Preclinical Noninvasive Markers of Atherosclerosis in Children andAdolescents with Type 1 Diabetes Are Influenced by Physical Activity

Beatrice Trigona, MOM, Yacine Aggoun, MD, Albane Maggio, MD, Xavier E. Martin, MS, Laetitia M. Marchand, MS,

Maurice Beghetti, PD, and Nathalie J. Farpour-Lambert, MD

Objectives To measure preclinical noninvasive markers of atherosclerosis in youth with type 1 diabetes (T1DM),and to determine their associations between physical activity level and cardiorespiratory fitness (maximal oxygenT1DM Type 1 diabetes mellitusI lial function is now considered an early sign of atherosclerosis in children, which precedes the atherosclerotic plaque for-mation and has therefore become an important noninvasive marker of cardiovascular risk,4,5 particularly in those withT1DM.6,7

The structure and function of large arteries can be studied by noninvasive high-resolution ultrasonograhy. The increase ofthe intima-media thickness (IMT) is measured at the right common carotid artery and is considered an early sign of arterial wallremodeling. The flow-mediated dilation (FMD) of the brachial artery, a marker of endothelial cell function, is assessed by mea-suring the arterial diameter response to increased flow. Arterial dilation occurs mainly as the result of endothelial release ofnitric oxide (NO).8 In youth with T1DM, previous studies have demonstrated a premature thickening of the arterial IMTand impaired endothelial function after a disease duration as short as 6 months.6,7,9-12

The benefits of physical activity in the prevention and treatment of CVD have been very well described in adults.13 In chil-dren, physical activity improves blood pressure, lipid profile, and body fatness,14 which are important determinants of athero-sclerosis. Enhanced blood flow in arteries induces a vascular stress that results in liberation of NO during but also afterexercise.15 This mechanism lowers vascular resistance and improves FMD. In adult patients with T1DM, a recent study hasshowed improvement in endothelial function after a bicycle training program; however, changes disappeared 8 months aftertraining cessation.16

From the Pediatric Cardiology Unit, Department of Childand Adolescent, University Hospitals of Geneva andUniversity of Geneva , Geneva, Switzerland

Supported by the Mimosa Fellowship of the PediatricDepartment, University of Geneva. The authors declareno conflicts of interest.

BP Blood pressure

CVD Cardiovascular diseases

FMD Flow-mediated dilation

IMT Intima-media thickness

NO Nitric oxide

NTGMD Nitroglycerin-mediated dilation

SLPA Sedentary-to-light physical activityt is well known that atherosclerotiwith cardiovascular diseases (CVDc process begins in childhood1 and is acceleraconsumption [VO2max]).Study design This was a cross-sectional study including 32 patients with T1DMand 42 healthy subjects aged 6 to17 years. Main outcome measures included arterial flow-mediated dilation (FMD) and intima-media thickness withhigh-resolution ultrasonography; physical activity by accelerometer (valid 26 patients with T1DM, 35 healthy sub-jects) and VO2max.Results Compared with healthy control subjects, patients with T1DM had higher intima-media thickness (mean0.50 mm [0.48-0.52, 95% CI] vs 0.48 [0.47-0.49], P = .02) and reduced FMD (4.9% [4.1%-5.7%] vs 7.3 [6.4-8.1],P = .001), VO2max (45.5 mL/kg/min [43.0-48.0] vs 48.7 [46.7-50.6], P # .001), total (567.1 [458.6-675.6] vs 694.9[606.6-883.2] counts per minute, P = .001) and moderate-to-vigorous physical activity. Patients with T1DM whodid more than 60 min/day1 of moderate-to-vigorous physical activity had similar FMD compared with relatively in-active healthy subjects, but not as high as active control subjects.Conclusion Youth with T1DM present early signs of atherosclerosis, as well as low physical activity level and car-diorespiratory fitness. Endothelial function is enhanced in patients who practice more than 60 min/day1 ofmoderate-to-vigorous physical activity. (J Pediatr 2010;157:533-9).

