcification [30] The results from the present study are in agreement with those of the previous study [15] and indicate a possible role of LBP in the progression of atherosclerosis. Furthermore, this study is the first to report the impact of LBP on arterial stiffness in patients with type 2 diabetes, who have advanced arterial stiffening [22, 27, 31,32,33] and elevated cardiovascular mortality [34].

Potential mechanisms underlying the relationship between LBP and arterial stiffness

Importantly, in this study, the relationship between serum LBP levels and aortic PWV was independent of traditional cardiovascular risk factors including age, obesity, renal dysfunction, hyperglycemia, and dyslipidemia. It is well recognized that low-grade inflammation is among the major factors involved in arterial stiffness in the general population [35] and in patients with type 2 diabetes [33, 36]. Recent evidence indicates that bacterial endotoxins, or LPS, are an important source of vascular inflammation in atherosclerosis [4]. In vitro studies have demonstrated that LPS induced expression of matrix metalloproteinase-9 through the TLR4/nuclear factor-κB pathway [37, 38] and stimulated the release of proinflammatory cytokines [39] in vascular smooth muscle cells [37, 39] and endothelial cells [38]. In vivo studies also showed that the blockade of LPS signaling by TLR4 antagonists reduced the infiltration of monocytes/macrophages and expression of interleukin-6 and matrix metalloproteinase-9 in the atherosclerotic lesions of diabetic mice [40]. In humans, prospective population-based studies showed that chronic infection [2] or endotoxemia [3] is a strong risk factor of carotid atherosclerosis [2, 3] and cardiovascular diseases [3]. In a large population-based study, soluble CD14, a mediator for the activation of immune cells by LPS, was independently associated with aortic PWV, but not with carotid intima-media thickness [41]. In light of the combined experimental and clinical evidence, and considering the fact that circulating LBP binds to LPS and promotes the innate immune response [5], our data may indicate a critical role of the LPS/LBP-induced inflammation in the pathogenesis of arterial stiffness in type 2 diabetes.

Alternatively, the association between serum LBP levels and aortic PWV can be explained by the indirect effects of LBP on aortic PWV via obesity and insulin resistance. Recently, moderately increased LPS in circulation, or metabolic endotoxemia, in response to a high-fat diet was shown to trigger obesity and insulin resistance in mice [42, 43]. Several studies also showed that LBP is produced by adipocytes and plays an essential role in inflammation- and obesity-associated adipose tissue dysfunction [44, 45]. The relationship between LBP and obesity, insulin resistance, and the metabolic syndrome has been demonstrated in a number of studies performed in humans in both cross-sectional [8, 9, 11, 12] and prospective [10, 13] designs. In agreement with these studies, we found that serum LBP levels were positively correlated with parameters of obesity, insulin resistance, and components of the metabolic syndrome in patients with type 2 diabetes (Table 2). Considering the evidence that the metabolic syndrome [46] and insulin resistance [33] are closely associated with increased arterial stiffness, it is conceivable that LBP affected aortic stiffness through insulin resistance in our subjects. However, in our data, the association of obesity and dyslipidemia with aortic PWV was less significant compared with that of age, hypertension, renal dysfunction, and serum LBP levels (Table 3). Moreover, HOMA-R was not independently associated with aortic PWV and an additional adjustment for log [HOMA-R] did not virtually affect the relationship between LBP and aortic PWV in the multivariate model (Model 2, Table 3). Thus, although LPS/LBP-induced immune response is commonly involved in arterial stiffness [41], obesity, and insulin resistance [6, 8,9,10,11,12,13], our results indicate that the LPS/LBP-induced innate immunity independently affects arterial stiffness in patients with type 2 diabetes.

