CLINICAL STUDY: VASCULAR EFFECTS OF DIABETES IN CHILDREN
Vascular function and carotid intimal-medial thickness in children with insulin-dependent diabetes mellitus
Tajinder P. Singh, MD, FACC*,*,
Harvey Groehn, BA, RVT and
Andris Kazmers, MD
* Division of Cardiology, Department of Pediatrics, Wayne State University, Detroit, Michigan, USA
Department of Vascular Surgery, Wayne State University, Detroit, Michigan, USA
Manuscript received July 3, 2002;
revised manuscript received September 30, 2002,
accepted November 1, 2002.
* Reprint requests and correspondence: Dr. Tajinder P. Singh, Division of Cardiology, Children’s Hospital of Michigan, 3901 Beaubien Boulevard, Detroit, Michigan 48201, USA.
tsingh{at}dmc.org
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Abstract
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OBJECTIVES: The objective of this study was to evaluate endothelium-dependent vasodilation and carotid intimal-medial thickness (IMT) in children with insulin-dependent diabetes mellitus.
BACKGROUND: Diabetes mellitus is an established risk factor for atherosclerosis. Vascular complications of diabetes are not clinically evident in diabetic children. However, preclinical atherosclerosis is more common in young subjects exposed to cardiovascular risk factors. Endothelial function and carotid IMT, known to be abnormal in preclinical atherosclerosis, have not been studied concurrently in a pediatric population exposed to a risk factor for atherosclerosis.
METHODS: We studied 31 diabetic teenagers (age 15.0 ± 2.4 years; duration of diabetes 6.8 ± 3.9 years) and 35 age-matched healthy children (age 15.7 ± 2.7 years). Using high-resolution vascular ultrasound, we compared carotid IMT and brachial artery responses to reactive hyperemia (endothelium-dependent vasodilation) and to sublingual nitroglycerin (endothelium-independent vasodilation).
RESULTS: There was no difference in baseline brachial artery diameter between the two groups. Endothelium-dependent vasodilation was significantly lower in diabetic children compared with healthy children (4.2 ± 3.8% vs. 8.2 ± 4.2%, p < 0.001). There was no difference in endothelium-independent vasodilation (17 ± 6% vs. 18 ± 6%, p = NS) or mean carotid IMT between the groups (0.33 ± 0.05 vs. 0.32 ± 0.08 mm, p = NS). Endothelium-dependent brachial vasodilation correlated with blood glucose levels (r = 0.58, p = 0.001) and was weakly and inversely related to the duration of diabetes (r = –0.4, p = 0.02), total cholesterol, and low-density lipoprotein cholesterol levels.
CONCLUSIONS: Endothelial function is impaired in children with diabetes mellitus within the first decade of its onset and precedes an increase in carotid IMT. The relative timing of these events is important in the evaluation of strategies to prevent progression of atherosclerosis and other vascular complications in this patient population.
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Abbreviations and Acronyms
| | DM | | diabetes mellitus | | ECG | | electrocardiogram | | FMD | | flow-mediated dilation | | HbA1c | | glycosylated hemoglobin | | IMT | | intimal-medial thickness | | LDL | | low-density lipoprotein | | vWF | | von Willebrand factor |
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There is increasing evidence that endothelial dysfunction and increased carotid intimal-medial thickness (IMT) are precursors of clinically detectable atherosclerosis (1–5). Diabetes mellitus (DM) is a well-established risk factor for early development of accelerated atherosclerosis and microangiopathy (6). These vascular complications of diabetes are not clinically evident in diabetic children. However, subclinical vascular involvement in the form of impaired endothelial function and increased carotid IMT has been demonstrated in young subjects with DM (7–9). These precursors of atherosclerosis have not been studied concurrently in children exposed to risk factors for atherosclerosis. The objective of this study was to evaluate endothelium-dependent vasodilation and carotid IMT in teenaged children with insulin-dependent DM. We hypothesized that the abnormalities of vascular reactivity become manifest before the anatomic changes of increased IMT in young diabetics.
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Methods
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Study population.
The study was approved by the Human Investigation Committee of Wayne State University, and all participants or their parents signed an informed consent. The study population consisted of 31 teenagers with insulin-dependent DM, all of whom were diabetic for at least one year. There were 18 boys and 13 girls (mean age 15.0 ± 2.4 years [range 10 to 18]). The duration of their diabetes was 6.8 ± 3.9 years (range 1 to 13). The subjects were taking no medications other than insulin. Thirty-five healthy teenagers (age 15.7 ± 2.7 years [range 10 to 18]; 17 males and 18 females) volunteered to be healthy control subjects for the study. We excluded subjects with hypertension, vascular complications of diabetes, microalbuminuria, obesity (body mass index >25 kg/m2), a history of smoking or significant passive exposure to smoking, and those taking angiotensin-converting enzyme inhibitors.