See editorial, p 523 and relatedarticles, p 540, and p 547

ted in patients with type 1 diabetes (T1DM),) being the major cause of morbidity and death in this population.2,3 Impaired endothe-0022-3476/$ - see front matter. Copyright 2010 Mosby Inc.All rights reserved. 10.1016/j.jpeds.2010.04.023

VO2max Maximal oxygen consumption

533

assessed by use of a validated self-assessment questionnaire.The brachial resting blood pressure (BP) was measured 3

THE JOURNAL OF PEDIATRICS www.jpeds.com Vol. 157, No. 4times at a 2-minute interval after 10 minutes of rest withthe patient in the supine position with the back supported,by use of a validated automated device (Colin Press-MateBP 8800C; Colin Medical Instruments Corporation, San An-tonio, Texas). The cuff covered at least two thirds of thelength of the upper arm, with the length of the bladder wrap-ping the arm circumference.The first aim of this study was to assess preclinical nonin-vasive markers of atherosclerosis in children and adolescentswith T1DM, compared with healthy subjects. The second aimwas to determine which volume and intensity of physical ac-tivity is beneficial for cardiovascular health in this popula-tion. Finally, we aimed to evaluate the relationship betweencardiorespiratory fitness and markers of atherosclerosis.

Methods

This was a cross-sectional study including 32 children andadolescents with T1DM (World Health Organization crite-ria) and 42 healthy subjects aged 6 to 17 years old. Physicalactivity data by accelerometer were obtained in 26 patientswith T1DM and 35 healthy subjects.Patients with T1DM were recruited in the Pediatric Endo-

crinology and Diabetology Unit of the University Hospitalsof Geneva and eligible subjects (32 of 45 patients) were in-vited to participate in the study. The disease duration wasat least 1 year. Subjects with T1DM were excluded from thestudy if they (1) had no known kidney and clinical cardiovas-cular complication; or another chronic disease; (2) had an or-thopedic disease or injury limiting physical activity; (3) tookany medications, which may influence cardiovascular func-tion or lipid metabolism.Healthy subjects were recruited from peers of children

with T1DM or from local schools. Subjects were asked to par-ticipate in the study if they met each of the following eligibil-ity criteria: (1) good health and no recent (previous 2 years)systemic illness; (2) no known history of chronic disease; (3)no orthopedic disease or injury limiting physical activity; (4)no medications, which might influence cardiovascular func-tion, lipid, or glucose metabolism. The study protocol wasapproved by the Mother and Child Ethics Committee ofthe University Hospitals of Geneva, and a written informedconsent was obtained from both parents and child.At baseline, participants visited the Childrens Hospital

from 8 to 12 A.M. The personal and medical history was as-sessed before testing, and the dose of insulin was calculatedin children with T1DM (U/kg/d). Subjects with diabetesand healthy subjects underwent identical testing. Observerswere blinded to subject grouping.Wemeasured bodymasswith light clothes at the nearest 0.1

kg with an electronic scale (Seca 701; Seca GmbH, Hamburg,Germany) and stature to the nearest 0.1 cmwith aHarpendenstadiometer. We calculated body mass index as body mass/stature squared (kg/m2). The pubertal stage (Tanner) was

17534Noninvasive measurements of arterial geometry and func-tion were performed with a real-time B-mode ultrasound im-ager (VingMed CFM800C system; VingMed Sound A/S,Horten, Norway) with a 10-MHz linear high-resolution vas-cular probe as previously described.18 Imaging of the intima-media thickness (IMT) was performed in the far wall of theright common carotid artery 2 to 3 cm proximal to the bifur-cation. The 2 parallel echogenic lines (double-line pattern),corresponding to the lumen-intima and media-adventitia in-terfaces defining the IMT, were obtained in the right carotidartery in all subjects. The correct IMT image was frozen inend-diastole by electrocardiography R-triggering, transferredto a computer, digitized into 640 580 peak cells with 256grey levels, and stored for offline analysis. All offline mea-surements of IMT were performed by the same reader(Y.A) without knowing subject group assignment and usingan automated computerized program (Iotec System; IodataProcessing, Paris, France).18 Average IMT was calculated asthe mean value of a great number of local IMTmeasurementsperformed every 100 mm along at least 1 cm of longitudinallength of the artery. The measurement field included specif-ically the far wall IMT and drew automatically a rectangle ofat least 1 cm in length in the longitudinal axis of the vesseland of at least 0.3 cm in width, perpendicular to the wall.The computerized program of measurement located the 2 in-terfaces (lumen-intima and media-adventitia) by discrimi-nating changes in gray levels inside the rectangle.Noninvasive assessment of endothelium-dependent

dilation (flow-mediated dilation [FMD]) and endothelium-independent dilation (in response to 300 mg sublingualnitroglycerin [NTGMD]) of the right brachial artery wereperformed by the same echocardiographic vascular linearprobe as previously described.19 After baseline measure, weassessed the dilation of the right brachial artery in responseto increased flow and nitroglycerin, and FMD and NTGMDwere calculated as absolute and percentage maximum in-crease in vessel size from baseline.Physical fitness was measured as maximal oxygen con-

