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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-1686
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 5 2823-2827
Copyright © 2005 by The Endocrine Society

Arterial Stiffness Is Related to Insulin Resistance in Nondiabetic Hypertensive Older Adults

David M. Sengstock, Peter V. Vaitkevicius and Mark A. Supiano

Department of Internal Medicine, Division of Geriatric Medicine, University of Michigan Health System and the Geriatric Research, Education and Clinical Center, Veterans Affairs Ann Arbor Health Care System, Ann Arbor, Michigan 48105

Address all correspondence and requests for reprints to: David Sengstock, M.D., M.S., Ann Arbor Department of Veterans Affairs Health System, Geriatric Research, Education, and Clinical Center (11G), 2215 Fuller Road, Ann Arbor, Michigan 48105. E-mail: dsmd{at}umich.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Hypertension, diabetes, obesity, and aging are associated with increased arterial stiffness. Both insulin resistance and hyperglycemia may contribute to the development of arterial stiffness. Older nondiabetic hypertensive adults were recruited to test the following hypotheses: (1) insulin resistance is associated with arterial stiffness, and (2) this relationship is independent of glucose tolerance status. Aortic pulse wave velocity (PWV), pulse pressure (PP), insulin sensitivity index (SI, measured by insulin-assisted frequently sampled iv glucose test), glucose tolerance status, and abdominal fat mass were assessed in 37 older (23 male, 14 female, mean age 69.4 ± 5.9 yr), nondiabetic, hypertensive adults after a 4-wk antihypertensive medication withdrawal. Both PWV and PP were negatively correlated with SI (r = –0.49, P = 0.002, and r = –0.38, P = 0.02, respectively). The mean PWV and PP in those with normal glucose tolerance were not significantly different from those with impaired glucose tolerance (9.8 ± 2.4 vs. 10.0 ± 3.1 m/sec, P = 0.79 and 71 ± 17 vs. 72 ± 18 mm Hg, P = 0.80, respectively). In multiple regression analysis, PWV and PP remained independently correlated with SI (P < 0.05) after adjusting for age, gender, fasting glucose, glucose tolerance status, body mass index, or abdominal fat mass. These results suggest that in hypertensive, nondiabetic, older adults, insulin resistance is associated with arterial stiffness independent of glucose tolerance status.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
HYPERTENSION, DIABETES, OBESITY, and aging are associated with a decrease in the compliance of the central arterial system. This decrease, termed arterial stiffness, results in increased cardiac workload (1, 2) and has been shown to be a predictor of overall survival (3, 4, 5). A number of factors are believed to be responsible for arterial stiffness. These include decreased elastin and increased collagen in the arterial wall, abnormal endothelial regulation of arterial smooth muscle tone, and the accumulation of advanced glycosylation endproducts (AGE) leading to protein cross-linking (6, 7, 8, 9). The accumulation of AGEs and protein cross-links is accelerated in diabetes and may contribute to arterial stiffness in these patients (10). However, in addition to the effects of the hyperglycemia seen in impaired glucose tolerance and diabetes, insulin and/or the insulin-resistant state may also contribute to the development of arterial stiffness. Insulin resistance is associated with endothelial dysfunction (11, 12), and hyperinsulinemia may contribute to the proliferation of arterial smooth muscle (13). These factors may lead to arterial stiffness before the development of impaired glucose tolerance or diabetes.

Some studies have suggested that there may be an association between insulin resistance and arterial stiffness. Variables of the metabolic syndrome or the insulin-resistant state have been shown to be associated with arterial stiffness in individuals without diabetes (14, 15). Euglycemic hyperinsulinemic clamp studies have shown a relationship between insulin resistance and arterial stiffness in both young healthy women and diabetic adults (16, 17, 18). None of these studies investigated the insulin resistance/arterial stiffness relationship in nondiabetic individuals who have significant insulin resistance, and none have controlled for measures of glucose tolerance. We therefore studied older nondiabetic hypertensive adults in whom the prevalence of insulin resistance and impaired glucose tolerance is high to test the hypotheses that insulin resistance is associated with arterial stiffness and that this relationship is independent of glucose tolerance status.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subject selection and study protocol

