Acta Diabetol DOI 10.1007/s00592-013-0548-9

ORIGINAL ARTICLE

Impaired baroreflex sensitivity in subjects with impaired glucose tolerance, but not isolated impaired fasting glucose Jin-Shang Wu • Feng-Hwa Lu • Yi-Ching Yang Shei-Hsi Chang • Ying-Hsiang Huang • Jia-Jin Jason Chen • Chih-Jen Chang



Received: 7 October 2013 / Accepted: 13 December 2013 Ó Springer-Verlag Italia 2014

Abstract Impaired baroreflex sensitivity (BRS) is associated with adverse cardiovascular outcomes. There are currently no studies on BRS changes in subjects with different glycemic statuses, including normal glucose tolerance (NGT), isolated impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and newly diagnosed diabetes (NDD). The aim of this study was to investigate the effects of NDD, IGT and isolated IFG on BRS, based on a community-based data. A total of 768 subjects were classified as NGT (n = 498), isolated IFG (n = 61), IGT (n = 126) and NDD (n = 83). Spontaneous BRS was determined by the spectral a coefficient method, i.e., the square root of the ratio between the power of the RR interval and the power of systolic blood pressure in the LF frequency region (0.04–0.15 Hz) after the subjects had rested in a supine position for 5 min. Valsalva ratio was calculated as the longest RR interval after release of the

Valsalva maneuver, divided by the shortest RR interval during the maneuver. As compared with NGT subjects, NDD (p = 0.039) and IGT (p = 0.041) subjects had a reduced spontaneous BRS in multivariate analysis based on analysis of covariance. NDD subjects exhibited a lower Valsalva ratio than NGT subjects (p = 0.043). However, there were no significant differences in spontaneous BRS and Valsalva ratio between subjects with isolated IFG and NGT. In conclusion, NDD and IGT subjects had an impaired BRS as compared to NGT subjects. However, reduced BRS was not apparent in subjects with isolated IFG. Keywords Diabetes mellitus  Impaired glucose tolerance  Impaired fasting glucose  Spontaneous baroreflex sensitivity  Valsalva ratio

Introduction Communicated by Massimo Federici. J.-S. Wu  F.-H. Lu  Y.-C. Yang  C.-J. Chang Department of Family Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC J.-S. Wu  F.-H. Lu  Y.-C. Yang  Y.-H. Huang  C.-J. Chang (&) Department of Family Medicine, National Cheng Kung University Hospital, 138, Sheng Li Road, Tainan 70403, Taiwan, ROC e-mail: [email protected] S.-H. Chang Department of Information and Communication, Kun Shan University, Tainan, Taiwan, ROC J.-J. J. Chen Institute of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan, ROC

The arterial baroreflex stabilizes systemic perfusion pressure, while impaired baroreflex sensitivity (BRS) is associated with adverse cardiovascular outcomes [1]. Recently, baroreflex activation therapy has been shown to be a promising treatment for patients with resistant hypertension [2]. The baroreflex pathway, consisting of afferent, central and efferent components, is associated with oscillations in blood pressure and heart rate. Any impairment in the reflex arc, such as the blunted afferent signal, central neuron activity and efferent cardiovascular response, may adversely affect homeostasis [3]. BRS can be assessed by traditional tests, such as the Valsalva maneuver, carotid sinus massage, neck chamber technique, electrical stimulation of carotid sinus nerves, and intravenous infusion of vasoactive agents, all of which

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require external stimuli. Some of these are invasive, time consuming and less specific with regard to BRS [4]. In contrast, spontaneous baroreflex analysis, a spectral analysis-derived estimate of BRS, is a technique based on computer analysis of spontaneous blood pressure and heart rate fluctuations, which does not rely on external stimuli and can be assessed in real life conditions [4]. The results of spontaneous baroreflex analysis have been shown to be significantly correlated with BRS estimated with more invasive measures [5, 6] and have satisfactory short-term reproducibility [7]. Abnormal BRS, as revealed by the Valsalva maneuver or spontaneous BRS analysis, has been identified in persons with diabetes [8, 9]. As for the relationship between pre-diabetes and BRS, the association of impaired glucose tolerance (IGT) with impaired BRS is still inconclusive [9– 11]. One study found that IGT subjects had lower Valsalva ratios than control subjects [11], but another two did not show any significant association between them [9, 10]. In addition, Watkins et al. [12] showed that subjects with a fasting plasma glucose (FPG) of 5.2–6.9 mmol/l did not exhibit any association between BRS and FPG. However, the subjects with impaired fasting glucose (IFG) of 5.2–6.9 mmol/l in this earlier work may have had IGT and even diabetes, because only using FPG to classify different glycemic statuses, without consideration of 2-h post-load glucose (2-h PG), may miss the detection of these conditions [13, 14]. There is paucity of studies which assess the spontaneous BRS in IGT and IFG subjects [9–12], and no work has been done to examine the BRS changes across different glycemic statuses, including normal glucose tolerance (NGT), isolated IFG, IGT, and diabetes. Therefore, the aim of this population-based study was to examine whether BRS is impaired in subjects with IGT and isolated IFG.

