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Objective: We compared arterial stiffness and heart rate variability (HRV) over time by diabetes type and determined the risk factors associated with worsening arterial stiffness and HRV in young adults with youth-onset diabetes., Research Design and Methods: Arterial stiffness (pulse wave velocity, augmentation index) and six indices of heart rate variability were measured twice, 4.5 years apart, among participants with either youth-onset type 1 or type 2 diabetes in the SEARCH for Diabetes in Youth study. Multivariable linear regression models were used to assess risk factors associated with arterial stiffness and HRV at follow-up., Results: Of 1,159 participants studied, 949 had type 1 diabetes (mean age 17.1 ± 4.7 years, 60.3% non-Hispanic White, 55% female) and 210 had type 2 diabetes (mean age 22.1 ± 3.5 years, 23.8% non-Hispanic White, 71% female) at initial assessment when diabetes duration was 7.9 years (both groups). Participants with type 2 versus type 1 diabetes had greater arterial stiffness and more abnormalities in HRV at initial and follow-up assessment and a greater change over time (all P < 0.05). Risk factors associated with worse arterial stiffness and HRV at follow-up in both types of diabetes included higher blood pressure, hemoglobin A1c, waist circumference, and triglycerides over time and longer diabetes duration., Conclusions: Arterial stiffness and HRV worsened over time with greater changes among participants with type 2 versus type 1 diabetes and among those with features of the metabolic syndrome. The risk factor profile documents potentially modifiable pathways to prevent or limit cardiovascular complications in young adults with youth-onset diabetes., (© 2022 by the American Diabetes Association.)

Objective: Pulse wave analysis estimates arterial wave reflections relating to left ventricular dysfunction and cardiovascular event risk in adults. Forward and backward waves (Pf and Pb) may improve risk stratification for cardiovascular events. Data in youth are lacking. We hypothesized that a significant difference in wave reflections would be identified in young subjects with adverse cardiovascular risk factors. Approach and Results: Vital signs and labs were obtained in 551 patients aged 10 to 24 years who were lean (L=199), obese (O=173), or had type 2 diabetes (T=179). Wave separation was performed. Differences in cardiovascular risk factors and wave reflections were assessed using ANOVA. General linear models were constructed to elucidate independent predictors of wave reflections. O and T subjects had an adverse cardiovascular risk profile versus L. O and T subjects had higher Pf and Pb versus L ( P ≤0.05). When adjusted for adiposity and other cardiovascular risk factors, reflection magnitude increased from L to O to T with higher T versus L values ( P ≤0.05) and near-significant O versus L values ( P =0.06). Adiposity and blood pressure were major determinants of wave reflections. Pb influenced log left ventricular mass index, log E/e', and log composite carotid intima-media thickness., Conclusions: Adolescents and young adults with obesity and type 2 diabetes have altered forward and backward wave reflections versus lean controls related to adiposity, BP, and insulin levels. These parameters may help risk stratify patients with adverse cardiovascular risk factors.

Background The normal rate of subclinical vascular aging from adolescence to young adulthood has not been well-characterized. We conducted a 5-year longitudinal study among adolescents with normal-weight, obesity, and/or type 2 diabetes mellitus to examine trajectories of early vascular aging. Methods and Results Adolescents (mean [SD] age 17.6 [3.5]; 35.3% male) had either normal weight (n=141), obesity (n=156), or type 2 diabetes mellitus (n=151) at baseline. Primary metrics used for early vascular aging included measures of vascular structure (carotid intima-media thickness [cIMT]; common, internal, and bulb) and arterial stiffness (carotid-femoral pulse wave velocity, and augmentation index). Longitudinal (5-year) outcomes were examined using generalized estimating equations adjusting for baseline value, sex, race, and age. Compared with participants with normal weight, those with obesity had greater positive change in common cIMT (0.05 mm [0.03, 0.06]; P <0.001), bulb cIMT (0.02 mm [0.00, 0.05]; P =0.033), internal cIMT (0.03 mm [0.01, 0.05]; P <0.001), and pulse wave velocity carotid-femoral (0.38 m/sec [0.14, 0.61]; P =0.001), and those with type 2 diabetes mellitus had greater positive change in common cIMT (0.05 mm [0.04, 0.07]; P <0.001), bulb cIMT (0.06 mm [0.04, 0.09]; P <0.001), internal cIMT (0.04 mm [0.02, 0.07]; P <0.001), augmentation index (4.67% [2.20, 7.13]; P <0.001), and pulse wave velocity carotid-femoral (0.74 m/sec [0.46, 1.02]; P <0.001). Higher baseline systolic blood pressure was associated with greater positive change in common cIMT (0.007 mm [0.003, 0.011]; P <0.001), bulb cIMT (0.009 mm [0.002, 0.016]; P =0.01), internal cIMT (0.008 mm [0.003, 0.013]; P =0.001), and pulse wave velocity carotid-femoral (0.066 m/sec [0.002, 0.130]; P =0.042). Conclusions These longitudinal data support the hypothesis that the presence of obesity, type 2 diabetes mellitus, and elevated baseline systolic blood pressure in early life accelerates the progression of risk factors key in the development of early vascular aging.