sumption (VO2 max) assessed by direct gas analysis (VmaxSpectra; Viasys Healthcare, Hong Kong, Republic of China)during a multistage treadmill test (Marquette 2000; GEHealthcare, Milwaukee, Wisconsin).20 After a sufficientwarm-up, the subject ran on the treadmill at a constantspeed, which varied by age and physical capacity (from 5 to9 km/h). The grade of the treadmill was increased by 2.5% ev-ery 2 minutes until the subject was exhausted and reached thepediatric VO2 max criteria: clinical signs of exhaustion and:heart rate >95% predicted maximal heart rate for age, or re-spiratory exchange ratio > 1.0, or oxygen plateau < 2 mL/kg/min increase in VO2 with increasing work rate.

21 Because thistest can provoke hypoglycemia, we measured capillary glu-cose concentration 20 minutes before and 30 minutes aftertesting. A supplement of glucose 15 to 30 g was given if thevalue was below 10 mmol/L. If the value was above 15mmol/L1, a urinary test was done to exclude the presenceof ketones, which is a contraindication to exercise. None ofthe patients had ketones.Trigona et al

ure, physical activity variables were adjusted for age, and aer-obic fitness was adjusted for age and sex. To compare thepercentage of moderate-to-vigorous physical activity amonggroups, we used a non-parametric test (Mann-Whitney) asthe distribution was not normal. The associations betweenvascular variables (IMT and FMD) and physical activity vari-ables, cardiovascular fitness, age, sex, and pubertal stage wereassessed with univariate and multivariate linear regressionanalysis. Differences were considered significant if P < .05.

Results

Physical characteristics and lipid concentrationsof subjects arereported in Table I. Groups were not intentionally matched,but there were no differences among groups for age, sex,pubertal stage, body mass index, and stature. The body massindex was significantly higher in patients with T1DM; 4patients with diabetes were overweight, but none wereobese.24 Lipid concentrations were not significantly differentamong groups and, as expected, patients with diabetes hadsignificantly higher HbA1c level than control subjects. Meandisease duration was 5.1 years (4.0-6.1, CI 95%), dailyinsulin dose was 0.8 U/kg/d (0.7-0.9), and the previous 12-month HbA1c level was 8.5% (8.0%-8.9%). Children withT1DM had significantly lower VO2max (67%), totalphysical activity count (618%), and moderate-to-vigorous physical activity (631%), whereas they hadhigher SLPA (6 +17%) compared with healthy subjects.

October 2010 ORIGINAL ARTICLESObjective measure of physical activity level was obtainedusing a uniaxial accelerometer (ActiGraph MT 6471; Acti-Graph, Pensacola, Florida). The monitor was set on a 1-min-ute cycle, at the end of which the sum was stored in thememory. The monitor was attached at the right hip with anelastic belt and was worn all day long except during bathingor swimming. This device has demonstrated good reliabilityin the pediatric population.22 The Excel software was used fordata reduction and further analysis. Only periods from awak-ening to sleep time were analyzed. For this study, zero activ-ity periods of 20 minutes or longer were interpreted as beingdue to unworn accelerometers and were removed from thetotal activity count. Data were expressed as total activitycounts per registered time (counts/min). We used cut-offsof different intensity levels for children as described by Eke-lund et al,23 where sedentary-to-light physical activity (SLPA)was defined as counts per minute below 1999 and moderate-to-vigorous physical activity above 2000. Subjects data weretaken into account if total counts per minute were under4000 to exclude artifacts, and if the monitor was worn duringat least 4 days, including at least 2 week days and 1 weekendday. In this study, 26 of 32 subjects with T1DM and 35 of 42healthy children fulfilled the above criteria. The monitor wasworn for a mean of 7.4 1.4 days, the days being similaramong groups.Blood samples were collected at 8 A.M. via venipuncture af-

ter a 10-hour overnight fast, before insulin injection in chil-dren with T1DM. They were analyzed in our laboratorywithin 2 hours after venipuncture. Total cholesterol (TC),high-density lipoprotein cholesterol (HDL-C), and triglycer-ide levels (mmol/L1) were determined by standard auto-mated techniques (Synchron LX20). Low-densitylipoprotein cholesterol (LDL-C) was calculated with the Frie-dewalds formula. The intraassay and interassay coefficientsof variation were 1.1% to 3.6% for TC, 2.0% to 6.8% forHDL-C, and 2.3% to 4.6% for triglycerides, respectively. Cal-ibration was performed every 14 days for TC and triglyceridesand every 30 days for HDL-C with the Multi Synchron (Syn-chron, Republic of Singapore).Glycosylated hemoglobin (HbA1c,%) was determined