Methods The subjects were recruited for an epidemiological followup study of chronic diseases in Tainan City, Taiwan, from 2002 to 2003. A total of 1638 subjects received their initial examinations in 1996, the details of which have been described elsewhere [15]. From 2002 to 2003, 1,104 subjects (67.4 %) completed the follow-up assessment. The reason for non-attendees in the follow-up study were relocation (n = 23), death (n = 49), failed contact (n = 275) and reluctance to participate (n = 187). Subjects with the following conditions were excluded from further analysis: (1) diabetes history (n = 79), (2) thyroid disorders (n = 5), (3) taking medications known to influence cardiac autonomic function, such as antihypertensive (n = 125), antidepressant (n = 3), sedative (n = 17),

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antipsychotic (n = 2), and antiparkinsonism medications (n = 4) within 2 weeks of the follow-up examination, and (4) an incomplete test schedule, poor quality signals, thus insufficient for processing, and a difference in the RR intervals of more than 30 % (n = 151) compared with the preceding ones [16]. Consequently, total of 768 participants with mean age of 49.6 ± 14.3 years (range 26.4–89.5 years) were included for the final analysis. The Institutional Review Board of National Cheng Kung University Hospital, Taiwan, approved the study. Demographic characteristics, life styles, medical history and medication use were assessed. All the subjects received a physical examination, along with body weight and height measurements. Waist circumference (WC) measurements were performed at the end of normal expiration in duplicate on bare skin at the midway between the lower rib margin and the iliac crest. Hip circumference was measured similarly at the level of the bilateral greater trochanters [17]. Waist-to-hip ratio (WHR) was calculated from these two measurements [17]. Baseline blood pressure and heart rate were measured with an automated oscillometric DINAMAP TM vital signs monitor (Model 1846SX, Critikon Inc, Irvine, Calif, U.S.A.) after the subject had rested in a supine position for at least 15 min. Smoking habit was defined as packs-years and computed by multiplying the number of packs of cigarettes smoked per day by the number of years the person had smoked. Average alcohol consumption, measured in grams per week, was calculated by multiplying the frequency (times per week) by the amount of alcohol consumed (alcohol percentage multiplied by volume each time). Total physical activity, including work, walking and leisure time exercise, was measured in metabolic equivalent-hours per week for the past year [18]. After a 10-h overnight fast, all subjects underwent blood tests, including FPG, total cholesterol, triglyceride, highdensity lipoprotein-cholesterol and creatinine, as well as routine urine tests. The subjects without a history of diabetes were given a drink containing 75 g of glucose, and blood samples were obtained 2 h after this. NGT was defined as an FPG \ 5.6 mmol/l, a 2-h PG \ 7.8 mmol/l [1920]. Isolated IFG was identified as an FPG of 5.6–6.9 mmol/l and a 2-h PG \ 7.8 mmol/l. IGT was defined as a 2-h PG of 7.8–11.1 mmol/l and an FPG \7.0 mmol/l. Subjects with both IFG and IGT were classified as IGT. Newly diagnosed diabetes (NDD) was defined as when subjects registered an FPG C 7.0 mmol/l or a 2-h PG C 11.1 mmol/l [19]. Both the heart rate and blood pressure measurements were obtained noninvasively by using an automatic beatto-beat blood pressure monitor (Colin BP-508 Automatic BP Monitor, Colin Co, Aichi, Japan) in a quiet room. A Colin BP-508 Automatic BP Monitor is an applanation