Background: Cardiovascular disease (CVD) is the leading cause of death among individuals with diabetes, but little is known about the role of exposures to environmental chemicals such as pesticides in the early development of CVD risk in this population., Objectives: To describe changes over time in concentrations of pesticide biomarkers among youth with diabetes in the United States and to estimate the longitudinal association between these concentrations and established risk factors for CVD., Methods: Pesticide biomarkers were quantified in urine and serum samples from 87 youth with diabetes participating in the multi-center SEARCH cohort study. Samples were obtained around the time of diagnosis (baseline visit, between 2006 and 2010) and, on average, 5.4 years later (follow-up visit, between 2012 and 2015). We calculated geometric mean (95% CI) pesticide biomarker concentrations. Eight CVD risk factors were measured at these two time points: body mass index (BMI) z-score, HbA1c, insulin sensitivity, fasting C-peptide (FCP), LDL cholesterol, HDL cholesterol, total cholesterol, and triglycerides. Linear regression models were used to estimate the associations between each pesticide biomarker at baseline and each CVD risk factor at follow-up, adjusting for baseline health outcome, elapsed time between baseline and follow up, sex, age, race/ethnicity, and diabetes type., Results: Participants were, on average, 14.2 years old at their baseline visit, and most were diagnosed with type 1 diabetes (57.5%). 4-nitrophenol, 3-phenoxybenzoic acid, 2,4-dichlorophenoxyacetic acid (2,4-D), 3,5,6-trichloro-2-pyridinol, 2,2-bis(4-chlorophenyl)-1,1-dichloroethene, and hexachlorobenzene were detected in a majority of participants at both time points. Participants in the highest quartile of 2,4-D and 4-nitrophenol at baseline had HbA1c levels at follow-up that were 1.05 percentage points (95% CI: -0.40, 2.51) and 1.27 percentage points (0.22, 2.75) higher, respectively, than participants in the lowest quartile of these pesticide biomarkers at baseline. These participants also had lower log FCP levels (indicating reduced beta-cell function) compared to participants in the lowest quartile at baseline: beta (95% CI) for log FCP of -0.64 (-1.17, -0.11) for 2,4-D and -0.39 (-0.96, 0.18) for 4-nitrophenol. In other words, participants in the highest quartile of 2,4-D had a 47.3% lower FCP level compared to participants in the lowest quartile, and those in the highest quartile of 4-nitrophenol had a 32.3% lower FCP level than those in the lowest quartile. Participants with trans-nonachlor concentrations in the highest quartile at baseline had HbA1c levels that were 1.45 percentage points (-0.11, 3.01) higher and log FCP levels that were -0.28 (-0.84, 0.28) lower than participants in the lowest quartile at baseline, that is to say, participants in the highest quartile of trans-nonachlor had a 24.4% lower FCP level than those in the lowest quartile. While not all of these results were statistically significant, potentially due to the small same size, clinically, there appears to be quantitative differences. No associations were observed between any pesticide biomarker at baseline with BMI z-score or insulin sensitivity at follow-up., Conclusions: Exposure to select pesticides may be associated with impaired beta-cell function and poorer glycemic control among youth with diabetes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: To optimize treatment and prevent cardiovascular disease in subjects with type 1 diabetes, it is important to determine how cholesterol metabolism changes with type 1 diabetes., Objective: The objective of the study was to compare plasma levels of campesterol and β-sitosterol, markers of cholesterol absorption, as well as lathosterol, a marker of cholesterol synthesis, in youth with and without type 1 diabetes., Methods: Serum samples were obtained from adolescent subjects with type 1 diabetes (n = 175, mean age 15.2 years, mean duration of diabetes 8.2 years) and without diabetes (n = 74, mean age 15.4 years). Campesterol, β-sitosterol, and lathosterol, were measured using targeted liquid chromatography tandem mass spectrometry, compared between groups, and correlated with the available cardiometabolic variables., Results: Campesterol and β-sitosterol levels were 30% higher in subjects with type 1 diabetes and positively correlated with hemoglobin A1c levels. In contrast, lathosterol levels were 20% lower in subjects with type 1 diabetes and positively correlated with triglycerides, body mass index, and systolic blood pressure., Conclusion: Plasma markers suggest that cholesterol absorption is increased, whereas cholesterol synthesis is decreased in adolescent subjects with type 1 diabetes. Further studies to address the impact of these changes on the relative efficacy of cholesterol absorption and synthesis inhibitors in subjects with type 1 diabetes are urgently needed., (Copyright © 2019 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Objective: To estimate the prevalence of and risk factors for cardiovascular autonomic neuropathy (CAN) in adolescents and young adults with type 1 and type 2 diabetes enrolled in the SEARCH for Diabetes in Youth Study., Methods: The study included 1646 subjects with type 1 diabetes (age 18 ± 4 years, diabetes duration 8 ± 2 years, HbA1c 9.1 ± 1.9%, 76% non-Hispanic Whites) and 252 with type 2 diabetes (age 22 ± 4 years, diabetes duration 8 ± 2 years, HbA1c 9.2 ± 3.0%, 45% non-Hispanic Blacks). Cross-sectional and longitudinal risk factors were assessed at baseline and follow-up visits. Area under the curve (AUC) was used to assess the longitudinal glycemic exposure and cardiovascular risk factors. CAN was assessed by time and frequency domain indices of heart rate variability (HRV). CAN was defined as the presence of ≥3 of 5 abnormal HRV indices., Results: The prevalence of CAN was 12% in adolescents and young adults with type 1 diabetes and 17% in those with type 2 diabetes. Poor long-term glycemic control (AUC HbA1c), high blood pressure, and elevated triglyceride levels were correlates of CAN in subjects with type 1 diabetes. In those with type 2 diabetes, CAN was associated with elevated triglycerides and increased urinary albumin excretion., Conclusions: The prevalence of CAN in this multiethnic cohort of adolescents and young adults with type 1 and type 2 diabetes are comparable to those reported in adults with diabetes. Suboptimal glycemic control and elevated triglycerides were the modifiable risk factors associated with CAN., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

Background: We aimed to (1) compare a subjective and objective measure of habitual physical activity (PA), (2) determine the association of PA and cardiovascular risk factors, and (3) test the hypothesis that PA is an independent determinant of target organ damage in youth., Methods: Cross-sectional analysis of youth with and without type 2 diabetes [mean age = 22 (3.9) y]. PA was measured with International Physical Activity Questionnaire and Actical accelerometer. Target organ damage was assessed with echocardiography and peripheral arterial testing. Subjects were stratified into tertiles of total PA, and differences were tested by analysis of variance and χ 2 tests. General linear models tested for independent associations., Results: The correlation between International Physical Activity Questionnaire and accelerometry was weak (r = .23, P = .0003). Less active subjects had worse cardiovascular risk profiles and target organ damage, including stiffer arteries (P < .01). These outcome differences did not reach statistical significance when adjusted for covariates, such as lipid levels and glycemic control., Conclusion: Survey assessment of PA is complicated by inaccurate reporting. There is a strong association of habitual PA with cardiovascular risk factor clustering. PA may exert its beneficial effect on arterial stiffness in obese youth through improved glycemic control.