Community-dwelling volunteers were recruited from newspaper advertisements and the University of Michigan Claude D. Pepper Geriatrics Center Research Subject Participant Core. To determine eligibility, volunteers completed a screening visit at the University of Michigan General Clinical Research Center (GCRC) that included a medical history, physical examination, laboratory studies, and a standard 75-g 2-h oral glucose tolerance test (OGTT). Volunteers were excluded if they had a body mass index (BMI) less than 19 or more than 40 kg/m2 or had diabetes (fasting glucose ≥126 mg/dl or 2-h OGTT glucose level ≥200 mg/dl). Other exclusion criteria included chronic kidney disease (serum creatinine > 2.0 mg/dl), anemia, atrial fibrillation by electrocardiogram (EKG), history of cardiovascular disease or stroke, treatment with more than one antihypertensive medication, or use of a medication that would influence glucose or insulin metabolism. All volunteers signed an informed consent approved by the University of Michigan Institutional Review Board before enrollment.

Forty-two hypertensive men and women aged 60–80 yr were enrolled in the study. To avoid the confounding effects of antihypertensive therapy, subjects who were taking antihypertensive medication completed a 4-wk medication withdrawal. During this period, subjects monitored their blood pressure daily at home. If a subject’s blood pressure exceeded 180 mm Hg systolic or 110 mm Hg diastolic, the individual was excluded from further study and the previous medication was restarted (n = 3).

The GCRC dietitian staff prepared a weight-maintaining diet of 150 mEq sodium per day. Subjects were asked to consume this diet for 3 d before reporting for further study. Twenty-four-hour ambulatory blood pressure monitoring was performed on the first day of the diet. Compliance with the diet was confirmed by the 24-h urinary sodium excretion on the third day of the diet. On the fourth day, subjects reported after an overnight fast for the frequently sampled iv glucose test (FSIGT). They remained on the metabolic diet that night and returned fasting on the following day to complete arterial stiffness and body composition protocols.

OGTT

Subjects recorded their dietary intake for the 3 d before the screening visit to document the consumption of at least 150 g of carbohydrate daily. Fasting plasma glucose was measured at baseline and after administration of 75 g of glucose at 30, 60, 90, and 120 min. Subjects were categorized into normal glucose tolerance (NGT, 2-h glucose level < 140 mg/dl) and impaired glucose tolerance (IGT, 2-h glucose level 140–200 mg/dl) by the screening OGTT.

Ambulatory blood pressure

After completion of medication withdrawal, blood pressure was measured on an ambulatory basis by an automatic 24-h monitor (model 90207; Spacelabs, Issaquah, WA). Measurements were taken every 30 min during daytime hours (0800–2000 h) and every hour during the night (2000–0800 h). These measurements were averaged to produce the average systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure over a 24-h period.

Body composition

Dual energy x-ray absorptiometry was used to measure total and abdominal body fat mass. Subjects were scanned using a whole-body scanner (Lunar, Madison, WI; software version 4.5). After the scan, a quadrilateral box was manually drawn around the L1–L4 abdominal region. The software calculated the fat tissue mass within this region of interest. We have previously reported that dual energy x-ray absorptiometry measurements of fat mass bounded by the L1–L4 region have been shown to correlate closely with volumetric computerized axial tomography scan measurements of abdominal fat (19).