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tonometer that was attached to the subject’s left wrist over the radial artery to monitor the blood pressure waveform. A sphygmomanometer with an oscillometric cuff measurement was attached to the right arm over the right brachial artery for the calibration of the tonometric blood pressure sensor. The validity and reliability of this noninvasive pressure-monitoring system have been demonstrated by good linear correlation with pulsatile intra-arterial pressure [20]. The heart rate and blood pressure signals were continuously recorded for at least 5 min after the subjects had been resting in a supine position for 15 min. Since the power spectra of heart rate and blood pressure variability might be affected by arrhythmia, ectopic beats and noise, data for certain subjects were excluded from the analysis for the following reasons: an incomplete test schedule, poor quality signals, thus insufficient for processing, and a difference in the RR intervals of more than 30 % compared to the preceding ones [16]. Based on the fast Fourier transformation, the power spectral densities of the RR intervals and systolic blood pressures were computed. The low frequency (LF, 0.04–0.15 Hz) and high frequency (HF, 0.15–0.4 Hz) components were identified for each subject [21]. Spontaneous BRS was determined by the spectral a coefficient method, i.e., the square root of the ratio between the power of the RR interval and the power of systolic blood pressure in the LF frequency region [4].   powerRR 1=2 BRS ¼ a coefficient ¼ powerSBP The Valsalva test was performed twice to evaluate baroreflex function following 15 s of constant expiratory pressure of 40 mmHg. The hemodynamic changes induced by the Valsalva maneuver were classified into four phases, as follows: phase 1: an onset of forced expiration with a subsequent increase in blood pressure and reflexly decreased heart rate; phase 2: continuation of the forcible exhalation with a fall in blood pressure compensated by reflex tachycardia; phase 3: a release of forced expiration with a further reduction in blood pressure and an increase in heart rate; phase 4: continuation of the release with a subsequent increase in blood pressure and reflexly decreased heart rate. The signal from the better of the two Valsalva tests was used to calculate the ratio between the longest RR interval after release of the Valsalva maneuver (phase 4) and the shortest RR interval during the maneuver (phase 2) [7].

Statistical analysis Data analyses were performed using the Statistical Package for the Social Sciences 17.0 software for Windows. In the univariate analysis, ANOVA or Kruskal–Wallis test, where

appropriate, was used to compare continuous variables among subjects with NGT, isolated IFG, IGT, and NDD. Bonferroni post hoc tests were also used to compare the results for the Valsalva ratio and a coefficient of spontaneous BRS among different glycemic groups. Comparisons of categorical variables were analyzed by the chi-square test or Fisher’s exact test, when the expected value in each cell was \5. In the multivariate analysis, analysis of covariance (ANCOVA) was used to compare the a coefficients of spontaneous BRS and Valsalva ratios among different glycemic groups, including NGT, isolated IFG, IGT and NDD, with adjustment for other confounders. Initially, age (year) and gender (male vs. female) were adjusted in basic model. Then, waist-hip ratio, systolic blood pressure (mmHg), total cholesterol/high-density lipoprotein-cholesterol ratio, smoking (packs-years), alcohol use (g/week) and physical activity (metabolic equivalent-hours per week) were further adjusted in full model. Throughout the analyses, results with p \ 0.05 were considered statistically significant.

Results The subjects were classified as NGT (n = 498), isolated IFG (n = 61), IGT (n = 126), and NDD (n = 83). Table 1 shows the comparisons of clinical variables among subjects with NGT, isolated IFG, IGT, and NDD. There were significant differences in age, body mass index, systolic and diastolic blood pressures, heart rate, pulse pressure, FPG, total cholesterol and triglyceride, 2-h PG, the prevalence of hypertension and smoking status among the four groups. Table 2 compares the results for the spontaneous BRS and Valsalva ratio among subjects with NGT, isolated IFG, IGT and NDD. There was a significant difference in spontaneous BRS and Valsalva ratio among these four groups. The results were then analyzed by the Bonferroni post hoc test. Both NDD and IGT subjects had a lower a coefficient of spontaneous BRS than NGT subjects. In addition, NDD subjects also had a lower a coefficient of spontaneous BRS than isolated IFG subjects. However, isolated IFG subjects did not have a significantly lower spontaneous BRS level than NGT subjects. As compared to NGT subjects, both NDD and IGT subjects had a lower Valsalva ratio, but isolated IFG subjects did not. When compared with isolated IFG subjects, NDD subjects, but not IGT subjects, exhibited a lower Valsalva ratio. There were no significant differences in Valsalva ratio between IGT and NDD subjects. For the multivariate analysis, Table 3 shows the comparisons of a coefficients of spontaneous BRS and Valsalva ratio among subjects with different glycemic status,