Background: The aim of this study was to examine the association between myocardial strain and arterial thickness and stiffness in young adults. Increased common carotid artery intima media thickness and peripheral arterial stiffness are known to precede coronary artery disease and cardiovascular (CV) events such as myocardial infarction and congestive heart failure. However, subclinical cardiac dysfunction can be detected in high-risk adults by myocardial strain echocardiography. The authors hypothesized that increased carotid artery intima media thickness would be associated with abnormal myocardial strain in young subjects who had obesity and type 2 diabetes mellitus., Methods: CV risk factors were collected in 338 young adults participating in a prospective, cross-sectional study. The CV parameters collected included intima-media thickness, peripheral arterial stiffness by brachial distensibility, and myocardial strain and strain rate. General linear models were constructed to determine if vascular structure and function measures were independently associated with myocardial strain and strain rate., Results: A linear relationship was found between global longitudinal strain obtained from the four-chamber view and global strain rate in systole and carotid intima-media thickness (four-chamber global longitudinal strain: β = 3.0, CV risk factor-adjusted R 2  = 0.34; global strain rate in systole: β = 0.0053, R 2  = 0.21; P ≤ .0001) and between four-chamber global longitudinal strain and lower brachial distensibility (β = -0.42, R 2  = 0.22; P < .001)., Conclusions: Adverse changes in vascular structure and function are simultaneously present with reduced myocardial systolic function., (Copyright © 2017 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Purpose: In this longitudinal study we explored the relationships between plasma n-3 and n-6 polyunsaturated fatty acids (PUFAs) and Δ5 and Δ6 desaturase activities (D5D and D6D, respectively) and fasting lipids in youth with type 1 diabetes (T1D)., Methods: Incident cases of T1D in youth <20years of age who were seen for a baseline study visit (N=914) and a 1-year follow-up visit (N=416) were included. Fasting blood samples were obtained at each visit and plasma phospholipid n-6 PUFAs were measured, which included linoleic acid (LA), dihomo-γ-linolenic acid (DGLA) and arachidonic acid (AA); n-3 PUFAs included α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Estimated D5D and D6D were calculated as FA product-to-precursor ratios, where D5D=AA/DGLA and D6D=DGLA/LA. To examine the longitudinal relationships between long chain PUFAs, desaturase activities and fasting plasma lipids in youth with T1D mixed effects models were used for each individual PUFAs, D5D and D6D, adjusted for demographics, clinic site, diabetes duration, insulin regimen, insulin dose/kg, HbA1c, insulin sensitivity score, and body mass index with random effects to account for the repeated measurements., Findings: Favorable lipid associations were found between LA and low-density lipoprotein (LDL) cholesterol (β=-0.58, p<0.05); AA, plasma triglycerides (TG) (β=-0.04, p<0.05) and TG/high-density lipoprotein (HDL)-C ratio (β=-0.04, p<0.05); and D5D, plasma TG (β=-0.2, p<0.05) and TG/HDL-cholesterol ratio (β=-0.23, p<0.05). Findings were mixed for the n-3 PUFAs and DGLA: ALA was positively associated with plasma TG (β=0.33, p<0.05) and HDL cholesterol (β=9.86, p<0.05); EPA was positively associated with total cholesterol (β=8.17, p<0.05), LDL cholesterol (β=5.74, p<0.01) and HDL cholesterol (β=2.27, p<0.01); and DGLA was positively associated with TG/HDL-cholesterol ratio (β=0.05, P<0.05)., Conclusion: Findings suggest that the most abundant PUFA, LA as well as its metabolic bi-product AA, may be important targets for CVD lipid risk factor reduction in youth with T1D., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Youth with type 1 diabetes have worse cardiovascular (CV) risk factors and higher carotid intima-media thickness (IMT) than their peers without diabetes. Whether the burden of CV risk factors over time is associated with carotid IMT at follow-up in youth with type 1 diabetes is not known., Research Design and Methods: Two hundred ninety-eight youth with type 1 diabetes (mean age 13.3 ± 2.9 years, 87.6% non-Hispanic white, 53.7% male) had two study visits 5 years apart. CV risk factors, including BMI, lipids, blood pressure, hemoglobin A(1c), and smoking status, were assessed at both visits, and carotid IMT was measured at follow-up using B-mode ultrasonography. Linear regression models with an area under the curve measurement that incorporated the baseline and follow-up CV risk factors were used to evaluate the relationship with carotid IMT at follow-up., Results: All CV risk factors worsened significantly over time (except LDL cholesterol) (P < 0.05). From baseline to follow-up, the number of abnormal CV risk factors also increased (P < 0.05). Predictors of carotid IMT were older age, male sex, and higher BMI z score area under the curve (all P < 0.05)., Conclusions: The CV risk factor burden increases over time in youth with type 1 diabetes. BMI z score was the only modifiable CV risk factor that predicted carotid IMT. This study highlights the critical need to better understand the risk factors that influence carotid IMT early in the course of type 1 diabetes., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Context: Severe obesity is the fastest growing subgroup of obesity in youth., Objective: We sought to explore the association between severe obesity and subclinical measures of cardiac and vascular structure and function in adolescents and young adults., Design, Setting, and Participants: This was a cross-sectional comparison of 265 adolescents and young adults with severe obesity (defined as body mass index [BMI] ≥120% of the 95th percentile) to 182 adolescents and young adults with obesity (defined as BMI ≥100-119th of the 95th percentile) at tertiary medical center., Main Outcomes: Noninvasive measures of cardiac and vascular structure and function were assessed., Results: Participants were a mean age of 17.9 years, 62% were non-Caucasian, and 68% were female. Systolic blood pressure, fasting insulin, C-reactive protein, IL-6, and frequency of type 2 diabetes were higher in participants with severe obesity (all P < .05). Arterial thickness and stiffness, cardiac structure, and diastolic function were also significantly worse in youth with severe obesity as measured by higher left ventricular mass index, worse diastolic function, higher carotid intima media thickness, and pulse wave velocity and lower brachial distensibility (all P < .05). Regression modeling showed that severe obesity (compared with obesity) was independently associated with each of the above outcomes after adjustment for age, race, sex, blood pressure, lipids, and inflammatory markers (P < .05)., Conclusions: Adolescents and young adults with severe obesity have a more adverse cardiovascular risk profile and worse cardiac and vascular structure and function. More importantly, severe obesity is independently associated with these subclinical cardiac and vascular changes.

