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Carotid intima-media thickness (IMT) provides a mechanism for detecting early atherosclerosis. Little information is available concerning changes in carotid IMT in youth with type 2 diabetes mellitus. HbA1c and duration of diabetes in the presence of traditional cardiovascular risk factors (male sex, LDL cholesterol, and blood pressure) were independent determinants.
Carotid intima-media thickness (IMT) provides a mechanism for detecting early atherosclerosis. Little information is available concerning changes in carotid IMT in youth with type 2 diabetes mellitus. HbA1c and duration of diabetes in the presence of traditional cardiovascular risk factors (male sex, LDL cholesterol, and blood pressure) were independent determinants.
Carotid intima-media thickness (IMT) provides a mechanism for detecting early atherosclerosis. Little information is available concerning changes in carotid IMT in youth with type 2 diabetes mellitus. HbA1c and duration of diabetes in the presence of traditional cardiovascular risk factors (male sex, LDL cholesterol, and blood pressure) were independent determinants.
Influence of Duration of Diabetes, Glycemic Control,
and Traditional Cardiovascular Risk Factors on Early
Atherosclerotic Vascular Changes in Adolescents and Young Adults with Type 2 Diabetes Mellitus Amy S. Shah, Lawrence M. Dolan, Thomas R. Kimball, Zhiqian Gao, Philip R. Khoury, Stephen R. Daniels, and Elaine M. Urbina Cincinnati Childrens Hospital Medical Center, Divisions of Endocrinology (A.S.S., L.M.D.) and Cardiology (T.R.K., Z.G., P.R.K., E.M.U.), Cincinnati, Ohio 45229; and University of Colorado Denver School of Medicine (S.R.D.), Division of Cardiology, Denver, Colorado 80262 Background: Carotid intima-media thickness (IMT) provides a mechanism for detecting early ath- erosclerosis. Little information is available concerning carotid IMT and the progression of athero- sclerosis in adolescents and young adults with type 2 diabetes mellitus. Objective: We sought to determine the factors that contribute to early changes in carotid IMT in youth with type 2 diabetes mellitus and to identify any predictors of increased carotid IMT. Methods: Demographic, anthropometric, laboratory data and carotid imaging were obtained in 129youthof mixedethnicity, ages 1023yr. Associations of carotidIMToutcomes andriskvariables were analyzed by regression analysis. Logistic regression was performed to elucidate independent determinants that predict a worse carotid IMT. Results: Carotid IMT increased with higher glycosylated hemoglobin (HbA1c) levels and longer duration of diabetes. Regression modeling showed that HbA1c and duration of diabetes in the presence of traditional cardiovascular risk factors (male sex, LDL cholesterol, and blood pressure) were independent determinants of carotid IMT. Logistic regression analysis demonstrated that each1%increaseinHbA1c or eachyear increaseindurationof type2diabetes mellitus is associated with approximately 30% increased odds of a thicker carotid IMT. Conclusions: Poorer glycemic control and longer disease duration have independent adverse ef- fects oncarotidIMTinyouthwithtype2diabetes mellitus. Theseadverseeffects appear tobemore prominent inmales. Developingeffectivestrategies toimprovebloodglucosecontrol inyouthwith type 2 diabetes mellitus is essential to prevent or limit the development and progression of ath- erosclerotic cardiovascular disease. (J Clin Endocrinol Metab 94: 37403745, 2009) C ardiovascular disease is a major cause of morbidity and mortality in adults with type 2 diabetes mellitus. Recent reports document that almost 70% of adults with type 2 diabetes mellitus will die from cardiovascular dis- ease (1). Although adolescents and young adults have ex- perienced a marked increase in the frequency of type 2 diabetes mellitus in the past two decades, little is known about the early development of cardiovascular disease and the atherosclerotic processes that occur in these youth. Most of the information regarding the development and progression of atherosclerosis in adolescents and youngadults is derivedfromautopsystudies performedon individuals who have died traumatic deaths (2). However, the development of noninvasive imaging techniques such ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright 2009 by The Endocrine Society doi: 10.1210/jc.2008-2039 Received September 17, 2008. Accepted July 17, 2009. First Published Online September 1, 2009 Abbreviations: BMI, Body mass index; BP, blood pressure; CI, confidence interval; CRP, C-reactive protein; HbA1c, glycosylated hemoglobin; HDL, high-density lipoprotein; IMT, intima-media thickness; LDL, low-density lipoprotein. O R I G I N A L A R T I C L E