with a quantitative automotative technique (SynchronLX20; Synchron). The intraassay and interassay coefficientsof variation were 2.8% to 2.7%, respectively. Calibrationwas performed every 30 days with the HbA1c Synchron. Be-cause patients visit the diabetes clinic every 3 months, we alsocalculated the mean past 12 months HbA1c level (DCA 2000;Bayer AG, Zurich, Switzerland). Calibration was done oncea month with a specific DCA calibration set.Statistical analyses were performed with the statistical soft-

ware program SPSS version 15.0 (SPSS, Inc., Chicago, Illi-nois). Data were screened initially for normal distribution.Flow-mediated dilation was transformed and successfullynormalized with the square root of the value. Results are ex-pressed as means and 95% confidence intervals. Statisticaldifferences between groups were determined with indepen-dent Student t test, c2 test, or analysis of covariance whenneeded: mean blood pressure was adjusted for sex and stat-Preclinical Noninvasive Markers of Atherosclerosis in Children anPhysical ActivityTable I. Physical characteristics and blood lipidconcentrations in children with T1DM and healthycontrol subjects

Variables T1DM (n = 32) Healthy (n = 42)P

value

Age (y) 11.5 (10.2-12.8) 10.7 (9.6-11.8) .32Sex (no. of female) 15 (47%) 25 (60%) .28Pubertal stage (no. of cases

per stage, from 1 to 5)16/3/3/5/5 29/0/3/7/3

Body mass (kg) 43.1 (36.9-49.2) 38.4 (33.6-43.1) .22Stature (m) 1.46 (1.40-1.53) 1.45 (1.40-1.51) .76BMI (kg/m) 19.2 (17.9-20.4) 17.4 (16.5-18.4) .03VO2 max (mL/kg/min) 45.5 (43.0-48.0) 48.7 (46.7-50.6)

In all subjects (n = 61 with valid accelerometer data), weperformed multivariate linear regression analysis includingFMD or IMT as dependent variables, and disease, age, puber-tal stage, and physical activity variables (total count,moderate-to-vigorous physical activity, or SLPA). We foundthat T1DM (beta coefficient = -0.3, P = .004) and physical ac-tivity count (beta coefficient = 0.4, P = .001) were indepen-dently associated with FMD. We observed a similarrelationship for moderate-to-vigorous physical activity(beta coefficient = 0.3, P = .006) or SLPA (beta coefficient=0.3, P = .011), but pubertal stage was also a significant de-terminant (beta coefficient =0.3, P = .03) of FMD.We then

the 95% confidence interval. *Significantly lower than activesubjects with T1DM and active healthy subjects (> 60minutesof moderate-to-vigorous physical activity), P < .05.

THE JOURNAL OF PEDIATRICS www.jpeds.com Vol. 157, No. 4The right brachial artery baseline diameter was not signif-icantly different between groups (Table II). Children withT1DM had higher diastolic BP and IMT, whereas they hadlower FMD and NTGMD than control subjects.Prepubertal children (Tanner stage 1) with T1DM had alsosignificantly reduced FMD (mean 5.2% [4.0%-6.6%, CI95%] vs 8.2% [7.4%-9.0%]), P < .001.We divided the diabetic and healthy subjects (separately)

into 2 groups, respectively: (1) equal or more than 60 min-utes per day of moderate-to-vigorous physical activity; and(2) less than 60 minutes per day of moderate-to-vigorousphysical activity (Figure). In children with T1DM, wefound a significantly lower FMD in the inactive comparedwith the active group (4.2% [3.4%-5.0%] vs 6.2% [3.9%-8.4%]; P = .02). Interestingly, similar differences werefound among inactive and active healthy subjects (5.3%[4.3%-6.3%] vs 8.9% [7.8%-10.0%], P # .001). Inaddition, FMD was not significantly different betweenactive patients with T1DM and inactive healthy children(P = .44), but it remained significantly lower comparedwith active healthy subjects (P = .02).We performed the same analysis after excluding the 4 over-

weight subjects with T1DM and obtained similar results forphysical characteristics, physical activity level, VO2max,blood pressure and vascular measures. Triglyceride concen-trations were significantly higher in healthy controls thanT1DM (P = .007); however, all values were within the normalrange.We investigated the within-group relationships between