Aims: Determine if parental diabetes (DM) is associated with unhealthier cardiovascular disease (CVD) risk profiles in youth with type 2 diabetes (T2D), and whether associations differed by race/ethnicity., Methods: Family history was available for 382 youth with T2D from 2001 prevalent and 2002-2005 incident SEARCH for Diabetes in Youth cohorts. Parental DM was evaluated in two ways: two-category-any parent vs. no parent DM (evaluated overall and stratified by race/ethnicity); and four-category-both parents, mother only, father only, or no parent DM (evaluated overall only). Associations with hemoglobin A1c (HbA1c), fasting lipids, blood pressure (BP), and urine albumin:creatinine ratio (ACR) were examined using regression models., Results: Overall, sample characteristics included: 35.9% male, 19.1% non-Hispanic white (NHW), mean T2D duration 26.6±22.2months, mean HbA1c 7.9%±2.5% (62.6±27.8mmol/mol). Unadjusted two-category comparisons showed that youth with parental DM had higher HbA1c, higher DBP, and higher frequency of elevated ACR. Adjusted two-category comparisons showed associations remaining in non-stratified analysis for ACR [OR (95% CI)=2.3 (1.1, 5.0)] and in NHW youth for HbA1c [6.8%±0.4 vs. 8.0±0.4 (51.1±4.8 vs. 63.9±4.2mmol/mol), p=.015], DBP (67.7%±4.5 vs. 76.9±4.4mm Hg, p=.014) and lnTG (4.7±0.3 vs. 5.3±0.3, p=.008). There were no significant findings in the adjusted four-category evaluation., Conclusions: Parental history of diabetes may be associated with unhealthier CVD risk factors in youth with T2D., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: In their Strategic Impact Goal Statement, the American Heart Association focused on primordial prevention of cardiovascular risk factors by defining metrics for ideal cardiovascular health (ICH). The prevalence of ICH among youth with type 1 diabetes is unknown. Youth with type 1 diabetes face an increased risk of cardiovascular disease (CVD) as they age. The purpose of this report was to examine the prevalence of ICH in a population of youth with type 1 diabetes and to examine the association of ICH with measures of cardiovascular structure and function., Research Design and Methods: This report is based on SEARCH CVD an ancillary study to the SEARCH for Diabetes in Youth. A total of 190 adolescents with type 1 diabetes had complete data on all of the ICH metrics at baseline and had measures of arterial stiffness [pulse wave velocity (PWV), brachial distensibility (BrachD), and augmentation index (AIx)] and carotid intima-media thickness completed at a follow-up visit [on average 5 yr after baseline (interquartile range 4-5)]., Results: No subjects met the ICH criteria for all 7 metrics. Meeting an increasing number of ICH metrics was significantly associated with lower arterial stiffness [lower PWV of the trunk (β = -0.02 ±0.01; p = 0.004) and AIx (β = -2.2 ±0.66; p = 0.001), and increased BrachD (β = 0.14 ±0.07; p = 0.04)]., Conclusions: Increasing number of ICH metrics was significantly associated with decreased arterial stiffness, but prevalence of ICH in this population was low. Youth with type 1 diabetes could benefit from improvements in their cardiovascular health., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To evaluate the effects of smoking on early markers of cardiovascular disease (arterial stiffness) in adolescents with and without type 1 diabetes (T1D) in the SEARCH Cardiovascular Disease Study., Study Design: Participants included 606 youth (18.9 ± 3.3 years, 83% non-Hispanic white; 50% male). Six groups were defined: (1) smokers with T1D (n = 80); (2) former smokers with T1D (n = 88); (3) nonsmokers with T1D (n = 232); (4) smokers without T1D (n = 40); (5) former smokers without T1D former (n = 51); and (6) nonsmokers without T1D (n = 115). Arterial stiffness measurements included pulse wave velocity (PWV), augmentation index, and brachial distensibility. Multivariate linear regression was used to assess the independent and joint effects of T1D and smoking on arterial stiffness., Results: Nearly 20% of both youth with and without T1D and T1D were smokers. In youth without T1D, smokers had higher trunk and arm PWV. After adjustment for potential confounders, T1D, but not smoking, was an independent predictor of PWV (P < .05). Moreover, smoking status did not modify the association between T1D and increased arterial stiffness., Conclusions: We found a high prevalence of smoking among youth with and without T1D; however, smoking status was not independently associated with increased arterial stiffness in youth with T1D., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To evaluate if presence of cardiovascular (CV) risk factors and their clustering as metabolic syndrome (MetS) is associated with increased arterial stiffness and accelerated progression over time among youth with type 1 diabetes., Research Design and Methods: Longitudinal study of 298 youth with type 1 diabetes (age 14.5 years; 46.3% female; duration 4.8 years), with two research visits conducted 5 years apart. CV factors included: waist circumference, blood pressure (BP), fasting lipids (HDL cholesterol, LDL cholesterol [LDL-c], triglycerides), albumin/creatinine ratio, and HbA1c. MetS was based on Adult Treatment Panel III criteria modified for youth. Pulse wave velocity (PWV) in the carotid-femoral segment was measured by tonometry. Mixed models were used to assess the rate of progression in PWV and the association between CV factors and PWV over time., Results: PWV increased significantly over time (0.145 m/s/year; P < 0.0001). MetS (P = 0.0035), large waist (P < 0.0001), and elevated BP (P = 0.0003) at baseline were each associated with worse PWV over time. These baseline factors, however, did not significantly influence the rate of progression. Increases in waist circumference (P < 0.0001), LDL-c levels (P = 0.0156), and declining glucose control (HbA1c; P = 0.0419) were independently associated with higher PWV over time., Conclusions: Presence, clustering, and worsening of CV risk factors are associated with increased arterial stiffness over time in youth with type 1 diabetes. Whether improvement in CV risk factors early in life will slow the progression of arterial stiffness and reduce the burden of CV disease in this population requires further study.

