Open Access

Is visceral adiposity a modifier for the impact of blood pressure on arterial stiffness and albuminuria in patients with type 2 diabetes?

  • Ryotaro Bouchi1Email author,
  • Norihiko Ohara1,
  • Masahiro Asakawa1,
  • Yujiro Nakano1,
  • Takato Takeuchi1,
  • Masanori Murakami1,
  • Yuriko Sasahara1,
  • Mitsuyuki Numasawa1,
  • Isao Minami1,
  • Hajime Izumiyama1, 2,
  • Koshi Hashimoto1, 3,
  • Takanobu Yoshimoto1 and
  • Yoshihiro Ogawa1, 4
Cardiovascular Diabetology201615:10

https://doi.org/10.1186/s12933-016-0335-3

Received: 25 November 2015

Accepted: 13 January 2016

Published: 21 January 2016

Abstract

Background

We aimed to investigate whether visceral adiposity could modify the impact of blood pressure on arterial stiffness and albuminuria in patients with type 2 diabetes.

Methods

This cross-sectional study examines the interaction of visceral adiposity with increased blood pressure on arterial stiffness and albuminuria. 638 patients with type 2 diabetes (mean age 64 ± 12 years; 40 % female) were enrolled. Visceral fat area (VFA, cm2) was assessed by a dual-impedance analyzer, whereby patients were divided into those with VFA < 100 (N = 341) and those with VFA ≥ 100 (N = 297). Albuminuria was measured in a single 24-h urine collection (UAE, mg/day) and brachial-ankle pulse wave velocity (ba-PWV, cm/s) was used for the assessment of arterial stiffening. Linear regression analyses were used to investigate the association of systolic blood pressure (SBP) and VFA with UAE and baPWV.

Results

Patients with VFA ≥ 100 were significantly younger, had higher SBP, HbA1c, triglycerides, UAE, alanine aminotransferase, C-reactive protein and lower high-density lipoprotein and shorter duration of diabetes than those with VFA < 100. SBP was significantly and almost equivalently associated with ba-PWV both in VFA < 100 (standardized β 0.224, p = 0.001) and VFA ≥ 100 (standardized β 0.196, p = 0.004) patients in the multivariate regression analysis adjusting for covariates including age, gender, HbA1c, diabetic complications and the use of insulin and anti-hypertensive agents. By contrast, the association of SBP with UAE was stronger in patients with VFA ≥ 100 (standardized β 0.263, p = 0.001) than that in patients with VFA < 100 (standardized β 0.140, p = 0.080) in the multivariate regression model. In the whole cohort, the significant interaction between SBP and VFA on UAE (standardized β 0.172, p = 0.040) but not on ba-PWV (standardized β −0.008, p = 0.916) was observed.

Conclusions

The effect of increased blood pressure on arterial stiffness is almost similar in type 2 diabetic patients with both low and high visceral adiposity, while its association with albuminuria is stronger in the latter.

Keywords

Visceral adiposity Blood pressure Arterial stiffness Albuminuria Type 2 diabetes

Background

Blood pressure is a strong risk factor for cardiovascular disease (CVD) [1, 2] and chronic kidney disease (CKD) [35]. Among patients with diabetes, hypertension is associated with the incidence of CVD and CKD as well [69]. The reduction of blood pressure could reduce the risks both for CVD and CKD.

Obesity, especially increased visceral adiposity is a major cause of hypertension, accounting for 65–75 % of the risk for human essential hypertension [10]. In addition, obesity has been reported to be associated with various cardio-metabolic risks including insulin resistance and dyslipidemia, and also be directly associated with CVD [1114]. Furthermore, abdominal obesity is a strong risk factor for CKD both in general population and patients with diabetes [15, 16]. Therefore, abdominal adiposity is thought to be an important determinant that can account for the association of cardio-metabolic risks with CVD and CKD.