Arterial stiffness

Arterial stiffness was assessed by measuring pulse pressure and carotid-femoral pulse wave velocity (PWV) (20). Subjects were placed in a supine position and EKG leads were positioned to continuously record heart rhythm. SBP and diastolic blood pressure were measured with a manual sphygmomanometer. Pulse pressure (PP) was calculated by subtracting these measurements. Subsequently the location of the maximal impulse of the right common carotid and right common femoral arterial pulses were marked as was the midpoint of the manubrium. To approximate the length of the descending aorta, the distance from the midpoint of the manubrium to the maximal pulse of the right carotid artery was subtracted from the distance from the midpoint of the manubrium to the maximal pulse of the right femoral artery [laorta (mm)]. A handheld high-fidelity tonometer (SPC-301; Millar Instruments, Houston, TX) was placed over the maximal impulse of the carotid artery to achieve a pressure wave contour with a consistent baseline, contour, and amplitude. A 20-sec time span of these carotid pulse contours was recorded (version 7.0; AtCor, West Ryde, Australia). The average time [tc (msec)] between each R-wave on the EKG and the foot of the corresponding carotid pressure waveform was calculated. Similarly, the tonometer was placed over the maximal impulse of the right common femoral artery [tf (msec)] for calculation. PWV (meters per second) was then calculated by the equation: PWV = laorta/(tf – tc). A measurement was excluded if the pressure contour was of poor quality or if a significant difference (>15%) in heart rate was found between the carotid and femoral measurements. Four PWV measurements were recorded for each subject. A subject’s PWV was the average of the technically acceptable measurements.

Insulin sensitivity

The insulin sensitivity index (SI) was calculated from the frequently sampled intravenous glucose tolerance test (FSIGT) (21) with the addition of insulin to enhance precision (22). Using the study protocol outlined in previous studies (23), SI was calculated using the MINMOD program (24). Measurements in our laboratory have shown FSIGT to have an intraindividual coefficient of variation for SI of 14% (our unpublished data), which is consistent with previous studies (25).

Statistical analysis

All calculations were made using SAS (version 8.0; Cary, NC). FSIGT studies from two subjects could not be used due to technical difficulties with blood sampling, leaving results from 37 subjects for the final analysis. Area under the curve (AUC-OGTT) was calculated by adding the areas under the glucose-time curve for the intervals 0–30, 30–60, 60–90, and 90–120 min. Continuous variables are expressed as means and SDs. A Student’s t test was used to compare group means. Linear regression was performed to analyze the univariate associations between PWV and insulin sensitivity as well as with previously reported predictors of arterial stiffness. Multiple linear regression was used to control for potential confounders including blood glucose. An alpha of 0.05 was considered significant and all P values were two sided.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Subject characteristics

Thirty-seven older adults (mean age 69.4 yr) with a history of hypertension (23 men and 14 women) were studied. The duration of hypertension varied widely from newly diagnosed to a reported 30-yr history (mean 7.7 ± 8.1 yr). Prior antihypertensive treatment included diuretics (n = 15), ß-blockers (n = 11), angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ACE/angiotensin receptor blockers) (n = 8), {alpha}-blockers (n = 2), calcium channel blockers (n = 1), and untreated (n = 6) (due to newly diagnosed hypertension). The majority of the group was overweight (mean BMI 27.0 ± 3.5 kg/m2) and none were current smokers. Most had mildly impaired renal function (mean glomerular filtration rate 71 ± 14.5 ml/min per 1.73 m2) by four-variable Modification of Diet in Renal Disease Study equation (26, 27).

Sixteen subjects (12 men and four women) had impaired glucose tolerance. The baseline characteristics of the group categorized by glucose tolerance status are shown in Table 1Go. Compared with subjects with NGT, those with IGT were more insulin resistant (P = 0.02) and tended to have higher BMI (P < 0.06). Individuals with NGT did not significantly differ from those with IGT in mean PP (71 ± 17 vs. 72 ± 18 mm Hg, P = 0.80) or PWV (9.8 ± 2.4 vs. 10.0 ± 3.1 m/sec, P = 0.79; Fig. 1Go).


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  		TABLE 1. Baseline subject characteristics1

 


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  		FIG. 1. PWV by glucose tolerance status (NGT, IGT).

 
Univariate correlations

Table 2Go displays a summary of the PWV and PP univariate associations with their respective Pearson correlation coefficients. PWV was significantly correlated with PP, the average 24-h SBP, BMI, abdominal fat mass, fasting insulin, and SI (Fig. 2Go). No measure of glucose (fasting, 2-h OGTT glucose, AUC-OGTT) significantly correlated with PWV. A significant negative correlation was also identified between PP and SI. Similarly, no correlation was found between PP and fasting glucose or AUC-OGTT, but a significant correlation was found between PP and 2-h OGTT glucose measurements.