E n d o c r i n e C a r e 3740 jcem.endojournals.org J Clin Endocrinol Metab. October 2009, 94(10):37403745 as carotid intima-media thickness (IMT) provides a mech- anism for studying the evolution of atherosclerosis. In adults, investigators have used carotid IMT to document the extent and progression of atherosclerosis (3). Studies have shown that increased carotid IMT is associated with known cardiovascular risk factors and is efficacious in predicting future coronary artery disease andstroke (4, 5). CarotidIMThas alsobeenusedtostudy atherosclerosis in adults with type 2 diabetes mellitus. These studies have shown that type 2 diabetes mellitus is associated with an increase in carotid IMT and a 40% higher risk of myo- cardial infarction and stroke (5). Despite these findings, little information is available concerning carotid IMTand the progression of atherosclerosis in adolescents with type 2 diabetes mellitus. To address this issue, we sought to determine the fac- tors that contribute to early changes in carotid IMT in youth with type 2 diabetes mellitus and to identify any predictors of increased carotid IMT. Subjects and Methods Study population A total of 129 adolescents and young adults (age range, 1023yr) withtype 2diabetes mellitus participatedinthis study. The diagnosis of type 2 diabetes was based on the American Diabetes Association criteria (6). Specifically, the participants had elevated fasting plasma glucose levels of at least 126 mg/dl, or symptoms of hyperglycemia and randomplasma glucose of at least 200 mg/dl, or 2-h plasma glucose of at least 200 mg/dl during an oral glucose tolerance test. All individuals also had no evidence of another specific type of diabetes and were non-in- sulin requiring in the basal state to prevent diabetic ketoacidosis. Atotal of 124subjects were islet cell antibody-negative (glutamic acid decarboxylase, islet cell antigen 512, insulin autoantibod- ies). Five individuals did not have islet cell antibody data avail- able. Pregnant females were excluded from the study. A majority of the study population was recruited from indi- viduals with type 2 diabetes followed at the Diabetes Center at Cincinnati Childrens Hospital (n 124). Of 329 eligible sub- jects in the Diabetes Center, we approached 140 subjects, be- ginning with the oldest eligible subjects. Atotal of 124 consented toparticipate. Those whoparticipatedwere similar tothe eligible population in mean age (19 vs. 20 yr), gender (62% female vs. 64% female), and mean body mass index (BMI) (36.7 vs. 36.4 kg/m 2 ). The eligible population had a slightly higher percentage of nonwhites than the participants (63 vs. 50%, respectively). Thus, for most demographic categories, the eligible and partic- ipant populations were similar. The five remaining subjects were recruited fromlocal medical practices. These individuals did not have islet cell antibody data available. Before enrollment in the study, written informed consent was obtained fromsubjects who were at least 18 yr old or the parent or guardian for subjects younger than 18 yr old, and written assent was obtained for subjects less than 18 yr old according to the guidelines established by the Institutional Review Board at Cincinnati Childrens Hospital and in accordance with the Dec- laration of Helsinki. Data collection After aminimum10-hovernight fast, participants came tothe Clinical ResearchCenter at Cincinnati Childrens Hospital Med- ical Center for an in-person study visit, during which demo- graphic and anthropometric data were collected, fasting veni- puncture and blood pressure (BP) were performed, and carotid IMTwas measured. Two measures of height were obtained with a calibrated stadiometer (Veeder-Rood, Elizabethtown, NC) by trainedpersonnel. Weight was alsomeasuredtwice andaveraged with a Health-O-Meter electronic scale (model 770; SECA, Hanover, MD). BMI was calculated as kilograms per meter squared. BP was obtained manually with a mercury Sphygmo- manometer (W. A. BaumCo., Inc., Copiague, NY) according to the standards of the Fourth Report on Blood Pressure Control in Children (7). Duration of disease was measured fromthe date of diagnosis to the date of study. Laboratory Plasma glucose was measured using a Hitachi model 704 glu- cose analyzer with intraassay and interassay coefficients of vari- ation of 1.2 and 1.6%, respectively (8). Plasma insulin was mea- sured by RIA using an antiinsulin serum raised in guinea pegs, 125 I labeledinsulin(Linco, St. Louis, MO) anda double antibody method to separate bound from free tracer. This assay has a sensitivity of 2 pmol and has intra- and interassay coefficients of variation of 5 and 8%, respectively (8). Assays of fasting plasma lipid profiles were carried out in a laboratory that