Sex-dependent association between LBP and arterial stiffness

This study further revealed that the effect of serum LBP levels on aortic PWV is modified by sex and that there is a significant association between serum LBP levels and aortic PWV in men only. A number of studies have shown sex-dependent association of arterial stiffness with metabolic risk factors, such as visceral adiposity [18], the metabolic syndrome, and its components [47, 48]. In previous studies on the LPS-related factors, sex-adjusted association was observed between LBP/soluble CD14 and aortic stiffness [41], carotid intima-media thickness [15], and cardiovascular disease [14]. However, unlike the present study, these previous studies did not stratify the data by sex. Several lines of evidence indicate the sex-associated difference in inflammatory responses to LPS-stimulation in neutrophils in vitro models [49, 50] and in mice in vivo models [51], with increased responses in males than in females. Recent studies have also indicated the sex-associated differences in the gut microbiome, one of the major sources of circulating LPS [42], and the sex-dependent effects of diet on the gut microbiota in mice and humans [52]. In a study performed in rats, systemic proinflammatory cytokine levels in response to an oligofructose-supplemented diet were higher in males than in females [53]. Based on these reports, we can hypothesize that men with type 2 diabetes are more prone to the immune response elicited by LPS from the gut microbiota than are women, leading to increased arterial stiffness in men. To our knowledge, this study is the first to elucidate the sex-related differences in the association between LBP and arterial stiffness.

Limitations

This study has several limitations. First, we evaluated the endotoxin-induced inflammation by measuring serum LBP levels, but not by a direct measurement of LPS. However, serum LBP levels, which have been proposed as a surrogate marker of LPS-induced immune response in humans, can be simply and stably measured by enzyme-linked immunosorbent assay [8, 10, 11]. We also did not include the evaluation of the LPS-related factors other than LBP, such as interleukin-6, soluble CD14, and tumor-necrosis factor-α, that could strengthen our study. Second, since this was a cross-sectional study, the causal relationship between LBP and arterial stiffness needs to be confirmed by longitudinal and/or interventional studies. Third, the subjects were receiving statins and/or RAS inhibitors, which could have influenced inflammation, vascular function, and related risk factors. To minimize the impact of these drugs, the presence of these treatments was adjusted for in the multiple regression analysis. Fourth, the sample size was too small in the sex-stratified analysis to conclude with statistical significance the relationship between serum LBP levels and aortic PWV in men after adjusting for log [HOMA-R]. Finally, because our subjects were hospitalized in a university hospital and had inadequate glycemic control, the present results may not be generalized to the entire population of patients with type 2 diabetes.

Conclusions

This study clearly demonstrated that serum LBP levels are independently and positively associated with arterial stiffness in patients with type 2 diabetes. Our data indicate a close link between LPS/LBP-induced innate immunity and arterial stiffness in these patients. This study further shows that LBP preferentially affects arterial stiffness in men over women, indicating sex-related differences in the link between LBP and arterial stiffness. Further interventional studies are warranted to clarify whether the reduction of serum LPS levels by antibiotics or probiotics would reduce arterial stiffness and the risk of cardiovascular diseases in patients with type 2 diabetes.

Abbreviations

LPS:

lipopolysaccharide

LBP:

lipopolysaccharide-binding protein

PWV:

pulse wave velocity

BMI:

body mass index

CD:

cluster of differentiation

TLR:

toll-like receptor

hs-CRP:

high-sensitivity C-reactive protein

eGFR:

estimated glomerular filtration rate

HOMA-R:

homeostasis model assessment of insulin resistance

SD:

standard deviation

HbA1c:

glycated hemoglobin A1c

HDL:

high-density lipoprotein

LDL:

low-density lipoprotein

RAS:

renin-angiotensin system

References

  1. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860–7.

    Article  CAS  PubMed  Google Scholar 

  2. Kiechl S, Egger G, Mayr M, Wiedermann CJ, Bonora E, Oberhollenzer F, Muggeo M, Xu Q, Wick G, Poewe W, et al. Chronic infections and the risk of carotid atherosclerosis: prospective results from a large population study. Circulation. 2001;103:1064–70.

    Article  CAS  PubMed  Google Scholar 

  3. Wiedermann CJ, Kiechl S, Dunzendorfer S, Schratzberger P, Egger G, Oberhollenzer F, Willeit J. Association of endotoxemia with carotid atherosclerosis and cardiovascular disease: prospective results from the Bruneck Study. J Am Coll Cardiol. 1999;34:1975–81.