Objective: Type 1 diabetes mellitus causes increased carotid intima-media thickness (IMT) in adults. We evaluated IMT in young subjects with type 1 diabetes., Research Design and Methods: Participants with type 1 diabetes (N = 402) were matched to controls (N = 206) by age, sex, and race or ethnicity. Anthropometric and laboratory values, blood pressure, and IMT were measured. ANCOVA was used to assess differences controlling for demographic risk factors, cardiovascular risk factors, and HbA1c., Results: Subjects were 18.9 ± 3.3 years old (50% male, 82.7% non-Hispanic white). Youth with type 1 diabetes had thicker bulb IMT, which remained significantly different after adjustment for demographics and cardiovascular risk factors. Age, sex, adiposity, and systolic blood pressure were consistent significant determinants of IMT. Adjustment for HbA1c eliminated the difference, suggesting the difference was attributable to poor glycemic control., Conclusions: Carotid IMT may be increased in youth with type 1 diabetes at high risk for cardiovascular disease. Better control of diabetes may be essential in preventing progression of atherosclerosis.

Recent studies suggest HDL exists as numerous subpopulations with distinct protein/lipid compositions that are not reflected in the HDL cholesterol (HDL-C) number. In this study, we sought to evaluate HDL subpopulations in adolescents with type 2 diabetes (T2D) to determine if changes in HDL composition are associated with early vascular disease. T2D (n = 10), lean (n = 9), and obese (n = 11) youth were recruited. Plasma was fractionated using gel-filtration chromatography, and lipid-associated proteins were identified using mass spectrometry. Concurrently, vascular stiffness was assessed using pulse wave velocity (PWV). We found youth with T2D exhibited decreased phospholipid content in fractions containing large HDL particles that was inversely associated with PWV (P < 0.001). No association was noted between HDL-C and PWV. Proteomic analysis revealed changes in 7 of 45 identified proteins in the T2D group, including apolipoprotein (apo) A-II, apoE, and paraoxonase-1 (P < 0.05). Our data demonstrate early changes in the lipid and protein compositions of specific HDL subspecies in adolescents with T2D that are related to early markers of arterial disease. These findings suggest that analyzing the composition of HDL, rather than HDL-C, may be useful in assessing cardiovascular risk in this population.