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  		TABLE 2. Univariate associations with pulse pressure and pulse wave velocity (PWV)

 


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  		FIG. 2. PWV compared with SI.

 
Multiple regression analysis

Multiple regression was performed to investigate whether heart rate, age, or previous antihypertensive therapy altered the SI-PWV or SI-PP relationships. After adjusting for resting heart rate and gender, SI remained independently associated with PWV (P < 0.01); an independent relationship also remained between SI and PP (P < 0.01). Similarly, after adjusting for age and gender, an independent relationship remained between SI and PWV (P < 0.01) as well as SI and PP (P < 0.02). Further adjustment for previous antihypertensive therapy (diuretics, ACE/angiotensin receptor blockers, or ß-blocker) did not alter the significance of the relationships between SI and PWV or SI and PP (P < 0.03 in all models).

Multiple regression was performed to investigate whether SI was independently associated with PP or PWV after adjusting for glucose tolerance status, fasting glucose, 2-h OGTT glucose, or AUC-OGTT. After adjustment for any glucose measurement, SI remained independently associated with PWV (P < 0.02). In a similar fashion, SI remained independently associated with PP (P < 0.05) after adjustment. No measure of glucose was significantly associated with PP or PWV in any of these models (P > 0.10). Age, SI, and glucose measurements were then entered into stepwise multiple regression models. After adjustment for gender, PWV remained independently associated with age (P < 0.01) and SI (P < 0.01); PP also remained independently associated with age (P = 0.08) and SI (P = 0.01). No measurement of glucose entered either of these models (P > 0.10).

PWV was associated with obesity measurements in the univariate correlations. Multiple regression analysis was therefore performed to investigate whether PWV was independently associated with SI after adjusting for BMI or abdominal fat mass. After adjustment for either obesity measurement, PWV remained independently associated with SI (P < 0.02). Neither measure of obesity was significant in either of these models (P > 0.20). Age, SI, and obesity measurements were then entered into stepwise multiple regression models. After adjustment for gender, PWV remained independently associated with age (P < 0.01) and SI (P < 0.01).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Epidemiological studies have shown that arterial stiffness is increased in individuals with type 2 diabetes (28, 29). Given that glucose intolerance and insulin resistance precede the development of overt diabetes, we were interested in determining whether these factors would be associated with arterial stiffness. The main finding of this study of older, hypertensive nondiabetic subjects is that insulin resistance is associated with arterial stiffness and that the association appears to be independent of glucose tolerance status and obesity. Previous studies have found an insulin resistance-arterial stiffness relationship in diabetic patients and in healthy young individuals (16, 17, 18). The present study, builds on these findings by focusing on a population of hypertensive, insulin-resistant, older adults who were carefully screened to exclude diabetes.

Hyperglycemia has been shown to lead to the formation of AGEs (30). It has, therefore, been suggested that individuals with IGT may have increased central arterial stiffness due to prolonged exposure to elevated glucose levels. Results from the present study did not identify an increase in central arterial stiffness among individuals with IGT. Furthermore, no association was found between arterial stiffness and other glucose measurements including fasting glucose, 2-h OGTT glucose level, and AUC-OGTT. Previous large-scale studies have also failed to identify a significant increase in central arterial stiffness measurements among those with IGT, compared with those with NGT (31). At the lower levels of hyperglycemia existing in nondiabetic individuals, the absence of a central arterial stiffness-IGT relationship suggests that mechanisms unrelated to glucose exposure may be more important in the development of central arterial stiffness than accumulation of AGEs.

Previous studies have shown that visceral fat in young healthy individuals (16) and older adults (28) is associated with increased central arterial stiffness (16). The present study confirms the association between body fat and arterial stiffness in this population. However, the present study found that insulin resistance appears to be more strongly associated with arterial stiffness than with measures of obesity, and the insulin resistance-arterial stiffness relationship was independent of the obesity measurements in the multiple regression models. These results suggest that the obesity-arterial stiffness relationship may be mediated in part through increasing insulin resistance.