Regarding the association between blood pressure and CVD, the impact of elevated blood pressure on CVD events has been reported to be stronger among people without obesity than those with [1719]. Also, it has been suggested that normal-weight patients with essential hypertension have increased arterial stiffness [20] and systemic vascular resistance. We recently reported that increased visceral adiposity with normal weight is strongly associated with cardio-metabolic risks and arterial stiffness in patients with type 2 diabetes [21]. These studies imply that visceral adiposity could modify the impact of blood pressure on CVD; however, it is uncertain whether increased blood pressure could more strongly affect arterial stiffening in people with low visceral adiposity than in those with high visceral adiposity. On the other hand, among obese people, especially those with high visceral adiposity, intra-renal renin-angiotensin-aldosterone system is activated [2224], leading to the glomerular hyperfiltration at the early stage of obesity-hypertension. Hyperglycemia also induces renal damage directly or through hemodynamic modifications including glomerular hyperfiltration [25]. Therefore, it is possible that increase in systemic blood pressure could more strongly affect the renal hemodynamics in obese, especially in obese patients with diabetes, than in non-obese people, resulting in more severe renal manifestations such as increased albuminuria and decreased glomerular filtration rate (GFR). Taken together, we conducted this cross-sectional study to investigate the interaction of visceral adiposity with blood pressure on the increased risk for arterial stiffening and albuminuria in patients with type 2 diabetes.

Methods

Subjects

Patients with type 2 diabetes who admitted to Tokyo Medical and Dental University Hospital for the purpose of glycemic control and/or evaluation of diabetic complications participated in this cross-sectional study. Patients were eligible, if they were aged ≥20 years, and patients who measured both brachia-ankle pulse wave velocity (ba-PWV) and visceral fat area (VFA) and subcutaneous fat area (SFA) by a dual bioelectrical impedance analyzer were enrolled. Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m2 or undergoing renal replacement therapy), pregnant women, and those with infectious or malignant diseases were excluded. Type 2 diabetes was diagnosed according to the criteria of the Japan Diabetes Society (JDS) [26]. As shown in Fig. 1, 638 patients were finally enrolled in this study. This study complies with the principles laid by Declaration of Helsinki and has been approved by the ethical committee of Tokyo Medical and Dental University (No. 1924).
Fig. 1

Flowchart of patient recruitment to the study

Clinical and biochemical analysis

Standardized questionnaires were used to obtain information on smoking, medication and past history. Smoking history was classified as either current smoker or non-smoker. CVD was defined as the presence of a previous stroke, myocardial infarction, coronary revascularization procedure. Blood pressure was measured in the sitting position after at least 5 min rest, using an electronic sphygmomanometer (ES-H55, Terumo Inc., Tokyo, Japan). HbA1c was measured by the latex agglutination method. HbA1c levels were expressed in accordance with the National Glycohemoglobin Standardization Programs recommended by the Japanese Diabetes Society [26]. Urinary albumin (UAE) and creatinine excretion were measured by the turbidimetric immunoassay and enzymatic method, respectively, in a single 24-h urine collection. GFR was estimated using the following equation for the Japanese, as proposed by the Japanese Society of Nephrology [27]; GFR = 194 × SCr−1.094 × age−0.287 [(if female) × 0.739], where SCr stands for serum creatinine in mg/dl, measured by an enzymatic method. Coefficient of variation of R–R intervals (CV-RR) was used for the assessment of diabetic neuropathy. BMI was calculated as weight divided by the square of height (kg/m2). VFA and SFA were measured at the level of umbilicus by dual bioelectrical impedance analyzer (DUALSCAN, Omron Healthcare Co., Kyoto, Japan). Patients were divided into those with VFA < 100 cm2 (low-V) and those with VFA ≥ 100 cm2 (high-V). Brachial-ankle pulse wave velocity (ba-PWV) was measured using a volume-plethysmographic apparatus (BP-203RPE II form PWV/ABI, Omron Healthcare Co., Kyoto, Japan), with subjects in the supine position after at least 5 min of rest [28, 29]. The ba-PWV was calculated as reported previously [30]. We simultaneously measured ba-PWV on both the right and left sides and the averaged values from each individual were subjected to statistical analysis.