Aims: High consumption of dietary fructose has been shown to contribute to dyslipidemia and elevated blood pressure in adults, but there are few data in youth, particularly those at greater risk of cardiovascular disease (CVD). The aim of this study was to examine the association between fructose intake and CVD risk factors in a diverse population of youth with type 1 diabetes (T1D)., Methods: This was a cross-sectional analysis of data from the SEARCH for Diabetes in Youth study, including 2085 youth ages 10-22 years with T1D, of which 22% were racial/ethnic minority and 50% were female. A semi-quantitative food frequency questionnaire was used to assess intake., Results: Median daily fructose consumption was 7.9% of total calories. Fructose intake was positively associated with triglycerides (p<.01), but not with total cholesterol, LDL-cholesterol, HDL-cholesterol, or blood pressure after adjustment for physical activity and socio-demographic, clinical, and dietary covariates. An increase in fructose intake of 22 g (equivalent to a 12 oz can of soda) was associated with 23% higher odds of borderline/high versus low triglycerides (p<.005)., Conclusion: These data suggest that children with T1D should moderate their intake of fructose, particularly those with borderline or high triglycerides., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: To determine whether arterial stiffness relates to left ventricular mass (LVM) in adolescents and young adults., Study Design: Demographic, anthropometric, laboratory, echo, carotid ultrasound and arterial stiffness data were obtained in 670 subjects 10 to 24 years of age (35% male, 62% non-Caucasian). Global stiffness index (GSI) was calculated from five measures of carotid artery stiffness, augmentation index, brachial distensibility, and pulse wave velocity (1 point if ≥95th% for subjects with body mass index <85th%). Stiff arteries (S = 73) were defined as GSI ≥95th%. Differences between flexible (F = 597) and S groups were evaluated by t tests. Models were constructed to determine whether GSI was an independent determinant of LVM index or relative wall thickness (RWT)., Results: The S group had more adverse cardiovascular risk factors, higher LVM index and RWT (P ≤ .05) with a trend for abnormal cardiac geometry. Independent determinants of LVM index were higher GSI, age, body mass index, systolic blood pressure, heart rate, glycated hemoglobin A1c, male sex, and sex-by-heart rate interaction (r(2) = 0.52; P ≤ .05). GSI was also an independent determinant of RWT., Conclusions: Increased arterial stiffness in adolescents and young adults is associated with LVM index independently of traditional cardiovascular risk factors. Screening for arterial stiffness may be useful to identify high risk adolescents and young adults., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Objective: Cardiovascular risk assessment is an accepted practice in adults and correlates with early changes in carotid structure and function. Its clinical use in pediatrics is less common. We sought to determine whether a simple method of clustering cardiovascular risks could detect early atherosclerotic changes in youth. In addition, we compared risk clustering with the accepted Patholobiological Determinants of Atherosclerosis in Youth score to assess its utility for predicting early vascular disease., Patients and Methods: We collected demographic, anthropometric, laboratory, and vascular measures in a cross-sectional study. The study population (n = 474; mean age: 18 years) was divided into low-risk (0-1) or high-risk (≥ 2) groups on the basis of the number of cardiovascular risk factors present at evaluation. Group differences and vascular outcomes were compared. General linear models were used to compare clustering cardiovascular risks with the Patholobiological Determinants of Atherosclerosis in Youth score., Results: The high-risk group had higher vascular thickness and stiffness compared with the low-risk group (P < .05). Regression models found that clustering cardiovascular risks is associated with abnormal vascular structure and function after adjustment for age, race, and gender. The Patholobiological Determinants of Atherosclerosis in Youth score also is associated with abnormal vascular structure and function but with lower R(2) values (P < .05)., Conclusions: Cardiovascular risk clustering is a reliable tool for assessing abnormal vascular function. Its simplicity, compared with the Patholobiological Determinants of Atherosclerosis in Youth score, provides an advantageous tool for the practicing clinician to identify those youth who are at higher risk for early cardiovascular disease.

Objective: This study explores whether the relationship between lower socioeconomic status and insulin resistance in adolescents is mediated by both physiological and psychological factors associated with increased cardiometabolic risk., Study Design: School-based longitudinal cohort study of 1222 healthy, non-Hispanic black and white teens. Parent education (PE), youth-specific Cook-Medley hostility scale, waist circumference, height, weight, pubertal status, and fasting plasma insulin (FPI) were measured and FPI reassessed 1 year later. Regression analyses utilizing bootstrapping (n=2000) were used to estimate the direct and indirect effects of PE on FPI and assess the role of hostility and adiposity while adjusting for covariates., Results: Lower PE predicted higher FPI (B=-1.52, P=.003), as did hostility (B=.19, P=.002) and adiposity (waist circumference B=.44, P<.001, BMI B=.98, P<.001). The effect of PE on FPI was mediated by both hostility and adiposity. When adiposity and hostility were accounted for, the effect of PE on FPI decreased by 32% (B=-1.04, P=.04); the total indirect estimate was -.485 (95% CI, -.652, -.041). Hostility accounted for 36% of the meditational effect., Conclusions: Lower PE influences insulin resistance through adiposity and hostility. Thus, interventions to reduce health disparities associated with insulin resistance should consider both physiological and psychological approaches., (Copyright (c) 2010 Mosby, Inc. All rights reserved.)

Background: Carotid intima-media thickness (IMT) provides a mechanism for detecting early atherosclerosis. Little information is available concerning carotid IMT and the progression of atherosclerosis 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 129 youth of mixed ethnicity, ages 10-23 yr. Associations of carotid IMT outcomes and risk variables 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 each 1% increase in HbA1c or each year increase in duration of type 2 diabetes mellitus is associated with approximately 30% increased odds of a thicker carotid IMT., Conclusions: Poorer glycemic control and longer disease duration have independent adverse effects on carotid IMT in youth with type 2 diabetes mellitus. These adverse effects appear to be more prominent in males. Developing effective strategies to improve blood glucose control in youth with type 2 diabetes mellitus is essential to prevent or limit the development and progression of atherosclerotic cardiovascular disease.

Background: The extent to which cardiovascular disease (CVD) risk factors cluster in youth with a diagnosis of type 1 (T1DM) or type 2 diabetes mellitus (T2DM) is unclear. Therefore, we aimed to evaluate potential clustering of traditional CVD risk factors that may reflect an unmeasured but unifying single pathology that may explain the phenomenon of the metabolic syndrome in these youths., Methods: Youths who participated in the SEARCH for Diabetes in Youth study with diabetes diagnosed <20 years, with current age >10 years (maximum current age, 22 years) were included. Confirmatory factor analysis (CFA) was performed to determine statistical associations among CVD risk factors, including obesity, blood pressure, triglycerides, and high-density lipoprotein cholesterol (HDL-C). Diabetes type was defined by diabetes autoantibodies (DAA) and fasting C-peptide (FCP); type 1 (T1DM, DAA positive, and FCP <0.8 ng/mL, n = 1198) and type 2 (T2DM, DAA negative, and FCP >2.9 ng/mL, n = 95). For T1DM, the sample was split randomly and analyses were conducted separately in each split sample., Results: Among five prespecified data structures ranging from a single underlying factor to a hierarchical structure of factors, the worst-fitting model for both of the T1DM split samples was the single-factor structure and the best-fitting model was a three-correlated-factor structure. The three correlated factors identified were obesity, lipids, and blood pressure. Results were very similar for youths with T2DM., Conclusion: There is little evidence that a single factor underlies the CVD risk factor pattern in youths with diabetes. The concept of the metabolic syndrome provides a useful description of clinical characteristics but does not efficiently capture a single target for etiologic research among youths with diabetes.