The mechanism underlying the relationship between insulin resistance and arterial stiffness is unknown, and this cross-sectional study cannot identify the causative factor. Studies have shown that insulin-resistant states such as diabetes and obesity are associated with decreased endothelium-dependent vasodilation (12), and arterial compliance may be a partially nitric oxide-dependent process (32). In addition, insulin has been shown to induce vascular smooth muscle proliferation and migration in cell culture (13). Animal studies have also suggested that, after balloon injury, hyperinsulinemia induces an increase in neointimal hyperplasia that was not seen in rats with streptozotocin-induced diabetes without hyperinsulinemia (13). Further research is needed to clarify the roles of hyperinsulinemia and/or insulin resistance in the progression of arterial stiffness and whether endothelial dysfunction or vascular smooth muscle proliferation mediate the observed association.

Additional studies will be needed to assess the effect of an improvement in insulin sensitivity to decrease arterial stiffness. An exercise intervention has been shown to decrease arterial stiffness in a population of middle-aged sedentary men (33). The mechanism by which this occurred was unclear, but aerobic exercise often results in an increase in insulin sensitivity (23). It is possible that the exercise intervention led to a decrease in arterial stiffness through an improvement in insulin sensitivity. Recently, treatment with rosiglitazone, an insulin-sensitizing medication, has been shown to improve both hyperinsulinemia and arterial stiffness in a diabetic population (34). However, it is not known whether this effect was mediated solely by an improvement in insulin sensitivity, other medication-related effects (i.e. deceased glucose levels, antioxidant effects) played a role, or this treatment would lead to similar changes in nondiabetic insulin-resistant individuals.

It is important to note several limitations in this study design. First, this study enrolled a relatively homogenous population of older hypertensive individuals carefully screened to exclude diabetes. Further research will be needed to confirm whether these results generalize to middle-aged, more insulin-sensitive individuals and those without the cardiovascular effects of hypertension. Second, the subjects were studied after a 4-wk antihypertensive medication withdrawal to avoid the likely confounding effects of these medications. Although further adjustment for previous antihypertensive therapy did not influence the results, the effect of varying levels of compliance with these medications could not be assessed. Finally, the measurements of glucose exposure (fasting, 2-h OGTT, OGTT-AUC, and glucose tolerance status) may not capture glucose exposure over time. To that end, future studies addressing this association should be designed to incorporate measures that may better reflect glucose exposure over time.

In conclusion, insulin sensitivity is negatively correlated with arterial stiffness in hypertensive older adults who do not have diabetes. This relationship is independent of glucose tolerance status or obesity. Further research is needed to understand the mechanism that underlies this association and determine whether therapies that specifically improve insulin sensitivity result in a decrease in arterial stiffness.


   Acknowledgments
 
The authors acknowledge the important contributions of many individuals to this study: Cathie Bloem, R.N., M.P.H., for coordinating the study; Marla Smith and Jeffrey Briesmiester for technical support; and Kathy Jarvenpaa, R.N., and the GCRC nursing staff.


   Footnotes
 
This work was supported in part by a Hartford/American Federation of Aging Research Academic Geriatric Fellowship Award; University of Michigan Institute of Gerontology Multidisciplinary Research Training in Aging Grant T32 AG00114, University of Michigan Training Program in Clinical Research (1 K30 HL04108-02), the Department of Veterans Affairs Medical Research Service/Ann Arbor Geriatric Research Education and Clinical Center, the University of Michigan General Clinical Research Center Grants M01-RR00042 and K24 AG00924 (to M.A.S.).

First Published Online February 22, 2005

Abbreviations: ACE, Angiotensin-converting enzyme; AGE, advanced glycosylation endproduct; AUC, area under the curve; BMI, body mass index; EKG, electrocardiogram; FSIGT, frequently sampled intravenous glucose tolerance test; IGT, impaired glucose tolerance; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; PP, pulse pressure; PWV, pulse wave velocity; SBP, systolic blood pressure; SI, insulin sensitivity index.

Received August 23, 2004.

Accepted February 16, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Schizophr Bull, November 1, 2008; 34(6): 1024 - 1032.
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