Statistical analysis

Statistical analysis was performed using programs available in the SPSS version 21.0 statistical package (SPSS Inc., Chicago, IL, USA). Data are presented as mean ± SD, median with interquartile range (IQR), or percent as appropriate according to data distribution. Normality was tested by the Kolmogorov–Smirnov test. Differences between low-V and high-V patients were tested with a t test or Mann–Whitney U test for continuous variables and Chi square test for categorical variables. Linear regression analyses were used to investigate the association of SBP and VFA with ba-PWV and UAE. We determined the linear relationship and multicollinearity for regression assumptions. We removed one variable if a strong correlation (coefficient of correlation >0.8) was observed between the two independent variables. In order to check the multicollinearity, we evaluated variance infiltration factors. If multicollinearity was found in the data, one variable was removed from the multivariate regression analysis. The following covariates were incorporated into the analysis with a stepwise procedure; duration of diabetes, smoking status, triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, HbA1c, eGFR, log CRP and the usage of insulin, calcium channel blockers (CCB), angiotensin receptor blockers (ARB), statins and anti-platelet agents. Age and gender were forced into the model. The interaction between SBP and VFA was also investigated in the multiple linear regression analyses. Differences were considered to be statistically significant at p value less than 0.05.

Results

Clinical characteristics of patients with low-V and high-V

Among 638 patients, 341 and 297 were classified as low-V and high-V patients. As shown in Table 1, high-V patients were significantly younger, had significantly higher SBP and DBP, lower HDL-C, higher triglycerides levels and a shorter duration of diabetes than the low-V patients. Urinary C-peptide and UAE levels in high-V patients were significantly higher than those in low-V patients. BMI, WC, VFA and SFA levels in high-V patients were significantly higher than in those with low-V. The high-V patients were more frequently receiving CCBs, ARBs and statin therapy and were less likely to receive insulin than low-V patients. baPWV in high-V patients was significantly lower than that in low-V patients.
Table 1

Clinical characteristics according to VFA levels

 

VFA < 100 cm2 (N = 341)

VFA ≥ 100 cm2 (N = 297)

p values

Age (years)

66 ± 12

62 ± 13

<0.001

Gender (% male)

57

63

0.196

SBP (mmHg)

128 ± 20

132 ± 17

0.016

DBP (mmHg)

73 ± 12

78 ± 12

<0.001

HbA1c (mmol/mol)

71.6 ± 20.2

75.0 ± 19.5

0.029

HbA1c (%)

8.7 ± 1.8

9.0 ± 1.8

 

HDL-cholesterol (mmol/l)

1.32 ± 0.42

1.19 ± 0.31

<0.001

LDL-cholesterol (mmol/l)

2.87 (2.29–3.56)

2.79 (2.26–3.44)

0.515

Triglycerides (mmol/l)

1.31 (0.98–1.86)

1.61 (1.19–2.26)

<0.001

Urinary C-peptide (μg/day)

42 (27–67)

60 (35–99)

<0.001

Duration of diabetes (years)

12 (5–20)

10 (4–16)

0.044

Current smoker (%)

22

25

0.452

History of CVD

13

17

0.183

UAE (mg/day)

11 (7–26)

19 (10–58)

0.001

eGFR (ml/min/1.73 m2)

72.0 ± 23.3

71.5 ± 25.6

0.791

AST (U/l)

22 (17–28)

24 (19–41)

<0.001

ALT (U/l)

19 (14–30)

28 (18–48)

<0.001

C-reactive protein (mg/l)

0.80 (0.40–1.95)

1.60 (0.80–3.60)

<0.001

PDR (%)

19

12

0.536

CV-RR (%)

3.3 (2.2–4.8)

3.6 (2.3–5.3)

0.109

ba-PWV (cm/s)