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Acta Diabetol Table 1 Comparison of clinical characteristics among subjects with NGT, isolated IFG, IGT, and NDD NGT (n = 498)

Isolated IFG (n = 61)

IGT (n = 126)

NDD (n = 83)

p value \0.001

Age (years)

45.8 ± 12.7

53.2 ± 15.4

55.9 ± 13.3

62.3 ± 12.4

Male (%)

42.0

49.2

49.2

53.0

Body mass index (kg/m2)

22.9 ± 3.1

24.5 ± 3.4

24.4 ± 2.7

25.3 ± 3.1

Waist-hip ratio

0.83 ± 0.08

0.86 ± 0.08

0.88 ± 0.08

0.149

0.93 ± 0.07

\0.001 \0.001 \0.001

Systolic blood pressure (mmHg)

111.9 ± 15.3

120.9 ± 18.5

125.5 ± 19.8

132.2 ± 22.1

Diastolic blood pressure (mmHg)

67.8 ± 9.1

72.7 ± 11.5

73.8 ± 10.0

76.2 ± 10.3

\0.001

19.7

17.5

28.9

\0.001

Hypertension history (%)

5.6

Heart rate (beat/min)

65.0 ± 9.1

64.8 ± 9.6

68.1 ± 11.3

67.7 ± 9.4

Pulse pressure (mmHg)

44.1 ± 10.3

48.2 ± 12.0

51.8 ± 13.4

56.0 ± 16.1

0.001 \0.001

Fasting plasma glucose (mmol/l)

4.8 ± 0.3

5.8 ± 0.3

5.4 ± 0.6

8.0 ± 3.3

\0.001

2-h post-load (mmol/l) Cholesterol (mmol/l)

5.5 ± 1.1 5.2 ± 1.1

6.1 ± 1.1 5.4 ± 1.2

9.0 ± 0.9 5.4 ± 1.1

9.7 ± 7.1 5.6 ± 1.3

\0.001 0.013

Triglyceride (mmol/l)

1.2 ± 1.0

1.2 ± 0.8

1.6 ± 0.9

1.9 ± 1.5

\0.001

HDL cholesterol (mmol/l)

1.5 ± 0.6

1.4 ± 0.3

1.4 ± 0.5

1.4 ± 1.1

0.193

Creatinine (mmol/l)

a

75.6 ± 20.6

81.2 ± 21.1

78.2 ± 20.3

87.4 ± 90.3

0.097

Alcohol use (g/week)a

34.5 ± 146.6

57.2 ± 174.1

40.6 ± 165.3

38.9 ± 131.7

0.071

Smoking (packs-years)a

4.8 ± 25.2

4.5 ± 11.4

6.0 ± 14.6

8.9 ± 20.0

0.033

72.3 ± 60.5

77.3 ± 64.6

78.3 ± 56.9

78.1 ± 56.1

0.154

Physical activity (m-h/week)a

HDL cholesterol high-density lipoprotein-cholesterol a

Kruskal–Wallis test

Table 2 Comparison of a coefficients of spontaneous BRS and Valsalva ratio among subjects with NGT, isolated IFG, IGT, and NDD

a coefficients of spontaneous BRS (m s/mmHg) Valsalva ratio

NGT (n = 498)

Isolated IFG (n = 61)

IGT (n = 126)

NDD (n = 83)

ANOVA p value

Test for trend p value

11.71 ± 6.09

11.50 ± 5.44

9.49 ± 5.27*

8.53 ± 5.03**

\0.001

\0.001

1.54 ± 0.24

1.50 ± 0.24

1.45 ± 0.23*

1.40 ± 0.21**

\0.001

\0.001

Bonferroni post hoc test: (1) compared with NGT: * p \ 0.01, ** p \ 0.001; (2) compared with isolated IFG:



p \ 0.05

Table 3 Comparisons of a coefficients of spontaneous BRS and Valsalva ratio among subjects with different glycemic status, including NGT, isolated IFG, IGT and NDD, based on ANCOVA Variables