    Article  CAS  PubMed  Google Scholar 

  4. Stoll LL, Denning GM, Weintraub NL. Potential role of endotoxin as a proinflammatory mediator of atherosclerosis. Arterioscler Thromb Vasc Biol. 2004;24:2227–36.

    Article  CAS  PubMed  Google Scholar 

  5. Triantafilou M, Triantafilou K. Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation cluster. Trends Immunol. 2002;23:301–4.

    Article  CAS  PubMed  Google Scholar 

  6. Kheirandish-Gozal L, Peris E, Wang Y, Tamae Kakazu M, Khalyfa A, Carreras A, Gozal D. Lipopolysaccharide-binding protein plasma levels in children: effects of obstructive sleep apnea and obesity. J Clin Endocrinol Metab. 2014;99:656–63.

    Article  CAS  PubMed  Google Scholar 

  7. Lepper PM, Schumann C, Triantafilou K, Rasche FM, Schuster T, Frank H, Schneider EM, Triantafilou M, von Eynatten M. Association of lipopolysaccharide-binding protein and coronary artery disease in men. J Am Coll Cardiol. 2007;50:25–31.

    Article  CAS  PubMed  Google Scholar 

  8. Ruiz AG, Casafont F, Crespo J, Cayon A, Mayorga M, Estebanez A, Fernadez-Escalante JC, Pons-Romero F. Lipopolysaccharide-binding protein plasma levels and liver TNF-α gene expression in obese patients: evidence for the potential role of endotoxin in the pathogenesis of non-alcoholic steatohepatitis. Obes Surg. 2007;17:1374–80.

    Article  PubMed  Google Scholar 

  9. Gonzalez-Quintela A, Alonso M, Campos J, Vizcaino L, Loidi L, Gude F. Determinants of serum concentrations of lipopolysaccharide-binding protein (LBP) in the adult population: the role of obesity. PLoS ONE. 2013;8:e54600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Liu X, Lu L, Yao P, Ma Y, Wang F, Jin Q, Ye X, Li H, Hu FB, Sun L, et al. Lipopolysaccharide binding protein, obesity status and incidence of metabolic syndrome: a prospective study among middle-aged and older Chinese. Diabetologia. 2014;57:1834–41.

    Article  CAS  PubMed  Google Scholar 

  11. Moreno-Navarrete JM, Ortega F, Serino M, Luche E, Waget A, Pardo G, Salvador J, Ricart W, Fruhbeck G, Burcelin R, et al. Circulating lipopolysaccharide-binding protein (LBP) as a marker of obesity-related insulin resistance. Int J Obes. 2012;36:1442–9.

    Article  CAS  Google Scholar 

  12. Sun L, Yu Z, Ye X, Zou S, Li H, Yu D, Wu H, Chen Y, Dore J, Clement K, et al. A marker of endotoxemia is associated with obesity and related metabolic disorders in apparently healthy Chinese. Diabetes Care. 2010;33:1925–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Tilves CM, Zmuda JM, Kuipers AL, Nestlerode CS, Evans RW, Bunker CH, Patrick AL, Miljkovic I. Association of lipopolysaccharide-binding protein with aging-related adiposity change and prediabetes among African ancestry men. Diabetes Care. 2016;39:385–91.

    Article  CAS  PubMed  Google Scholar 

  14. Lepper PM, Kleber ME, Grammer TB, Hoffmann K, Dietz S, Winkelmann BR, Boehm BO, Marz W. Lipopolysaccharide-binding protein (LBP) is associated with total and cardiovascular mortality in individuals with or without stable coronary artery disease—results from the Ludwigshafen Risk and Cardiovascular Health Study (LURIC). Atherosclerosis. 2011;219:291–7.

    Article  CAS  PubMed  Google Scholar 

  15. Serrano M, Moreno-Navarrete JM, Puig J, Moreno M, Guerra E, Ortega F, Xifra G, Ricart W, Fernandez-Real JM. Serum lipopolysaccharide-binding protein as a marker of atherosclerosis. Atherosclerosis. 2013;230:223–7.

    Article  CAS  PubMed  Google Scholar 

  16. Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, Ducimetiere P, Benetos A. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension. 2001;37:1236–41.