Study design
The study was performed in the morning after the usual morning dose of insulin for diabetic subjects and a light, low-fat breakfast for which subjects received specific instructions. The subjects were instructed to abstain from caffeine for 24 h before the study. After arrival, the subjects rested in a quiet, temperature-controlled room for 15 min in the supine position and then underwent vascular ultrasound imaging of the brachial and carotid arteries, as described. After completion of imaging, a blood sample was obtained by venipuncture, and blood levels of glycosylated hemoglobin (HbA1c), lipid profile, total plasma homocysteine, blood glucose, creatinine, and von Willebrand factor (vWF) antigen, a marker of endothelial activity, were measured.
Imaging protocol
A single experienced vascular sonographer, who had no knowledge of the clinical or laboratory profile of the study subjects, performed all imaging studies. The images were obtained using a standard 10/5-MHz linear array transducer and an ATL HDI 3000 system (Phillips, Bothell, Washington) with the subject in the supine position. A continuous three-lead electrocardiogram (ECG) was recorded for timing diastole. A sphygmomanometer cuff was placed on the proximal right forearm. The right brachial artery images were obtained above the antecubital fossa using B-mode imaging in the longitudinal plane of the artery (10). A baseline image was acquired using a resolution box function to magnify this part of the artery. Blood flow was estimated by time-averaging the pulsed Doppler velocity signal obtained from a mid-artery sample volume. The cuff was inflated to 100 mm Hg above the systolic pressure to occlude arterial flow for 5 min. The cuff was then released, and the longitudinal image of the brachial artery was recorded continuously from just before to 1 min after cuff deflation. A mid-artery pulse Doppler signal was obtained immediately after cuff release to assess hyperemic velocity. Endothelium-dependent, flow-mediated dilation (FMD) was assessed by measurement of the brachial artery diameter 60 s after release of the cuff. The subject then rested for 15 min, after which a second baseline image of the brachial artery was obtained. A sublingual dose of nitroglycerin spray (400 µg) was then administered, and the brachial artery response (endothelium-independent vasodilation) was assessed by imaging the artery continuously for 3 min after the nitroglycerin dose.
The right and left common carotid arteries were then imaged in the neck. A longitudinal section of the common carotid artery 1 cm proximal to the carotid bulb was imaged, and a resolution box function was used to magnify this part of the artery. Five IMT measurements of the far wall of the artery at 3-mm intervals were obtained starting at 1 cm proximal to the bulb and moving proximally (2). The reported IMT for each subject is the average of these 10 measurements (5 measurements from the right and 5 from the left common carotid artery).
Measurements of the brachial artery lumen diameter were performed off-line at end-diastole, as identified by the onset of the R-wave on the ECG. For each state (baseline, endothelium-dependent dilation, and endothelium-independent dilation), at least three brachial artery diameter measurements were obtained (and averaged) from the longitudinal image by identifying the lumen-intimal boundary with electronic calipers (10).
Data analysis
We compared the diabetic patients and control subjects for risk factors, brachial artery vascular reactivity (endothelium-dependent and -independent vasodilation) and carotid IMT. Endothelium-dependent vasodilation was estimated as the absolute and percent increase in brachial artery diameter from baseline, 60 s after release of the cuff. Endothelium-independent vasodilation was estimated as the percent increase in brachial artery diameter 3 min after the nitroglycerin dose. We related brachial vascular reactivity to the subjects’ glucose level, risk factors (lipid profile, homocysteine), HbA1c, and, in diabetic subjects, duration of diabetes. A bi-variate correlation matrix was created to examine the strength of the relationship between the variables. We then performed multiple stepwise linear regression analysis using SPSS statistical software to identify the variables that best predicted the relationship. All measures are expressed as the mean value ± SD. The diabetic and control groups were compared using the unpaired Student t test. A p value <0.05 was used to define statistical significance.
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Results
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Table 1 demonstrates a comparison of the metabolic profile between diabetic and control children. There was no difference in the lipid levels (total, low-density lipoprotein [LDL], and high-density lipoprotein cholesterol and triglycerides) between the two groups. As expected, however, plasma glucose and HbA1c values were higher in diabetics. Total plasma homocysteine levels were lower in diabetics than in control subjects, the mean values being within normal range for both groups. There was no difference in vWF antigen levels between the two groups.
The brachial artery diameter at baseline was similar in diabetics and control subjects (3.13 ± 0.44 vs. 3.20 ± 0.60 mm, p = NS). The degree of reactive hyperemia was similar in the two groups. The brachial artery diameter increased in response to reactive hyperemia (FMD) in both groups. However, the increase in diameter was significantly lower in diabetics than in control subjects (0.13 ± 0.11 vs. 0.25 ± 0.12 mm, p < 0.001) (Fig. 1). As a result, the percent increase in diameter from baseline was lower in diabetics than in control subjects (4.2 ± 3.8% vs. 8.2 ± 4.2%, p < 0.001) (Fig. 2). In contrast to endothelium-dependent FMD, endothelium-independent vasodilation, determined as the increase in brachial artery diameter with nitroglycerin, was similar in diabetics and control subjects (16.7 ± 5.6% vs. 18.2 ± 5.5%, p = NS). There was no difference in carotid IMT between the two groups (0.33 ± 0.05 vs. 0.32 ± 0.08 mm, p = NS).