Objectives: Type 2 diabetes mellitus is associated with obesity, dyslipidemia, and hypertension, all well-known risk factors for cardiovascular disease. Surgical weight loss has resulted in a marked reduction of these risk factors in adults. We hypothesized that gastric bypass would improve parameters of metabolic dysfunction and cardiovascular risk in adolescents with type 2 diabetes mellitus., Patients and Methods: Eleven adolescents who underwent Roux-en-Y gastric bypass at 5 centers were included. Anthropometric, hemodynamic, and biochemical measures and surgical complications were analyzed. Similar measures from 67 adolescents with type 2 diabetes mellitus who were treated medically for 1 year were also analyzed., Results: Adolescents who underwent Roux-en-Y gastric bypass were extremely obese (mean BMI of 50 +/- 5.9 kg/m(2)) with numerous cardiovascular risk factors. After surgery there was evidence of remission of type 2 diabetes mellitus in all but 1 patient. Significant improvements in BMI (-34%), fasting blood glucose (-41%), fasting insulin concentrations (-81%), hemoglobin A1c levels (7.3%-5.6%), and insulin sensitivity were also seen. There were significant improvements in serum lipid levels and blood pressure. In comparison, adolescents with type 2 diabetes mellitus who were followed during 1 year of medical treatment demonstrated stable body weight (baseline BMI: 35 +/- 7.3 kg/m(2); 1-year BMI: 34.9 +/- 7.2 kg/m(2)) and no significant change in blood pressure or in diabetic medication use. Medically managed patients had significantly improved hemoglobin A1c levels over 1 year (baseline: 7.85% +/- 2.3%; 1 year: 7.1% +/- 2%)., Conclusions: Extremely obese diabetic adolescents experience significant weight loss and remission of type 2 diabetes mellitus after Roux-en-Y gastric bypass. Improvements in insulin resistance, beta-cell function, and cardiovascular risk factors support Roux-en-Y gastric bypass as an intervention that improves the health of these adolescents. Although the long-term efficacy of Roux-en-Y gastric bypass is not known, these findings suggest that Roux-en-Y gastric bypass is an effective option for the treatment of extremely obese adolescents with type 2 diabetes mellitus.

Background: Clustering of cardiovascular (CV) risks begins in childhood, yet studies of the factor structure underlying this clustering have focused on adults. The increasing rates of obesity and type 2 diabetes and the growing importance of metabolic syndrome among adolescents make assessment of CV risk clustering even more urgent in this age group., Methods and Results: Exploratory factor analysis (principal components analysis) was performed with data from 1578 healthy seventh to 12th graders from the Princeton School District Study, a school-based study in Cincinnati, Ohio. Measured CV risks included cholesterol, triglycerides, fasting insulin and glucose, body mass index (BMI), waist circumference, fibrinogen, and blood pressure. Factor analysis yielded 4 uncorrelated factors (adiposity [BMI, waist, fibrinogen, insulin], cholesterol [LDL and total cholesterol], carbohydrate-metabolic [glucose, insulin, HDL cholesterol, triglycerides], and blood pressure [systolic and diastolic blood pressure]). These factors explained approximately 67% of the total variance. A summary cumulative risk scale was derived from factor scores, and high risk was defined as scoring in the top 5%. Although insulin loaded onto both the adiposity and carbohydrate-metabolic factors, obesity was a much stronger correlate of high cumulative risk (odds ratio=19.2; 95% CI, 7.6 to 48.5) than hyperinsulinemia (odds ratio=3.5; 95% CI, 1.8 to 6.8). A sizable proportion (18.5%; n=12) of those who were at high cumulative risk were not at high risk for any of the individual factors., Conclusions: The patterning of CV risk clustering seen among adults is present in healthy adolescents. Among youth, obesity is the predominant correlate of cumulative risk.

Objective: Cardiovascular disease, which begins early in life but often is not manifest until adulthood, is the nation's leading cause of mortality. Social inequalities in cardiovascular disease are pervasive, yet the process by which they accrue is poorly understood. The objective of this study was to explore the associations between socioeconomic status, a range of biomarkers reflective of cardiovascular risks, and a cumulative physiological risk score among adolescents., Methods: Non-Hispanic black and white high school students (N = 758) in a suburban Midwestern public school district had a physical examination to measure height, weight, and waist circumference and a fasting morning blood sample drawn to assess cortisol, insulin, glucose, glycosylated hemoglobin, fibrinogen, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, and triglycerides. A cumulative risk score was created from these physiological measures and waist circumference. Information on parent education and household income was obtained from a parent in a separate survey. Generalized estimating equation models were used to assess the association of parent education to the risks and the cumulative risk score adjusting for age, gender, and race., Results: Lower parent education was associated with higher insulin, higher glucose, greater insulin resistance, higher LDL cholesterol, lower HDL cholesterol, higher waist circumference, and higher body mass index (p <.05 for all), but not cortisol, fibrinogen, glycosylated hemoglobin, or triglycerides in adjusted analyses. Cumulative risk scores ranged from 0 to 7 and were highly skewed; the median risk score was 1. A total of 7.4% had risk scores of 4 or more. Lower parent education was also associated with higher cumulative risk score (p <.001) and this association was maintained after adjustment for body mass index. Risk scores were highest, on average, among those with insulin levels greater than 1 standard deviation above the mean (mean risk score = 3.2, standard error = 0.18, median = 3)., Conclusion: Lower parent education is associated with multiple metabolic risks and cumulative risk in adolescents, suggesting that there is a strong intergenerational transfer of education's influence on cardiovascular health. Our data imply that regulation of insulin may be a key factor underlying the influence of lower parent education on cardiovascular health early in the life course.