1711 (1459–1906)

1582 (1411–1785)

0.007

Body mass index (kg/m2)

23.5 ± 3.2

29.4 ± 4.4

<0.001

Waist circumference (cm)

86 ± 9

102 ± 11

<0.001

Visceral fat area (cm2)

74 (57–87)

133 (114–152)

<0.001

Subcutaneous fat area (cm2)

144 (120–178)

236 (194–284)

<0.001

Insulin (%)

75

61

0.002

CCBs (%)

29

39

0.023

ARBs (%)

35

53

<0.001

Statin (%)

42

52

0.050

Anti-platelets (%)

17

22

0.322

ALT alanine aminotransferase, ARB angiotensin receptor blocker, AST asparatate aminotransferase, baPWV brachial-ankle pulse wave velocity, CCB calcium channel blocker, CVD cardiovascular disease, CV-RR coefficient of variation of R–R intervals, DBP diastolic blood pressure, eGFR estimated glomerular filtration rate, HDL high-density lipoprotein, LDL low-density lipoprotein, PDR proliferative diabetic retinopathy, SBP systolic blood pressure

Association between SBP and baPWV according to VFA categories

Table 2 shows the linear regression analyses to investigate the association between SBP and ba-PWV in patients with low-V and those with high-V. In the univariate model, SBP was significantly and equivalently associated with ba-PWV. After adjusting for age and gender, the statistical significance of SBP with ba-PWV was unchanged both in patients with low-V and those with high-V. In the multivariate model including covariates such as eGFR and anti-hypertensive agents, the association of SBP with ba-PWV remained significant regardless of visceral adiposity (standardized β 0.224, p = 0.001 in low-V and standardized β 0.196, p = 0.004 in high-V). Among patients with high-V, SFA was inversely associated with ba-PWV (standardized β −0.199, p = 0.007). eGFR was a significant covariate regardless of visceral adiposity.
Table 2

Linear regression analysis to investigate the association of blood pressure and visceral adiposity with arterial stiffness in patients with type 2 diabetes

 

VFA < 100 cm2

VFA ≥ 100 cm2

Standardized β

p values

Standardized β

p values

Univariate

 Systolic blood pressure

0.183

0.001

0.215

 

Age- and gender-adjusted

 Systolic blood pressure

0.172

0.001

0.253

 

 Age

0.426

<0.001

0.421

 

 Gender (male versus female)

0.071

0.151

0.044

 

Multivariate

 Systolic blood pressure

0.224

0.001

0.196

0.004

 Age

0.430

<0.001

0.383

<0.001

 Gender (male versus female)

0.130

0.051

0.007

0.920

 eGFR

−0.087

0.055

−0.199

0.042

 SFA

NA

 

0.149

0.007

 CCB

NA

 

−0.155

0.031

CCB calcium channel blocker, eGFR estimated glomerular filtration rate, SFA subcutaneous fat area, VFA visceral fat area

Association between SBP and UAE according to VFA categories

Table 3 shows the association between SBP and UAE according to VFA categories among patients with type 2 diabetes. In the univariate model, SBP was significantly associated with UAE both in patients with low-V and those with high-V. The association of SBP with UAE was unchanged in age- and gender-adjusted model regardless of visceral adiposity (standardized β 0.205, p = 0.001 in patients with low-V and standardized β 0.290, p < 0.001 in patients with high-V). In the multivariate model adjusting for covariates including age, gender, diabetic complications such as neuropathy and retinopathy and HbA1c level, SBP remained significantly associated with UAE in patients with high-V (standardized β 0.263, p = 0.001); whereas, its association with UAE was attenuated in those patients with low-V (standardized β 0.140, p = 0.080).
Table 3

Linear regression analysis to investigate the association of blood pressure and visceral adiposity with albuminuria in patients with type 2 diabetes

 