a coefficients of spontaneous BRS

Valsalva ratio

Basic model

Full model

Basic model

Full model

p value adjusted mean ± SE

p value adjusted mean ± SE

p value adjusted mean ± SE

p value adjusted mean ± SE

NGT (Reference) Isolated IFG

11.461 ± 0.264 0.771

11.690 ± 0.733

11.343 ± 0.269 0.592

11.764 ± 0.733

1.523 ± 0.011 0.856

1.517 ± 0.029

1.521 ± 0.011 0.871

1.519 ± 0.029

IGT

0.007

9.872 ± 0.518

0.041

10.085 ± 0.526

0.128

1.487 ± 0.021

0.245

1.495 ± 0.021

NDD

0.004

9.328 ± 0.658

0.039

9.791 ± 0.676

0.010

1.447 ± 0.026

0.043

1.448 ± 0.025

Basic model (n = 768): adjustment for age (year) and gender (male vs. female). Full model (n = 765): adjustment for age (year), gender (male vs. female), waist-hip ratio, systolic blood pressure (mmHg), total cholesterol/high-density lipoprotein-cholesterol ratio, smoking (packs-years), alcohol use (g/week) and physical activity (metabolic equivalent-hours per week)

including NDD, IGT, IFG and NGT, based on analysis of covariance (ANCOVA). After adjustment for age and gender, NDD (p = 0.004) and IGT (p = 0.007) were inversely associated with a coefficient of spontaneous BRS

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in basic model. In full model, NDD (p = 0.039) and IGT (p = 0.041) were still negatively related to a coefficient of spontaneous BRS after further adjustment for waist-hip ratio, systolic blood pressure (mmHg), total cholesterol/

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high-density lipoprotein-cholesterol ratio, smoking (packsyears), alcohol use (g/week) and physical activity (metabolic equivalent-hours per week). However, isolated IFG was not the independently associated factor of a coefficient of spontaneous BRS in basic and full models. As for Valsalva ratio, NDD was its associated factor in basic (p = 0.010) and full (p = 0.043) models. In contrast, IGT and isolated IFG were not independently related to Valsalva ratio in both basic and full models.

Discussion The autonomic nervous system in cardiovascular control is affected in people with diabetic neuropathy [22] and abnormal BRS, as shown by the Valsalva maneuver or spontaneous BRS analysis, in individuals with diabetes [8, 9, 23]. Similar results were found in the current study, in which diabetes was associated with decreased BRS, even after adjustment for many important determinants of BRS. In addition, the results also showed that IGT subjects suffered a higher risk of having lower BRS. However, an insignificant relationship was found between IGT and BRS in the Hoorn Study [9], and differences in the selection of subjects may be one explanation for the inconsistency between our results and those of this earlier work. Specifically, our study excluded subjects with antihypertensive, antidepressant, anxiolytic, antipsychotic or antiparkinson medication within 2 weeks of the examination. In contrast, the Hoorn Study included subjects who were taking antihypertensive medication, which may improve BRS [24, 25], and this may have underestimated the effect of IGT in BRS. As for the relationship between isolated IFG and BRS, Watkins et al. [12] found that FPG is negatively related to BRS, with significant reductions observed in subjects with FPG of 5.2–6.9 mmol/l, but the association between FPG and BRS was no longer significant after adjustment for other variables. Similarly, our findings showed no significant relationship between isolated IFG and BRS, based on the results of the multivariate analysis. In addition, our study included subjects with different glycemic statuses, based on FPG and the 75-g oral glucose tolerance test, and provided epidemiological evidence that BRS was significantly lower in subjects with diabetes or IGT, but not in those with IFG. The exact mechanism underlying impaired BRS in subjects with diabetes and IGT is still not fully understood, although any impairment in the baroreflex arc may be responsible for this. The impact of metabolic changes due to hyperglycemia on neural circulation, causing reduced blood flow and hypoxia, could be important with regard to the insult to nerves and neurons that occurs in the development of neuropathy [26]. In addition, reduced BRS may