    Article  CAS  PubMed  Google Scholar 

  17. American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care. 2014;37(Suppl 1):S14–80.

    Article  Google Scholar 

  18. Morigami H, Morioka T, Yamazaki Y, Imamura S, Numaguchi R, Asada M, Motoyama K, Mori K, Fukumoto S, Shoji T, et al. Visceral adiposity is preferentially associated with vascular stiffness rather than thickness in men with type 2 diabetes. J Atheroscler Thromb. 2016;23:1067–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Morioka T, Emoto M, Yamazaki Y, Kawano N, Imamura S, Numaguchi R, Urata H, Motoyama K, Mori K, Fukumoto S, et al. Leptin is associated with vascular endothelial function in overweight patients with type 2 diabetes. Cardiovasc Diabetol. 2014;13:10.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92.

    Article  CAS  PubMed  Google Scholar 

  21. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–9.

    Article  CAS  PubMed  Google Scholar 

  22. Kimoto E, Shoji T, Shinohara K, Inaba M, Okuno Y, Miki T, Koyama H, Emoto M, Nishizawa Y. Preferential stiffening of central over peripheral arteries in type 2 diabetes. Diabetes. 2003;52:448–52.

    Article  CAS  PubMed  Google Scholar 

  23. Numaguchi R, Morioka T, Yamazaki Y, Imamura S, Urata H, Motoyama K, Mori K, Fukumoto S, Shoji T, Emoto M, et al. Leptin is associated with local stiffness of the carotid artery in overweight patients with type 2 diabetes. J Diabetes Metab. 2015;6:627.

    Google Scholar 

  24. Ramos LF, Shintani A, Ikizler TA, Himmelfarb J. Oxidative stress and inflammation are associated with adiposity in moderate to severe CKD. J Am Soc Nephrol. 2008;19:593–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cao JJ, Arnold AM, Manolio TA, Polak JF, Psaty BM, Hirsch CH, Kuller LH, Cushman M. Association of carotid artery intima-media thickness, plaques, and C-reactive protein with future cardiovascular disease and all-cause mortality: the Cardiovascular Health Study. Circulation. 2007;116:32–8.

    Article  PubMed  Google Scholar 

  26. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation. 2007;115:459–67.

    Article  PubMed  Google Scholar 

  27. Shoji T, Emoto M, Shinohara K, Kakiya R, Tsujimoto Y, Kishimoto H, Ishimura E, Tabata T, Nishizawa Y. Diabetes mellitus, aortic stiffness, and cardiovascular mortality in end-stage renal disease. J Am Soc Nephrol. 2001;12:2117–24.

    CAS  PubMed  Google Scholar 

  28. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol. 2010;55:1318–27.

    Article  PubMed  Google Scholar 

  29. Bouchi R, Ohara N, Asakawa M, Nakano Y, Takeuchi T, Murakami M, Sasahara Y, Numasawa M, Minami I, Izumiyama H, et al. Is visceral adiposity a modifier for the impact of blood pressure on arterial stiffness and albuminuria in patients with type 2 diabetes? Cardiovasc Diabetol. 2016;15:10.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Lee JY, Ryu S, Lee SH, Kim BJ, Kim BS, Kang JH, Cheong ES, Kim JY, Park JB, Sung KC. Association between brachial-ankle pulse wave velocity and progression of coronary artery calcium: a prospective cohort study. Cardiovasc Diabetol. 2015;14:147.

    Article  PubMed  PubMed Central  Google Scholar 

  31. El Ghoul B, Daaboul Y, Korjian S, El Alam A, Mansour A, Hariri E, Samad S, Salameh P, Dahdah G, Blacher J, et al. Etiology of end-stage renal disease and arterial stiffness among hemodialysis patients. Biomed Res Int. 2017;2017:2543262.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Schram MT, Henry RM, van Dijk RA, Kostense PJ, Dekker JM, Nijpels G, Heine RJ, Bouter LM, Westerhof N, Stehouwer CD. Increased central artery stiffness in impaired glucose metabolism and type 2 diabetes: the Hoorn Study. Hypertension. 2004;43:176–81.