VFA < 100 cm2

VFA ≥ 100 cm2

Standardized β

p values

Standardized β

p values

Univariate

 Systolic blood pressure

0.203

0.001

0.280

<0.001

Age- and gender-adjusted

 Systolic blood pressure

0.205

0.001

0.290

<0.001

 Age

0.079

0.188

0.172

0.172

 Gender (male versus female)

0.074

0.219

0.087

0.087

Multivariate

 Systolic blood pressure

0.140

0.080

0.263

0.001

 Age

−0.042

0.649

−0.090

0.236

 Gender (male versus female)

0.120

0.122

0.166

0.28

 eGFR

−0.191

0.042

NA

 

 Insulin

0.145

0.064

NA

 

 PDR

0.172

0.024

NA

 

 CV-RR

−0.142

0.075

−0.161

0.034

 HbA1c

  

0.135

0.076

CV-RR Coefficient of variation of RR intervals, eGFR estimated glomerular filtration rate, PDR proliferative diabetic retinopathy, VFA visceral fat area

Interaction between SBP and VFA accounting for the risk of arterial stiffening and albuminuria

Table 4 shows the multivariate linear regression analyses to investigate whether binary interaction between SBP and VFA could account for the risks of arterial stiffening and albuminuria in the whole cohort. The significant interaction between SBP and VFA was observed in the model where UAE was used for a dependent variable; whereas, no significant interaction of SBP with VFA was found as for ba-PWV.
Table 4

Interaction between blood pressure and visceral adiposity accounting for the risk of arterial stiffening and albuminuria in patients with type 2 diabetes

 

ba-PWV

UAE

Standardized β

p values

Standardized β

p values

SBP × VFA

−0.008

0.916

0.172

0.040

Systolic blood pressure

0.177

<0.001

0.171

0.001

Visceral fat area

0.149

0.149

−0.060

0.471

Age

0.430

<0.001

NA

 

Body mass index

−0.299

0.001

NA

 

eGFR

−0.146

0.008

NA

 

Calcium channel blocker

0.109

0.029

NA

 

HbA1c

NA

 

−0.138

0.009

CV-RR

NA

 

0.148

0.005

Gender (male versus female)

NA

 

0.130

0.015

Angiotensin receptor blocker

NA

 

0.114

0.030

Insulin

NA

 

0.109

0.035

ba-PWV brachial-ankle pulse wave velocity, CV-RR Coefficient of variation of RR intervals, eGFR estimated glomerular filtration rate, SBP systolic blood pressure, UAE urinary albumin excretion, VFA visceral fat area

Discussion

Both increased arterial stiffness and albuminuria are strong predictors for mortality, CVD and CKD in patients with diabetes [3136]. Therefore, it is important to elucidate the high risk groups both for increased arterial stiffness and albuminuria among diabetic patients. This study clearly demonstrates that increased SBP can equivalently account for the risk for arterial stiffening regardless of visceral adiposity; whereas, the impact of SBP on albuminuria is stronger in diabetic patients with high visceral adiposity than those with low visceral adiposity.

Association of blood pressure and visceral adiposity with organ damage

Visceral adiposity has been reported to be associated with incident hypertension [37, 38] and albuminuria [39, 40]. More recently, we found that high visceral fat with low subcutaneous fat accumulation is an important determinant of carotid atherosclerosis and high subcutaneous fat could be protective against atherosclerosis in patients with type 2 diabetes [41], and others reported that subcutaneous fat thickness assessed by ultrasound is inversely associated with carotid atherosclerosis in diabetic patients, particularly in men [42]. Moreover, visceral adiposity is strongly associated with the alteration of myocardial glucose uptake and its association further relates to type 2 diabetes [43]. These studies suggest that visceral and subcutaneous adiposities are directly associated not only cardio-metabolic risks but also target organ damage including heart and arterial wall injuries. We found in this study a stronger association of blood pressure with albuminuria in patients with high visceral adiposity than those with low visceral adiposity, suggesting that visceral adiposity could modify the association of blood pressure at least with albuminuria in patients with type 2 diabetes.