Table II. Blood pressure, vascular reactivity and intima-media thickness in children with T1DM and healthycontrol subjects

VariablesT1DM

(n = 32)Healthy(n = 42) P value

Systolic BP (mm Hg) 108.3 (104.1-112.5) 109.0 (106.3-111.7) .36Diastolic BP (mm Hg) 57.6 (54.7-60.5) 52.8 (50.9-54.8) .003Baseline RBA

diameter (mm)2.74 (2.57-2.92) 2.74 (2.62-2.87) .99

IMT (mm) 0.50 (0.48-0.52) 0.48 (0.47-0.49) .02FMD (%) 4.91 (4.14-5.68) 7.28 (6.44-8.12)

116 min/day in 9-year-olds and 88 minutes in 15-year-olds in the forth quintile).31 The mean difference between

October 2010 ORIGINAL ARTICLESthe third (high CVD risk) and the forth quintile (low CVDrisk) was 24 minutes in 9-year-olds and 18 minutes in 15-year-olds. In patients with T1DM, physical activity levelmay be reduced because of fear of hypoglycemic events, fre-quent capillary glucose measurements, or difficulty of adjust-of FMD.We then repeated the analysis including VO2max in-stead of physical activity, adjusting for age and sex, and didnot find any relationship with FMD or IMT. Only T1DM(beta coefficient = 0.3, P = .011) was independently associ-ated with IMT.

Discussion

Endothelial variables were impaired even before puberty inyouth with T1DM, with no evidence of clinical cardiovascu-lar complications or dyslipidemia (annual screening), and anHbA1c level of 8.5% 1.0% (target value 5% to 8%). Previ-ous studies have demonstrated early modifications of endo-thelial function, which is considered the first sign ofatherosclerosis.6,7 Singh et al6 reported reduced FMD in 31adolescents with diabetes (mean age 15 years) with a durationof disease of 6 years and no known complications. Othersconfirmed these findings in a cohort of 45 patients (meanage 11 years).7 Endothelial dysfunction in T1DM appearsto be due to reduced local NO concentrations caused bysuperoxide-mediated NO destruction.25

In this study, we also found increased IMT (between groupdifference +0.02 mm), even in absence of dyslipidemia, sug-gesting that the arterial wall remodeling may be a conse-quence of hemodynamic stress, as previously described.26,27

In adults, increased IMT and impaired FMD are associatedwith cardiovascular risk factors and coronary atherosclero-sis.28,29 A meta-analysis of 8 trials showed that a carotidIMT increment of 0.1 mm increases the risk of myocardial in-farction by 10% to 15% and the risk of stroke by 13% to 18%,after adjusting for age and sex.30 We may therefore hypothe-size that an augmentation of IMT by 0.02 mm (20% of 0.1mm) in youth with T1DM, compared with healthy controlsubjects, may result in a higher risk of cardiovascular diseaselater in life. These results highlight the importance to opti-mize the management of T1DM during growth, particularlyby motivating and supporting patients to practice regularphysical exercise.Reduced physical activity during childhood is an impor-

tant risk factor for CVD. International recommendations in-dicate that school-aged children should do at least 60minutesof moderate-to-vigorous physical activity per day to improvetheir cardiovascular health, reduce adiposity, and increasebone mineral density and well-being.14 In The EuropeanYouth Heart Study including 1732 children and adolescents,Andersen et al31 demonstrated that the first to the third quin-tile of physical activity had a raised CVD risk (odds ratiofrom 3.3 to 2.5) compared with the most active quintile(mean time spent in moderate-to-vigorous physical activity

1Preclinical Noninvasive Markers of Atherosclerosis in Children anPhysical Activitying insulin doses.32 In our study, total physical activity countand the time spent in moderate-to-vigorous physical activitywere significantly lower in subjects with T1DM than healthychildren (mean difference 24 minutes). Moreover, almosttwo third of patients with diabetes were below the minimaltime of moderate-to-vigorous physical activity recommen-ded (

THE JOURNAL OF PEDIATRICS www.jpeds.com Vol. 157, No. 4health. n

We thank theMimosa Fellowship of the Pediatric Department, Univer-sity of Geneva, which supported financially this project. We also thankthe subjects for volunteering for the study, as well as Valerie Schwitzge-bel, Emmanuelle Golay, Francois Herrmann, and the nurses of the pe-diatric policlinic for their assistance.