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Figure 1 Absolute (left) and percent (right) change in brachial artery diameter from baseline during flow-mediated dilation. The horizontal lines represent the group mean values.
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Figure 2 Relationship of flow-mediated dilation with duration of diabetes (left; r = –0.4) and blood glucose level (right; r = 0.58) in diabetic patients.
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When analyzed for all subjects (diabetics and control subjects) as a single population, FMD (percent change in brachial artery diameter) was weakly related to homocysteine (r = 0.26, p = 0.04) and HbA1c levels (r = –0.3, p = 0.02). There was no relationship between FMD and blood glucose levels or the lipid profile. When analyzed only for diabetic subjects, FMD correlated best with blood glucose levels (r = 0.58, p = 0.001). Flow-mediated dilation was also inversely related to the duration of diabetes (r = –0.39, p = 0.02), total cholesterol (r = –0.36, p = 0.05), and LDL cholesterol levels (r = –0.37, p = 0.05) on univariate analysis, but was unrelated to homocysteine or HbA1c levels. On multiple stepwise regression analysis, the blood glucose level was the single best predictor of FMD (r2 = 0.31, p = 0.002); LDL cholesterol levels added another 12% to the explained variance. Importantly, FMD remained significantly lower in diabetics, even after adjustment for glucose levels as a co-variate.
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Discussion
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The results of this study demonstrate that children with insulin-dependent DM develop endothelial dysfunction within the first decade after the onset of diabetes. Importantly, these changes are manifest before an increase in carotid IMT can be identified. These findings are important because they describe, for the first time, the relative timing of these two precursors of atherosclerosis in this cohort of children. This timing should be taken into account for designing studies that address the effect of therapeutic interventions on these preclinical events.
Endothelium-dependent vasodilation during reactive hyperemia is predominantly modulated by local release of nitric oxide (11). Impaired local availability of nitric oxide and endothelium-dependent vasodilation may result from either short- or long-term exposure to several factors. A transient abnormality in endothelial function lasting a few hours may occur shortly after a high-fat meal, under mental stress, and within hours of induced hyperglycemia (12–14). Persistent or recurrent exposure to risk factors of atherosclerosis such as active or passive smoking, hypercholesterolemia, and diabetes results in abnormal vascular endothelial function, even without additional exposure to the aforementioned acute factors (2,15). The increase in IMT in response to these factors is likely to occur only after long-term exposure and is the likely explanation for the findings in our study. A similar relationship between the timing of endothelial dysfunction and the increase in IMT may occur in the presence of other risk factors, as well. It may be speculated that exposure to a risk factor initially leads to episodic and transient endothelial dysfunction. The length and severity of these episodes are related to the intensity of exposure to the risk factor. With recurrent or persistent exposure, there is a state of persistent endothelial dysfunction and altered vascular wall milieu that promotes structural changes of atherosclerosis.
Some arteries, such as the coronary arteries, and the abdominal aorta may be at particularly high risk of developing such changes; autopsy studies in the young have detected fatty streaks and fibrous plaques in these arteries that appear to relate to antemortem risk-factor exposure (16). A recent study in children in Finland demonstrated that an increase in IMT of the abdominal aorta may occur before these changes appear in the carotid artery (17). We did not examine the aortic wall in our study. However, our results are in contrast to this study, which found a significant, albeit small, increase in carotid IMT in Finnish diabetic children compared with control subjects. A closer comparison of the results between these two studies reveals an interesting observation—the carotid IMT in a teenaged Finnish control population was 30% higher than that in the U.S. teenaged control population. These differences in results in the two populations may represent the potential influence of additional genetic and environmental cardiovascular risk factors on atherosclerosis burden and thereby carotid IMT.
The measurements of IMT are accurate and reproducible (3,17). We minimized the variability in measurements by reporting for each subject a single value of IMT that was an average of 10 measurements (5 on each side) along a segment of the common carotid artery. The sample size in each group was adequate to detect (77% power) a 10% increase in IMT in diabetics (p = 0.02); a smaller difference was not considered to have substantive significance.
Several studies have demonstrated that a better control of diabetes in young subjects results in a lower incidence of long-term vascular complications (18). The mechanism of endothelial dysfunction in insulin-dependent DM is modulated by a decreased local nitric oxide availability, presumably due to superoxide-mediated nitric oxide destruction (19). Several short-term interventions have been studied in diabetics for their potential beneficial effect on endothelial dysfunction (20–24). Children and young adults would be ideal subjects for studying the effect of long-term interventions in preventing the onset or progression of atherosclerosis. Identification of such a benefit in the young will require a clear understanding of the relative timing of various identifiable preclinical precursors of atherosclerosis.
Conclusions.
Functional changes of endothelial dysfunction appear in children with insulin-dependent DM within the first decade of its onset and precede an increase in carotid IMT. These findings should be considered when designing intervention studies to prevent atherosclerosis and other vascular complications in these patients.
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Footnotes
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This study was supported by a grant from Children’s Research Center of Michigan.
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Abstract
Methods