be related to arterial stiffening because of impaired baroreceptor afferent responses to decreased arterial wall stretching [27] in the hyperinsulinemic state. Some studies also show diabetes-related attenuation of the afferent limb of the baroreceptor reflex [28, 29]. Insulin resistance may be one possible explanation for impaired BRS in subjects with diabetes and IGT, because insulin resistance has shown to be associated with sympathetic activity [30] which was one of the main determinants of BRS [31]. In addition, brain insulin may be one another mechanism based on the finding that increased insulin in the brain, via lateral ventricular infusion, enhancing arterial baroreflex control of lumbar sympathetic nerve activity in rats [32]. There have been few studies on the relationship between IFG and BRS. In Watkins et al., FPG was not independently related to reduced BRS in subjects with FPG of 5.2–6.9 mmol/l [12]. In our study, BRS was not significantly reduced in subjects with isolated IFG after adjustments for other cardiometabolic variables. As compared to IGT subjects with normal to slightly reduced hepatic insulin sensitivity and moderate to severe muscle insulin resistance, IFG subjects predominantly have hepatic insulin resistance and normal muscle insulin sensitivity [33]. Whether the difference in the severity and site of insulin resistance between IGT and isolated IFG may explain the decreased BRS in IGT subjects, but not subjects with isolated IFG, requires further investigation. With regard to cardiovascular mortality, BRS is a surrogate marker of adverse cardiovascular outcomes [1]. IGT subjects have been shown to exhibit greater cardiovascular mortality, and the predictive properties of IGT with regard to cardiovascular risk are not fully explained by the development of overt diabetes during follow-up [34]. In contrast, IFG subjects seem to have a higher risk of cardiovascular mortality, although this is explained by the shift from IFG to diabetes [35]. This was another point consistent with our finding that isolated IFG does not seem to have a detrimental effect on BRS. Our study showed spontaneous BRS, but not Valsalva ratio, was reduced in IGT subjects. This may be related to Valsalva ratio which is less specific for the measurement of BRS because Valsalva maneuver may trigger chemoreceptor and cardiopulmonary receptor activity. The specificity may be further reduced by the stimulation of skeletal muscle receptors due to the increase in respiratory muscle tone, especially when subjects cannot cooperate under Valsalva test. In contrast, spontaneous BRS, significantly correlated with phenylephrine baroreflex [5, 6], was measured at rest and does not rely on external stimuli [4]. This may make the difference in Valsalva ratio insignificant between NGT and IGT subjects. One limitation in this study was insulin level and insulin resistance were not available. Although the difference in the severity and site

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of insulin resistance may be perceived as one explanation for decreased BRS in subjects with IGT, not isolated IFG, it requires further studies. In addition, the possible effect of atherosclerotic damage, such as peripheral artery disease and coronary artery disease, was not shown, because none of the subjects had history of peripheral artery disease and coronary artery disease based on exclusion criteria. Finally, the classification of antidepressant was not addressed in our study. Although cardiac autonomic function may be worsened by tricyclic antidepressants, specific serotonin reuptake inhibitors may have little impact on it [36], because tricyclic antidepressants are the most used agents (61.6 %) for all new antidepressant users in Taiwan from 2000 to 2009. During 2000–2003, the incident depressant use of tricyclic antidepressants was around 12–16 per 1,000 population, as compared to SSRI of 2–4 per 1,000 population [37]. It is possible that tricyclic antidepressants may be the most used antidepressant in this study, and thus, we excluded subjects with antidepressant for the final analysis. In either excluding or including subjects with antidepressants (data not shown) in multivariate analysis, our finding that NDD and IGT, not isolated IFG, being independently associated with BRS was not influenced. Thus, excluding participants taking antidepressants would not likely have a direct influence on the generalizability since most of the participants excluded for antidepressant use were already excluded due to comorbid medical disease/other medication use. In conclusion, the NDD and IGT subjects examined in this work had impaired BRS independent of arterial stiffness, cardiac autonomic function and other cardiovascular risk factors. However, the risk of reduced BRS was not significant in subjects with isolated IFG. Acknowledgments This study was supported by grants from National Cheng Kung University Hospital (NCKUH 910072) and the National Science Council, Taiwan, R.O.C. (NSC 92-2314-B-006117). Conflict of interest

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Human and Animal Rights All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent The Institutional Review Board of National Cheng Kung University Hospital approved the study and waived the need for informed consent (IRB approval number B-ER-102-060).

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Impaired baroreflex sensitivity in subjects with impaired glucose tolerance, but not isolated impaired fasting glucose.

Impaired baroreflex sensitivity (BRS) is associated with adverse cardiovascular outcomes. There are currently no studies on BRS changes in subjects wi...
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