Submitted for publication Sep 22, 2009; last revision received Mar 16, 2010;

accepted Apr 13, 2010.

Reprint requests: Nathalie Farpour-Lambert, MD, Pediatric Cardiology Unit,

Department of Child and Adolescent, University Hospitals of Geneva, 6, rue

Willy-Donze, 1211 Geneva 14, Switzerland. E-mail: nathalie.farpourlambert@

hcuge.ch.

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34. Fukai T, SiegfriedMR, Ushio-Fukai M, Cheng Y, Kojda G, Harrison DG.

itric

ular

evels

8.

and

nary

ization after birth.We also now know that both intrauterine and postnatal growth restriction of the preterm infant can

al outcomes. We look forward to continued progress.

October 2010 ORIGINAL ARTICLESPreclinical Noninvasive Markers of Atherosclerosis in Children anPhysical ActivitySailaja Ghanta, MDJames F. Padbury, MD

Department of PediatricsWomen & Infants Hospital of Rhode Island

Warren Alpert Medical School at Brown UniversityProvidence, Rhode Island10.1016/j.jpeds.2010.04.014prebiotics, probiotics, and long-term neurodevelopmentresult in long-term cardiovascular and metabolic disorders, as well as impaired behavioral, motor, and cognitive out-comes. Current studies are focusing on new fortifiers, the role of the fatty acids DHA and ARA, alternative fat sources,235-41.

orenz MWMH, Bots ML, Rosvall M, Sitzer M. Prediction of clinical

ardiovascular events with carotid intima-media thickness: A systemic

eview and meta-analysis. Circulation 2007;115:459-67.

ndersen LB, Harro M, Sardinha LB, Froberg K, Ekelund U, Brage S,

t al. Physical activity and clustered cardiovascular risk in children:

cross-sectional study (The European Youth Heart Study). Lancet

006;368:299-304.

Regulation of the vascular extracellular superoxide dismutase by n

oxide and exercise training. J Clin Invest 2000;105:1631-9.

35. Roche DM, Edmunds S, Cable T, Didi M, Stratton G. Skin microvasc

reactivity in childrenandadolescentswith type1diabetes in relation to l

of physical activity and aerobic fitness. Pediatr Exerc Sci 2008;20:426-3

36. Sato S, Makita S, Uchida R, Ishihara S, Majima M. Physical activity

progression of carotid intima-media thickness in patients with coro

heart disease. J Cardiol 2008;51:157-62.

50 Years Ago in THE JOURNAL OF PEDIATRICS

The Feeding of Prematurely Born Infants A Critique of Current StatusDavidson M. J Pediatr 1960;57:604-10.

M.J. Davidson reviewed the evidence supporting enteral nutrition for premature infants. Although there were stillsignificant areas of debate that needed clarification and further research, this report provided a review of morethan two decades of direct clinical experience in nutritional support for the smallest infants of their times. They usedempiric trials to identify the best formula composition for prematurely born infants. Importantly, they defined think-ing in terms of free water, protein, carbohydrate, and fats. Perhaps one of Davidsons most important points was iden-tifying the need to define the terms adequate and optimal before we can proceed with research testing them.Today, most agree that optimal nutrition of the preterm infant should achieve a postnatal growth rate and compo-

sition of weight gain approximating that of the normal fetus of the same gestational age. We have gained insight intothe composition of enteral feedings required to achieve this goal. We recognize the benefits of human milk, albeitneeding some discrete supplementation. We have developed humanized formulas with respect to protein contentand composition, such as whey-to-casein ratios. Protein intake between 3.5 to 4 g/kg/d is now recommended to pro-mote weight gain and is well tolerated. Fat requirements have been shown to be 5 to 7 g/kg/d. Preterm infants have noproblems absorbing the saturated fats of human milk or the medium-chain triglycerides and polyunsaturated long-chain triglycerides of formula. The carbohydrate recommendation is 10 to 14 g/kg/d.As the field of neonatology continues to make significant advances that are allowing smaller and earlier infants to

survive, the need to answer Davidsons challenges is more important than ever. Although we have succeeded indefining a goal for optimal nutrition, we still have room for improvement. Despite increased understanding of therequired composition of feedings, many preterm infants experience postnatal growth restriction during the hospital-d Adolescents with Type 1 Diabetes Are Influenced by 539

Preclinical Noninvasive Markers of Atherosclerosis in Children and Adolescents with Type 1 Diabetes Are Influenced by Physical ActivityMethodsResultsDiscussionReferences