    Article  CAS  PubMed  Google Scholar 

  33. Stehouwer CD, Henry RM, Ferreira I. Arterial stiffness in diabetes and the metabolic syndrome: a pathway to cardiovascular disease. Diabetologia. 2008;51:527–39.

    Article  CAS  PubMed  Google Scholar 

  34. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229–34.

    Article  CAS  PubMed  Google Scholar 

  35. Jain S, Khera R, Corrales-Medina VF, Townsend RR, Chirinos JA. Inflammation and arterial stiffness in humans. Atherosclerosis. 2014;237:381–90.

    Article  CAS  PubMed  Google Scholar 

  36. de Boer SA, Hovinga-de Boer MC, Heerspink HJ, Lefrandt JD, van Roon AM, Lutgers HL, Glaudemans AW, Kamphuisen PW, Slart RH, Mulder DJ. Arterial stiffness is positively associated with 18F-fluorodeoxyglucose positron emission tomography-assessed subclinical vascular inflammation in people with early type 2 diabetes. Diabetes Care. 2016;39:1440–7.

    Article  PubMed  Google Scholar 

  37. Li H, Xu H, Sun B. Lipopolysaccharide regulates MMP-9 expression through TLR4/NF-κB signaling in human arterial smooth muscle cells. Mol Med Rep. 2012;6:774–8.

    CAS  PubMed  Google Scholar 

  38. Paolillo R, Iovene MR, Carratelli CR, Rizzo A. Induction of VEGF and MMP-9 expression by toll-like receptor 2/4 in human endothelial cells infected with Chlamydia pneumoniae. Int J Immunopathol Pharmacol. 2012;25:377–86.

    Article  CAS  PubMed  Google Scholar 

  39. Yang X, Coriolan D, Murthy V, Schultz K, Golenbock DT, Beasley D. Proinflammatory phenotype of vascular smooth muscle cells: role of efficient Toll-like receptor 4 signaling. Am J Physiol Heart Circ Physiol. 2005;289:H1069–76.

    Article  CAS  PubMed  Google Scholar 

  40. Lu Z, Zhang X, Li Y, Lopes-Virella MF, Huang Y. TLR4 antagonist attenuates atherogenesis in LDL receptor-deficient mice with diet-induced type 2 diabetes. Immunobiology. 2015;220:1246–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Amar J, Ruidavets JB, Sollier CBD, Bongard V, Boccalon H, Chamontin B, Drouet L, Ferrieres J. Soluble CD14 and aortic stiffness in a population-based study. J Hypertens. 2003;21:1869–77.

    Article  CAS  PubMed  Google Scholar 

  42. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, Burcelin R. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008;57:1470–81.

    Article  CAS  PubMed  Google Scholar 

  43. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56:1761–72.

    Article  CAS  PubMed  Google Scholar 

  44. Moreno-Navarrete JM, Escote X, Ortega F, Serino M, Campbell M, Michalski MC, Laville M, Xifra G, Luche E, Domingo P, et al. A role for adipocyte-derived lipopolysaccharide-binding protein in inflammation- and obesity-associated adipose tissue dysfunction. Diabetologia. 2013;56:2524–37.

    Article  CAS  PubMed  Google Scholar 

  45. Moreno-Navarrete JM, Escote X, Ortega F, Camps M, Ricart W, Zorzano A, Vendrell J, Vidal-Puig A, Fernandez-Real JM. Lipopolysaccharide binding protein is an adipokine involved in the resilience of the mouse adipocyte to inflammation. Diabetologia. 2015;58:2424–34.

    Article  CAS  PubMed  Google Scholar 

  46. Safar ME, Thomas F, Blacher J, Nzietchueng R, Bureau JM, Pannier B, Benetos A. Metabolic syndrome and age-related progression of aortic stiffness. J Am Coll Cardiol. 2006;47:72–5.

