Longitudinal studies in adult populations, such as the

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1 Relation of Weight and Rate of Increase in Weight During Childhood and Adolescence to Body Size, Blood Pressure, Fasting Insulin, and Lipids in Young Adults The Minneapolis Children s Blood Pressure Study Alan R. Sinaiko, MD; Richard P. Donahue, PhD; David R. Jacobs, Jr, PhD; Ronald J. Prineas, MD, PhD Background Weight gain is of concern during early development because adult obesity and its cardiovascular consequences appear to have their origins during childhood. Insulin resistance is known to be related to obesity. Thus, weight gain beginning in childhood may influence the development of insulin-induced cardiovascular risk during adulthood. Methods and Results We monitored 679 individuals from years of age with repeated measures of height, weight, and systolic blood pressure (SBP) until years of age, when blood samples were obtained for measurements of insulin and lipids. Initial childhood weight, body mass index (BMI), and height were significantly correlated with young adult weight, BMI, and height and with fasting insulin, lipids, and SBP. The increases in weight and BMI but not height during childhood were significantly related to the young adult levels of insulin, lipids, and SBP. Conclusions These data suggest that weight gain in excess of normal growth during childhood is a determinant of adult cardiovascular risk. The finding in multiple linear regression analysis that weight gain during childhood rather than the childhood weight at 7.7 years of age is significantly related to young adult risk factors suggests that a reduction in weight gain could reduce subsequent levels of cardiovascular risk. (Circulation. 1999;99: ) Key Words: insulin obesity lipids blood pressure children Longitudinal studies in adult populations, such as the Framingham study, 1 have shown that weight is strongly associated with cardiovascular risk. 2,3 These findings are particularly relevant to early development because adult obesity and its cardiovascular consequences appear to have their origins during childhood. 4 Young children with obese parents tend to become obese adults. 5 Obesity in older children is a significant predictor of adult obesity independent of parental weight 5 and is associated with a significant increase in death during adulthood from coronary heart disease. 6 Offspring of parents with coronary heart disease are generally overweight beginning in childhood and tend to have higher levels of lipids and fasting insulin as adults. 7 The mechanisms linking overweight to cardiovascular risk are not clearly defined. However, insulin resistance is known to be strongly related to obesity, 8,9 and the association of obesity with the cardiovascular risk factors of hyperlipidemia and hypertension form the well-recognized insulin resistance syndrome A direct association between weight and insulin resistance has been reported in children, as has the association of insulin resistance with lipids 16,17 and blood pressure. 16,18,19 It has been suggested that the rate of weight gain during childhood may be a more significant factor for adult cardiovascular risk than an isolated measurement of weight at any single point in time. 20 From this and the studies noted above, it seems reasonable to propose that weight gain, beginning in childhood and continuing through the first 2 decades of life, may influence the development of insulin-induced cardiovascular risk that leads ultimately to clinical adverse events in adulthood. The present study addresses this issue by assessing the effect of body size and change in body size during childhood and adolescence on the cardiovascular risk factors of fasting insulin, lipids, and systolic blood pressure (SBP) in young adulthood. Methods The Minneapolis Children s Blood Pressure Study was started in the 1977 to 1978 school year with blood pressure screening of first through third grade children (99% of all children enrolled in those grades) in the Minneapolis public schools. After this screening, Received July 15, 1998; revision received November 17, 1998; accepted December 7, From the Department of Pediatrics, University of Minnesota Medical School (A.R.S.), and Division of Epidemiology, University of Minnesota School of Public Health (D.R.J., R.J.P.), Minneapolis, Minn, and Department of Social and Preventive Medicine, SUNY, Buffalo, NY (R.P.D.). Correspondence to Alan R. Sinaiko, MD, University of Minnesota Medical School, 420 Delaware St SE, Box 491 Mayo, Minneapolis, MN Sinai001@maroon.tc.umn.edu 1999 American Heart Association, Inc. Circulation is available at