Potential mechanisms regarding the interaction between blood pressure and adiposity on albuminuria

By which mechanisms are involved in the greater impact of elevated blood pressure on albuminuria in patients with high visceral adiposity than in those with low visceral adiposity? Sympathetic activity and local (renal) renin-angiotensin-aldosterone system could account for the association. Obesity increases sympathetic activity in the kidneys and skeletal muscle; however, cardiac sympathetic activity may not be elevated [4446]. Furthermore, excessive weight gain, especially visceral adiposity increases leptin level, promotes renal compression, activates renal renin-angiotensin-aldosterone system [47], all of which could impair renal-pressure natriuresis, increase glomerular pressure, leading to progression of albuminuria. These observations could at least partly explain why elevated blood pressure is more strongly associated with albuminuria among patients with high visceral adiposity than among patients with low visceral adiposity.

Strengths and limitations

The strength of our study is that we directly measured VFA by a dual-impedance analyzer for the assessment of visceral adiposity. Previous studies assessed the interaction of adiposity with the association between hypertension and CVD using BMI or WC [7, 8, 48]. Thus, to the best our knowledge, this study is the first to investigate the interaction of visceral adiposity directly measured and blood pressure both with arterial stiffness and albuminuria. This study has a couple of limitations that should be mentioned. First, it has recently been reported that absolute loss of visceral fat mass may play a major role in resolution of diabetes following bariatric surgery, regardless of the amount of weight loss [49], suggesting the importance of prospectively evaluating the change in visceral adiposity to investigate the association between cardio-metabolic risks including blood pressure and organ damage such as arterial stiffening and albuminuria; however, it is impossible to infer causality because of its cross-sectional design. Second, population in this study was ethnically and socially homogeneous, because this study was hospital-based; therefore, generalization of our findings might be limited. Third, we were unable to obtain information on renin-angiotensin-aldosterone system and sympathetic activity. Fourth, we were unable to obtain any information on diet including vitamin A which may reduce visceral fat [50]. Finally, it is to be elucidated whether the association of blood pressure with arterial stiffness and albuminuria could be mediated by visceral adiposity in populations other than diabetic patients.

Conclusion

The effect of increased blood pressure on arterial stiffness is almost similar in type 2 diabetic patients with both low and high visceral adiposity, while its association with albuminuria is stronger in the latter.

Abbreviations

ALT: 

Alanine Aminotransferase

ARB: 

angiotensin receptor blocker

AST: 

Asparatate Aminotransferase

baPWV: 

brachial-ankle pulse wave velocity

CCB: 

calcium channel blocker

CI: 

confidence interval

CRP: 

C-reactive protein

CVD: 

cardiovascular disease

CV-RR: 

coefficient of variation of R–R intervals

eGFR: 

estimated glomerular filtration rate

HDL: 

high-density lipoprotein

LDL: 

low-density lipoprotein

PDR: 

proliferative diabetic retinopathy

SFA: 

subcutaneous fat area

UAE: 

urinary albumin excretion

VFA: 

visceral fat area

Declarations

Authors’ contributions

All authors have made substantial contributions to this study. RB designed the study, researched data, and wrote and edited the manuscript. RB, IM, TY, and YO contributed to intellectual discussion and reviewed and edited the manuscript. MN, YS, MA, TT, MM, YN, NO, HI and KH researched data. As the corresponding author and guarantor of this manuscript, RB is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors read and approved the final manuscript.

Acknowledgements

This study was supported by grants-in-aid from the Ministry of Health, Labor, and Welfare of Japan (Comprehensive Research on Lifestyle-Related Diseases Including Cardiovascular Diseases and Diabetes Mellitus).

Competing interests

The authors declare that they have no competing interests.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/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://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University
(2)
Center for Medical Welfare and Liaison Services, Tokyo Medical and Dental University
(3)
Department of Preemptive Medicine and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University
(4)
CREST, Japan Agency for Medical Research and Development

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