    Article  PubMed  Google Scholar 

  47. Gomez-Sanchez L, Garcia-Ortiz L, Patino-Alonso MC, Recio-Rodriguez JI, Fernando R, Marti R, Agudo-Conde C, Rodriguez-Sanchez E, Maderuelo-Fernandez JA, Ramos R, et al. Association of metabolic syndrome and its components with arterial stiffness in Caucasian subjects of the MARK study: a cross-sectional trial. Cardiovasc Diabetol. 2016;15:148.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Kim HL, Lee JM, Seo JB, Chung WY, Kim SH, Zo JH, Kim MA. The effects of metabolic syndrome and its components on arterial stiffness in relation to gender. J Cardiol. 2015;65:243–9.

    Article  PubMed  Google Scholar 

  49. Aomatsu M, Kato T, Kasahara E, Kitagawa S. Gender difference in tumor necrosis factor-alpha production in human neutrophils stimulated by lipopolysaccharide and interferon-γ. Biochem Biophys Res Commun. 2013;441:220–5.

    Article  CAS  PubMed  Google Scholar 

  50. Lefevre N, Corazza F, Duchateau J, Desir J, Casimir G. Sex differences in inflammatory cytokines and CD99 expression following in vitro lipopolysaccharide stimulation. Shock. 2012;38:37–42.

    Article  CAS  PubMed  Google Scholar 

  51. Queen AE, Moerdyk-Schauwecker M, McKee LM, Leamy LJ, Huet YM. Differential expression of inflammatory cytokines and stress genes in male and female mice in response to a lipopolysaccharide challenge. PLoS ONE. 2016;11:e0152289.

    Article  Google Scholar 

  52. Bolnick DI, Snowberg LK, Hirsch PE, Lauber CL, Org E, Parks B, Lusis AJ, Knight R, Caporaso JG, Svanback R. Individual diet has sex-dependent effects on vertebrate gut microbiota. Nat Commun. 2014;5:4500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Shastri P, McCarville J, Kalmokoff M, Brooks SP, Green-Johnson JM. Sex differences in gut fermentation and immune parameters in rats fed an oligofructose-supplemented diet. Biol Sex Differ. 2015;6:13.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors’ contributions

TaS, TM, and AS conceived the study, participated in its design and coordination, and helped in drafting the manuscript. TaS carried out the immunoassays. TaS and TM performed the statistical analyses. TaS, YK, YM, and YY enrolled patients and performed the vascular examinations. KMot, KMor, SF, TeS, ME, and MI contributed to discussions and were involved in either drafting the manuscript or revising it critically. All authors read and approved the final manuscript.

Acknowledgements

The authors wish to acknowledge the excellent technical assistance of Ms. Asako Katsuma from the research laboratory of the Department of Vascular Medicine, Osaka City University Graduate School of Medicine.

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

This study was performed in accordance with the Declaration of Helsinki (1975, as revised in 2013). This study was approved by the Ethics Committee of Osaka City University Graduate School of Medicine (No. 308). All participants provided written informed consent prior to the study.

Funding

This study was supported by a Grant-in-Aid for Scientific Research (No. 20591068) from the Japan Society for the Promotion of Science (to ME and KMor).

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Authors and Affiliations

  1. Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan

    Takeshi Sakura, Tomoaki Morioka, Yoshinori Kakutani, Yuya Miki, Yuko Yamazaki, Koka Motoyama, Masanori Emoto & Masaaki Inaba

  2. Department of Vascular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan

    Atsushi Shioi & Tetsuo Shoji

  3. Vascular Science Center for Translational Research, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan

    Atsushi Shioi, Tetsuo Shoji & Masaaki Inaba

  4. Department of Nephrology, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan

    Katsuhito Mori

  5. Department of Premier Preventive Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan

    Shinya Fukumoto

Authors
  1. Takeshi Sakura
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  2. Tomoaki Morioka
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  11. Masanori Emoto
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  12. Masaaki Inaba
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Corresponding author

Correspondence to Tomoaki Morioka.

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Sakura, T., Morioka, T., Shioi, A. et al. Lipopolysaccharide-binding protein is associated with arterial stiffness in patients with type 2 diabetes: a cross-sectional study. Cardiovasc Diabetol 16, 62 (2017). https://doi.org/10.1186/s12933-017-0545-3

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Keywords

Cardiovascular Diabetology

ISSN: 1475-2840