2 1472 Childhood Weight and Young Adult Risk Factors a cohort was selected for long-term evaluation as follows: all children from the top and bottom 5 percentiles of the SBP distribution, 50% of the remaining black children, 1 of 9 of the remaining white children, and all others. There were no exclusion criteria. Written consent for longitudinal evaluation was obtained from 1207 of the 2641 children in the selected cohort. 21,22 The 1207 children were examined approximately twice yearly through their grade school and junior high school years and once yearly during high school. At each examination, measurements of height, weight, and blood pressure were obtained by trained examiners according to a standardized protocol. Blood pressure was measured 2 times with participants in the seated position, and the average was used for all analyses. A post high school (PH) examination was conducted within 2 years of graduation from high school, at which time blood pressure and anthropometric data were obtained from 817 participants of the original group of This group of 817 was recontacted 5 years after the PH visit, and 679 were reexamined in 1993 to 1995 (age, years), forming the sample for the present study. In addition to the anthropometric and blood pressure data, a fasting blood sample was obtained at the 1993 to 1995 visit for insulin, cholesterol, HDL cholesterol (HDL-C), triglycerides, and LDL cholesterol (LDL-C). Childhood is defined in this study as the period from examination 1 (age, years) through examination 9 (age, years); the mean number of observations per participant was Adolescence is defined as the period from examination 10 (age, years) through examination PH (age, years); the mean number of observations per participant was To determine the rate of increase (slope) for weight, body mass index (BMI), or height during the childhood and adolescent periods of observation, simple linear regression was used to fit a straight line to the respective measurements over time for each individual. Then, the individual slopes were used in regression analyses in which each of the risk factors (ie, fasting insulin, lipids, and SBP) was taken as the dependent variable and the slopes of the respective childhood or adolescence weight, BMI, or height measurements were taken as the independent variable. Serum lipids were measured by the University of Minnesota Hospital laboratory on a Cobas FARA. Cholesterol was determined by a standard enzymatic-cholesterol oxidase-based method; HDL-C was determined after precipitation on non-hdl lipoproteins with magnesium/dextran precipitating reagent; triglycerides were determined by use of a standard glycerol-blanked, enzymatic triglyceride method. LDL-C was calculated by the Friedewald equation. Fasting insulin was measured with a radioimmunoassay kit (Equate RIA, Binax Corp). Data were analyzed by ANOVA, simple linear regression, multiple linear regression analysis, and Pearson correlation analysis. All data are expressed as mean SEM. Percentiles for obesity were determined from recently published data for children 23 and from the NIH Consensus Development Conference Statement. 24 TABLE 1. Participant Data at 1993 to 1995 Examination Male Subjects (n 356) Female Subjects (n 323) Age, y Ethnicity White Black Native American 19 9 Other Height, cm Weight, kg BMI, kg/m Waist-to-hip ratio Triceps skin fold, mm SBP, mm Hg Fasting insulin, pmol/l Fasting glucose, mg/dl Cholesterol, mmol/l Triglycerides, mmol/l LDL-C, mmol/l HDL-C, mmol/l Values are mean SEM. There were 679 total subjects. Results As noted, the sample for this study consisted of 679 of the original cohort of 1207 children entering the study at baseline. Comparison of baseline data (sex, race, height, weight, BMI, SBP, and diastolic blood pressure) between this sample and the nonparticipants (n 528) did not show any significant differences. The mean BMI at baseline for the 679 participants was kg/m 2 (range, 8 to 34 kg/m 2 ). A BMI between the 85th and 95th percentiles (ie, increased risk of overweight) was found in 64 children and 95th percentile (obesity) was found in 50 children. The mean BMI at the young adult evaluation was kg/m 2 (range, 17 to 64 kg/m 2 ), with BMI exceeding standards for obesity in 165. Data describing the participants at the young adult (age, 23.6 years) evaluation, including anthropometric and laboratory data, are presented in Table 1. The cohort was predominantly white (66%), with 25% blacks and 4% Native Americans. The male-to-female distribution was 52% to 48%. As would be expected, the male participants were taller and heavier and had a higher mean SBP than female participants, but BMI was similar between male and female subjects. At the young adult evaluation, weight, BMI, waist-to-hip ratio, and triceps skin-fold thickness were positively correlated with fasting insulin (P ), cholesterol (P to ), triglycerides (P ), and LDL-C (P to ) and negatively correlated with HDL-C (P ); height was positively correlated with triglycerides (P 0.003) and negatively correlated with HDL-C (P 0.001). Fasting insulin was positively correlated with cholesterol, triglycerides, and LDL-C and negatively correlated with HDL-C (P ). For these and the following analyses, results were virtually identical when male, female, black, or white subjects were analyzed separately. Initial childhood weight and BMI (mean age, 7.7 years) were highly correlated with young adult weight and BMI, respectively (P ) (Figure 1). A highly significant correlation was also noted (r 0.479, P ) between childhood and young adult height. Young adult fasting insulin, triglyceride, HDL-C, and SBP levels were significantly related to initial childhood weight, BMI, and height (Table 2), but the relations of cholesterol and LDL-C to body measurements were not significant. Figure 2 shows the mean slopes for height, weight, and BMI for the 679 subjects during childhood and adolescence. As expected, the rate of increase in height decreased substantially during adolescence. The rate of increase in weight also decreased during adolescence, but only by 25%, and the rate of increase in BMI decreased by only 10%. Table 3