is National Heart, Lung, and Blood Institute/Centers for Disease Control and Prevention standardized with the low-density lipoprotein (LDL) cholesterol concentration calculated using the Friedewald equation. IL-6, TNF-, and C-reactive protein (CRP) were mea- sured using a high sensitivity ELISA. Glycosylated hemoglobin (HbA1c) was measured in red blood cells using HPLCmethods. Carotid IMT Carotid ultrasound studies were performed by a single reg- isteredvascular technologist. The carotidarteries were evaluated with high-resolution B-mode ultrasonography using a GE Vivid 7 ultrasound imaging system(GEMedical Systems, Wauwatosa, WI) with a high-resolution linear array vascular ultrasound cen- tered at 7.5 MHz. For each subject, each carotid wall and seg- ment was examined independently from continuous angles to identify the thickest carotid IMT. Three segments were imaged with left and right sides averaged for the common artery, bulb (bifurcation), and the internal carotid artery. Multiple digital image loops were digitally transmitted using the Camtronics Medical System(Hartland, WI) for offline reading and analyses. A trace technique was employed to measure the maximum ca- rotid thickness from the leading edge. All images were read by a single research-trained vascular technician, who was blinded to subjects and has greater than 3 yr experience reading carotid ultrasound studies. Carotid IMTwas measured fromthe leading edge (lumen-intima) to the leading edge (medial-adventia). This technique was found to be more reproducible than point-to- point measurements (coefficient of variation for repeat readings, 5.3 to 8% for trace vs. 8.4 to 11.6% for point to point for the three carotid segments; Urbina, E. M., unpublished data, 2008). J Clin Endocrinol Metab, October 2009, 94(10):37403745 jcem.endojournals.org 3741 Statistical analysis All analyses were performed with Statistical Analysis Soft- ware (version 9.1.3; SAS Institute Inc., Cary, NC) (9). Average values for demographic, anthropometric, laboratory values and medication information were obtained for the entire group and by sex. 2 tests were used to detect differences in race and med- ication use between sex groups, whereas t tests were used to detect sex differences in age, weight, height, BMI, systolic and diastolic BP. The Wilcoxon rank sum test was used to compare total cholesterol, LDL and high-density lipoprotein (HDL) cho- lesterol, triglycerides, fasting glucose, HbA1c, TNF-, IL-6, CRP, and duration of the disease between males and females. Associations of carotid IMT outcomes with demographic, an- thropometric, laboratory measures, and medications were ana- lyzed using linear regression modeling with the aid of stepwise and forward procedures. Sex was forced in the models because of apparent sex differences in both outcomes and many inde- pendent variables. Normality of outcome variables was evalu- ated using Shapiro-Wilk tests (P 0.05 as normal) and visually checked by normal probability plots and QQ-plots. All three outcome variables were not normally distributed. After log transformation, normal distributions were assumed for all three variables. The Shapiro-Wilk test for bulb (log) was of marginal significance (P 0.0326), but normality was assumed after re- viewing the normal quantile plot. Linear relationships of carotid IMT outcomes and individual independent variables were as- sessed by scatter plot. Residuals of each model were inspected to assure a good fit. Logistic regression analysis was performed to elucidate independent determinants of elevated carotid IMT. An elevated carotid IMT was defined as greater than the 95th per- centile for the measure taken in 215 lean healthy control subjects participating in the parent study fromwhich the study data were obtained. For both linear and logistic regression, one TNF- outlier was excluded fromanalysis. Fasting insulin was not con- sidered because about half of the patients were on insulin med- ication. Statin medication was not included in analysis because there were only six patients using it. Secondary interactions be- tween age, race, sex, HbA1c, and duration of disease were also examined. Results Table 1 lists the average demographic, anthropometric data, and laboratory and carotid measurements for all subjects, stratified by sex. There were more non-Cauca- sian and female participants in the study, but there was no significant race difference by sex. Males were taller and heavier withhigher systolic BPandlower HDLcholesterol and CRP levels. Males had a significantly thicker common and internal carotid artery, with a trend toward a thicker artery in the bulb (P 0.0798). Of the subjects on med- ications, 57% were taking metformin, 45% insulin, 18% an antihypertensive