Purpose: Youth with type 1 diabetes mellitus (T1DM) are at risk of cardiovascular disease (CVD). We evaluated if metformin or statin use was associated with surrogate measures of improved CVD. Methods: We included participants from the SEARCH observational study. Participants treated with insulin plus metformin (n=42) or insulin plus statin (n=39) were matched with 84 and 78 participants, respectively, treated with insulin alone. Measures of arterial stiffness obtained were pulse wave velocity (PWV), augmentation index (AI75), and heart rate variability as standard deviation of the normal-to-normal interval (SDNN) and root mean square differences of successive NN intervals (RMSSD). Results: CVD measures were not significantly different among participants on insulin plus metformin versus those on insulin alone: PWV (5.9±1.0 m/sec vs. 5.8±1.5 m/ sec, P=0.730), AI75 (1.8 [-6.0 to 8.0] vs. -2.4 [-10.7 to 3.8], P=0.157), SDNN (52.4 [36.8– 71.1] m/sec vs. 51.8 [40.1–74.9] m/sec, P=0.592), and RMSSD (43.2 [29.4–67.6] vs. 47.4 [28.0–76.3], P=0.952). CVD measures were not different for statin users versus nonusers: PWV (5.7±0.8 m/sec vs. 5.9 ±1.1 m/sec, P=0.184), AI75 ( -4.0 [-9.5 to 1.7] vs. -6.7 [-11.3 to 5.7], P=0.998), SDNN (54.6 [43.5–77.2] m/sec vs. 63.1 [44.2–86.6] m/sec, P=0.369), and RMSSD (49.5 [31.2–74.8] vs. 59.2 [38.3–86.3], P=0.430). Conclusion: We found no associations of statin or metformin use with surrogate measures of CVD. Future prospective pediatric clinical trials could address this issue. [ABSTRACT FROM AUTHOR]

Cavallo A, Daniels SR, Dolan LM, Khoury JC, Bean JA. Blood pressure response to melatonin in type 1 diabetes. Diminished decline of blood pressure at night has been associated with increased risk of cardiovascular disease. Exogenous melatonin given to healthy normotensive adults reduces blood pressure. We hypothesized that melatonin increases the decline of blood pressure during sleep in normotensive adolescents with type 1 diabetes. Eleven normotensive normoalbuminuric patients with type 1 diabetes of 7.0 ± 3.5 yr duration and 10 healthy controls aged 14–18 yr participated in a randomized placebo-controlled double-blind crossover study of 5 mg melatonin for 1 wk, with a 1-wk washout. Blood pressure was measured every 20 min for 24 h by an ambulatory device on the day before and on the last day of each treatment. Sleep measures were recorded by a diary and a wrist activity meter. Blood pressure measures were grouped by 24 h, sleep, and wake periods. Statistical analysis used sleep duration, number of awakenings, and treatment sequence as covariates for the blood pressure comparisons by treatment. In the patients with type 1 diabetes, the decline in diastolic blood pressure during sleep was significantly greater on melatonin (17.8 ± 4.4 mmHg) than on placebo (16.0 ± 3.0 mmHg, p < 0.01). No significant drug effect was present in the controls. No significant side effects were noted. Melatonin amplifies the nocturnal decline in diastolic blood pressure in patients with type 1 diabetes. We propose that dose–response studies of short- and long-acting preparations of melatonin be conducted and that melatonin be considered in trials of prevention of hypertension in type 1 diabetes. [ABSTRACT FROM AUTHOR]

Background Proprotein convertase subtilisin/kexin type 9 ( PCSK9) is a key regulator of low-density lipoprotein cholesterol and cardiovascular disease risk, and is an emerging therapeutic target. Objective We compared serum PCSK9 levels in young adults, with and without type 2 diabetes. Subjects and methods Cross-sectional analysis was conducted in a cohort, aged 15 to 26 years, in Cincinnati, OH, from 2005 to 2010. Serum PCSK9 levels were measured in 94 youth with type 2 diabetes, 93 obese control subjects, and 99 lean control subjects. Correlative analyses were conducted to determine significant covariates of PCSK9 by group and sex, and multivariate linear regression models were used to study the independent determinants of PCSK9. Results In females, PCSK9 levels were significantly increased in the obese and type 2 diabetes subjects relative to the lean controls ( P < .01). Moreover, PCSK9 was positively correlated with multiple metabolic parameters in females: body mass index, systolic blood pressure, fasting glucose, fasting insulin, and C-reactive protein levels ( P ≤ .02). In males, PCSK9 levels were decreased overall compared with females ( P = .03), and did not differ between the lean, obese, or type 2 diabetes groups. Conclusions Obesity and type 2 diabetes were associated with significantly higher levels of PCSK9 in young women, but not in young men. These data suggest that sex could modify the effects of obesity and diabetes on PCSK9 in young adults. [ABSTRACT FROM AUTHOR]

Aims: We examined the association between inflammation and progression of arterial stiffness in a population of youth with type 1 diabetes (T1D).Methods: A total of 287 youth with T1D (median age 13 years) from SEARCH CVD, an ancillary study to the SEARCH for Diabetes in Youth, were included. Markers of inflammation (CRP, IL-6, fibrinogen, leptin, and adiponectin) and measures of pulse wave velocity (PWV) of the arm (PWV-R), trunk (PWV-T), and lower extremity (PWV-LE) were measured at baseline. Measures of PWV were repeated approximately five years later.Results: PWV-R (0.50 m/s), PWV-T (0.65 m/s), and PWV-LE (1.0 m/s) significantly increased over the follow-up (p < 0.001 for each). A significant interaction was found between waist circumference and fibrinogen (p = 0.036) on the progression of PWV-T, suggesting that fibrinogen is more strongly associated with PWV progression in lean participants.Conclusions: Improved understanding of adiposity, inflammation, and functional changes in the vascular system in patients with T1D is crucial. [ABSTRACT FROM AUTHOR]