3 Sinaiko et al March 23, Figure 1. Correlation of weight (r 0.605; P ) and BMI (r 0.612; P ) between 7.7 and 23.6 years of age for 679 subjects. shows the regression analyses of fasting insulin, lipid, and SBP levels on rates of increase in body size measurements. The rate of increase in height during childhood was not significantly related to any of the risk factors in young adulthood, except for a weak relation to LDL-C; the rate of increase in height during adolescence was significantly related only to SBP. In contrast, rates of increase in both weight and BMI during childhood were related significantly to young adult fasting insulin, all lipid, and SBP levels. Rates of increase in weight and BMI during adolescence were significantly related to fasting insulin, HDL-C, and SBP; weight also was related significantly but less strongly to triglycerides. Multiple linear regression analysis was used to examine the relation of initial childhood weight, rate of weight increase during childhood, and rate of weight increase during adolescence on young adult fasting insulin, with fasting insulin as the dependent variable. The relation between fasting insulin TABLE 2. Correlation of Fasting Insulin, Lipids, and SBP at Mean Age of 23.6 Years With Weight, BMI, and Height at Mean Age of 7.7 Measurement at 7.7 y Risk Factor at 23.6 y Weight BMI Height Fasting insulin r P Cholesterol r P Triglycerides r P LDL-C r P HDL-C r P SBP r P n 679 subjects. and initial childhood weight was not significant (P ), whereas the relations to both childhood and adolescent rates of weight gain were highly significant (P ). The influence of weight on young adult fasting insulin also was evaluated by constructing a 2 2 analysis with subjects divided according to their position above or below the median childhood and adolescent rates of weight gain (Table 4). Subjects above the median of weight gain during both childhood and adolescence had a significantly greater mean fasting insulin in young adulthood ( pmol/l) than subjects below the median during both childhood and adolescence ( pmol/l), below the median during childhood and above the median during adolescence ( pmol/l), or above the median during childhood and below the median during adolescence ( pmol/l) (all P ). The mean fasting insulin in the last 2 groups was slightly greater than in the group with rate of weight gain below the median during both childhood and adolescence (P and P , respectively). Similar results were obtained when BMI was substituted for weight or when 2 2 tables were constructed for each of the lipids and SBP. Thus, a rate of weight gain below the median in both childhood and adolescence resulted in the lowest level of risk as a young adult, whereas a rate of weight gain above the median in both childhood and adolescence placed a subject at the highest level of risk as a young adult. Discussion Weight is directly correlated with cardiovascular disease. The Framingham study followed a cohort of individuals for 26 years and showed that each 1-SD increment in relative weight was associated with a 15% increase in the risk of cardiovascular events in men and a 22% increase in women. 1 Weight is also directly related to the risk factors for cardiovascular disease. In the Community Hypertension Evaluation Clinic, a collaborative clinic screening of 1 million subjects, overweight was associated with a 50% higher prevalence of hypertension in both younger and older individuals. 25 Young adults (mean age, 22 years) in the Beaver County Lipid Study had positive and significant correlations between BMI and LDL-C and triglycerides. 26 Conversely, weight loss reduces risk in overweight individuals. 27,28 The relation between weight and cardiovascular risk factors is also present during childhood. Waist-to-hip ratio has

4 1474 Childhood Weight and Young Adult Risk Factors Figure 2. Mean rate of increase (slope) for height (a), weight (b), and BMI (c) for 679 subjects determined from repeated measurements during childhood (F) and adolescence (E). been positively correlated with serum cholesterol and LDL-C as early as 4 years of age. 29 A direct association between weight and insulin resistance has been reported in children, and body size has been shown to be a significant correlate of blood pressure and lipids in children and adolescents. 18,19,30 32 An increase in obesity during childhood is related to changes in lipids and lipoproteins that are consistent with a more atherogenic lipid profile. Children examined at 5 to 12 years of age in the Bogalusa Study and reexamined 5 years later had significant correlations between change in triceps skin-fold thickness and change in cholesterol, triglycerides, LDL-C, HDL-C, and VLDL cholesterol 33 ; in 2 separate Bogalusa cohorts evaluated after an 8-year period of observation, increases in weight were accompanied by adverse changes in lipids and lipoproteins. 34 The relevance of childhood weight to adult cardiovascular risk is beginning to be firmly established. As recently reviewed, 35 BMI shows a strong tracking effect from childhood into young adulthood. In particular, the BMI tracking correlations in the Muscatine Study from childhood to early adulthood ranged from 0.58 to 0.91, and most obese children became obese adults. 