medication, and 5% a lipid-lowering agent. Multiple regression modeling revealed age, HbA1c, and male sex as the only significant determinants of com- mon carotid IMT explaining 26% of the variance. The modeling was then repeated for each of the carotid seg- ments. Table 2 demonstrates that whereas HbA1c was found to be an important determinant in the common carotid artery, duration of diabetes was important in the TABLE 1. Characteristics of the study population Variables Females (n 79) Males (n 50) P values Caucasians (n) 29 18 Non-Caucasians (n) 50 32 Age (yr) 18.9 3.2 18.9 3.2 Weight (kg) 101.7 27.3 112.4 31.8 0.0453 a Height (cm) 165.1.0 7.8 176.2 9.6 0.0001 a BMI (kg/m 2 ) 37.2 9.4 36.0 9.2 Systolic BP (mm Hg) 120 12 127 11 0.0008 a Diastolic BP (mm Hg) 68 13 68 16 Total cholesterol (mg/dl) 188 37 188 48 LDL cholesterol (mg/dl) 112 34 120 48 HDL cholesterol (mg/dl) 48 12 41 10 0.0010 b Triglycerides (mg/dl) 142 98 158 106 Fasting glucose (mg/dl) 154 85 178 91 HbA1c (%) 8.6 3.3 8.6 3.3 Insulin (mU/ml) 24.4 13.3 26.9 20.6 IL-6 (pg/ml) 2.9 2.1 2.0 1.1 0.0299 b TNF- (pg/ml) 1.9 1.1 1.8 1.0 CRP (mg/liter) 6.8 6.9 3.8 3.6 0.0232 b Duration of diabetes (yr) 4.4 2.6 4.3 2.9 Common carotid (mm) 0.52 0.09 0.58 0.11 0.0035 b Bulb (mm) 0.51 0.14 0.55 0.12 0.0798 b Internal carotid (mm) 0.42 0.09 0.48 0.11 0.0015 b Data are expressed as mean SD. a t Test. b Wilcoxon rank sum test, P value 0.05. 3742 Shah et al. Carotid IMT in Youth with Diabetes J Clin Endocrinol Metab, October 2009, 94(10):37403745 bulb and internal carotid segments. These linear relation- ships are illustrated in a scatter plot by sex in Figs. 13. Regression modeling demonstrated that male sex was sig- nificant in all three carotid segments, whereas elevated BP (systolic or diastolic) was important in the bulb and in- ternal segments. LDL cholesterol was significant in the internal carotid segment. Medications, including met- formin, insulin, antihypertensives, and lipid-lowering agents, were included in the regression models and were not significant. Logistic regression was performed to elucidate inde- pendent determinants of elevated carotid IMT. In our youth with type 2 diabetes mellitus, 13.4% had an ele- vated common carotid IMT, 16.5% had an elevated bulb IMT, and 18.9% had an elevated internal carotid IMT. For the common carotid, sex, HbA1c, insulin adminis- tration, and systolic BP z-score (z) were significantly associated with thicker common carotid artery. After controlling for sex, systolic BP z-score, and insulin ad- ministration, the odds for a thicker common IMT in- creased 35%with each 1%increase in HbA1c [95%con- fidence interval (CI), 1.121.63; P 0.0016]. In the carotid bulb, systolic BP z-score and duration of diabetes were significantly associated with thicker IMT, whereas higher HDL cholesterol was associated with a better out- come. After controlling for systolic BP z and HDL cho- lesterol, the odds of having a thicker bulb increased by 33% for each year increase in duration of diabetes (95% CI, 1.081.65; P 0.0076). For the internal carotid ar- tery, the odds for a thicker vessel increased with male sex, higher LDL cholesterol or TNF- levels, lower HDL cho- lesterol levels, and longer duration of diabetes. After con- trolling for sex, cholesterol levels, andTNF-, the odds for thicker internal carotid IMT increased by 29% with each year increase in duration of diabetes (95%CI, 1.011.65; P 0.0399). Discussion This study demonstrates that increased carotid IMT is as- sociated with higher HbA1c concentrations and longer duration of type 2 diabetes mellitus in youth. Specifically, the logistic regression analysis established that each 1% increase in HbA1c or each year of duration of diabetes is associated with approximately 30% increased odds of a thicker carotid IMT. These data suggest that poor glyce- FIG. 3. Linear relationship of internal carotid IMT and duration of diabetes. TABLE 2. Significant determinates of carotid IMT a Region b Common carotid Bulb Internal carotid Age 0.0146 Sex (male) 0.0982 0.0999 0.1532 Height 0.0050 Systolic BP z-score 0.0679 Diastolic BP z-score 0.0393 LDL cholesterol 0.0014 HbA1c (%) 0.0131 Duration 0.0244 0.0159 R 2 (adjusted) 0.23 0.22 0.32 a All models have P 0.0001. b All parameter estimates listed have P 0.05. FIG. 1. Linear relationship of common carotid IMT and HbA1c. FIG. 2. Linear relationship of bulb IMT and duration of diabetes. J Clin Endocrinol Metab, October 2009, 94(10):37403745 jcem.endojournals.org 3743 mic control is associated with structural changes in the carotid artery that are consistent with early atherosclero- sis. In addition, regression models demonstrated that tra- ditional cardiovascular risk factors, including BP, LDL cholesterol, andmale sex, are alsoimportant determinants of carotid IMT in this population. To examine whether age, race, or sexintensifies the associationbetweenHbA1c or duration or disease and carotid IMT, we included these interaction terms in regression models. We found no sig- nificant interactions. These data establishthat HbA1c and duration of diabetes are independent factors in the pro- gression of thickening of carotid IMT. Thus, this cross- sectional study demonstrates that HbA1c, duration of di- abetes, and traditional cardiovascular risk factors provide individual contributions tothe development of atheroscle- rosis in adolescents and young adults with type 2 diabetes mellitus. Previous studies in adults have demonstrated an asso- ciation between glucose control and increased carotid IMT. Doruk et al. (10) reported that healthy adults with normal HbA1c levels (6%) show no evidence of in- creased carotid IMT. Other investigators showed im- paired glucose tolerance to be associated with an increase in carotid IMT but one third less than that seen in adults with type 2 diabetes mellitus (5). Our data provide evi- dence that the degree of hyperglycemia is associated with increased carotid IMT in youth. These findings suggest that improvement in glucose control at an early age may reduce the progression of atherosclerosis. The relationship between sex and carotid IMT is com- plex. Studies in adults with type 2 diabetes mellitus have demonstrated similar rates of coronary artery disease and mortality in men and premenopausal women. Investiga- tors suggest that the presence of diabetes eliminates the protection from cardiovascular disease in these females (11). However, there are currentlynostudies documenting similarities or differences in carotid IMT by sex in adults. CarotidIMTstudies inyouthwithtype 1diabetes mellitus have demonstrated conflicting results. Peppa-Patrikiou et al. (12) demonstratedsignificantlyhigher carotidIMTval- ues in male vs. female subjects, whereas Yavuz et al. (13) demonstrated no sex differences. To date, we are unaware of any studies that have examined sex differences in ado- lescents withtype 2diabetes mellitus. Our findings present new data that demonstrate that sex is a significant inde- pendent determinant of carotid IMT in adolescents with type 2 diabetes mellitus, and male sex is associated with worse outcomes in carotid IMT. Furthermore, these find- ings suggest that the protective effect of female sex may still be present in youth with type 2 diabetes mellitus who on average have had disease less than 5 yr. In adults, Liu et al. (14) reported recently that carotid IMTwas significantly associatedwiththe durationof type 2 diabetes mellitus for longer than 2 yr. A few studies in adolescents withtype 1diabetes mellitus have investigated the relationship between duration of diabetes and carotid IMT. Disease duration appeared to be associated with increased carotid IMT in two studies (13, 15), but others have not confirmed this association (12, 16, 17). To our knowledge, durationof diabetes andcarotidIMThave not been studied in adolescents with type 2 diabetes mellitus. In the present study, we demonstrate that duration of di- abetes is associated with increased carotid IMT in the in- ternal carotid and bulb segments. In conclusion, HbA1c and disease duration have indi- vidual adverse effects on carotid IMT in adolescents with type 2 diabetes mellitus in the presence of traditional car- diovascular riskfactors. These adverse effects appear tobe more prominent in males. Our findings suggest that the arterial tree is vulnerable to hyperglycemia beginning in youth. Adult data show that carotid IMT is linked to the atherosclerotic process andis associatedwithanincreased risk of myocardial infarction and stroke (5, 18). Therefore, developingeffective strategies toimprove bloodglucose con- trol in youth with type 2 diabetes mellitus is essential to pre- vent or limit the development and progression of cardiovas- cular disease. Acknowledgments The authors greatly acknowledge the excellent sonography work of Connie McCoy, RVT, and the participants of the Type 2 Diabetes Mellitus and Cardiovascular Disease Study and their families. Address all correspondence and requests for reprints to: Amy S. Shah, M.D., Divisionof Endocrinology, Cincinnati Childrens Hospital Medical Center, 3333Burnet Avenue, MLC7012, Cin- cinnati, Ohio 45229. E-mail: amy.shah@cchmc.org. This work was supported by National Institutes of Health (National Heart, Lung, and Blood Institute) Grant R01 HL076269. Disclosure Summary: The authors have nothing to disclose. References 1. Panzram G 1987 Mortality and survival in type 2 (non-insulin-de- pendent) diabetes mellitus. 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