36 This tracking effect is accompanied by an increase in adult cardiovascular risk. A 40-year follow-up in Stockholm, Sweden, showed a significant relation between overweight in adolescence and adult premature death and cardiovascular disease. 37 Similarly, a recent evaluation of adults who were enrolled as children in the Harvard Growth Study in the 1920s showed that increased adult morbidity and mortality from coronary heart disease were related to overweight in adolescence. 6 TABLE 3. Correlation of Fasting Insulin, Lipids, and SBP at Mean of 23.6 Years on Rate of Increase (Slope) of Body Size (Weight, BMI, and Height) During Childhood and Adolescence Rate of Increase During Childhood and Adolescence (n 679) Childhood Adolescence Risk Factor Weight BMI Height Weight BMI Height Fasting insulin r P Cholesterol r P Triglycerides r P HDL-C r P LDL-C r P SBP r P

5 Sinaiko et al March 23, TABLE 4. Young Adult Fasting Insulin According to Rate of Weight Gain During Childhood and Adolescence Rate of Weight Gain During Adolescence Below Median Above Median Rate of Weight Gain During Childhood Below median Above median Mean age was 23.6 y. Values are pmol/l. The present study has shown not only that height, weight, and BMI measured in early childhood (mean age, 7.7 years) are significantly associated with body size in young adulthood (mean age, 23.6 years) but also that these measurements are significantly related to young adult levels of fasting insulin, lipid, and SBP. However, when the associations between these risk factors and the rate of increase in height, weight, or BMI, determined from multiple measurements obtained throughout childhood and adolescence, were examined, a significant relation was found with only weight and BMI. The lack of association with change in height may reflect the relatively stable rate of increase in height generally noted during growth. Although height tends to accelerate coincident with weight in children becoming obese before puberty, the relative change in height is considerably less than the relative change in weight. 38 Thus, the results from this study suggest that weight gain in excess of normal growth during childhood is a major constitutional determinant of young adult cardiovascular risk. This is of particular interest with regard to the finding that rate of change in weight and BMI predict fasting insulin levels. Hyperinsulinemia and insulin resistance are strongly correlated with obesity ,39 Experimental studies of obesity in humans, in which weight was increased 20% over 3 months, have shown a corresponding 50% increase in fasting insulin levels. 40 Dose-response insulin clamp studies comparing obese and normal weight subjects have shown significantly reduced insulin-mediated glucose uptake in the obese subjects. 9 Insulin, in turn, is directly related to blood pressure and lipid levels in adults and children. 16,18,19 Although the mechanism controlling these relations is not well defined, insulin may influence the development of hypertension via a direct effect on sodium retention in the kidney, 41 an increase in sympathetic nervous system activity, 42 and/or stimulation of growth in vascular smooth muscle 43 and may influence the concentration of serum lipids via an influence on hepatic lipid metabolism. 10 Thus, the rate of increase in weight and body mass during the first 2 decades of life appears to result in a concomitant increase in serum insulin levels and an adverse effect on cardiovascular risk factors, as noted in these young adults. The significance of this association is further suggested from studies in obese adults and adolescents showing improved insulin sensitivity after weight loss. 28,44 The significant correlation in this study between the initial childhood weight at 7.7 years of age and the young adult risk factors was no longer present when multiple regression analyses were conducted with each risk factor as the dependent variable and childhood weight, rate of increase in weight during childhood, and rate of increase in weight during adolescence as independent variables. These data suggest that regardless of body weight at a given point during early childhood, reduction in rate of weight gain during either childhood or adolescence has the potential to reduce subsequent levels of young adult cardiovascular risk; ie, the overweight 7-year-old child is not preordained to become a young adult with elevated insulin, lipid, or blood pressure level. It has been estimated that the risk of myocardial infarction is 35% to 55% less in normal-weight compared with obese adults. 45 However, the influence of obesity on cardiovascular risk begins before adulthood, and overweight during adolescence is associated with an increased risk of coronary heart disease in male 6,37 and female subjects. 37 The present study helps to explain this influence by showing that the degree of weight gain during childhood and adolescence is directly related to levels of cardiovascular risk factors in young adulthood. Thus, the potential public health implications are compelling. The prevalence of overweight in youth is increasing, 46 and childhood obesity predicts adult obesity. 5 On the basis of the data from this study, it can be expected that there will be a steady increase in the number of at-risk individuals as today s children become adults. 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