PEDIATRICS Vol. 101 No. 4 April 1998, p. e12

ELECTRONIC ARTICLE:
Cardiovascular Disease Insulin Risk in Mexican-American and Anglo-American Children and Mothers

Peter Reaven^*, Philip R. Nader, Charles Berry^§, and Tricia Hoy

From the ^* Department of Medicine/Endocrinology, the  Department of Pediatrics, and the ^§ Department of Family and Preventive Medicine, University of California, San Diego, La Jolla, California.

	ABSTRACT

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Objective.  To evaluate the relationship between insulin levels and cardiovascular risk factors in children and determine whether it varies among ethnic groups.

Methods.  Cardiovascular risk factors and insulin levels were compared in 144 Mexican-American and Anglo-American mother-child pairs, when the children were 11 years of age.

Results.  Although mean age did not differ between ethnicities, Mexican-American mothers and children both had a greater body mass index (mothers: 29.2 ± 6.2 vs 27.2 ± 7.9; children: 21.7 ± 4.7 vs 19.7 ± 4.6) and sum of skinfolds than did Anglo-Americans. Triglycerides, very low-density lipoprotein cholesterol, fasting insulin, and cholesterol/high-density lipoprotein ratio were higher, while high-density lipoprotein cholesterol was lower in both Mexican-American adults and children compared with Anglo-Americans. After adjusting for measures of obesity, only high-density lipoprotein cholesterol levels remained significantly lower in Mexican-Americans. For both adults and children, higher quartiles of insulin levels were associated with significantly higher triglycerides, blood pressure and lower high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol/apolipoprotein B levels (estimate of dense low-density lipoprotein size). A summary variable representing cardiovascular risk factors present in adult syndrome X patients was higher in both Mexican-American adults and children than in Anglo-Americans.

Conclusion.  Mexican-American children and adults have higher levels of many cardiovascular risk factors, and this appears related to higher insulin levels and overweight. Appropriate nutrition, weight control, and exercise at early ages could be important in slowing the development of atherosclerosis.

	INTRODUCTION

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There is increasing recognition of the need for cardiovascular risk factor prevention programs in children. Epidemiologic studies have demonstrated that children from families with a history of early heart disease or increased cardiovascular risk factors have a greater prevalence of cardiovascular risk factors.^1,2 Other studies in youth have documented abnormal levels of obesity, blood pressure, low-density lipoprotein (LDL), triglycerides, and lower high-density lipoprotein (HDL) levels in unselected populations.³ In addition, it is now becoming clear that many cardiovascular risk factors occur early in life and track into adulthood.^3,5,7 This is well demonstrated for cardiovascular risk factors such as total and HDL cholesterol levels and obesity, but recent studies have also demonstrated that insulin levels also track well with age.^4,11,12 Moreover, autopsy studies in youth have demonstrated that atherosclerosis has an early onset and that it is positively related to the levels of very low-density lipoproteins (VLDL) plus LDL cholesterol, hypertension, glycohemoglobin, obesity, and cigarette smoking, but inversely related to HDL cholesterol levels.¹³ Cardiovascular risk factors measured in children and young adults are also associated with the early development of coronary calcification.¹⁷

There is good evidence that many cardiovascular risk factors may cluster in certain individuals as a result of underlying insulin resistance.¹⁸ Risk factors that have been demonstrated to cluster in adults in this syndrome of insulin resistance, or "syndrome X," include: hyperinsulinemia, hypertriglyceridemia, low HDL cholesterol, hypertension, plasminogen activator inhibitor 1, and small dense LDL.^21,22 Obesity, which is frequently associated with these metabolic variables, appears to contribute importantly to insulin resistance,²³ although it may not be necessary or sufficient for the full expression of this syndrome.^21,24 Recent studies suggest that the insulin resistance syndrome may also contribute to the development of cardiovascular risk factors in children and that this relationship persists into adulthood.^11,25 Whether the association of insulin resistance with cardiovascular risk factor varies between ethnic groups, particularly in young individuals, is not well studied.

In the current study we addressed several issues. First, we compared cardiovascular risk factors between Mexican-American and Anglo children and mothers. Second, we evaluated the relationship between obesity and plasma insulin levels and cardiovascular risk factors that are commonly present in the syndrome of insulin resistance. Third, studying both children and their mothers provided the opportunity to look for familial patterns in cardiovascular risk factors profiles.

	METHODS

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Subjects

The study population includes 144 biologic mother-child pairs who agreed to have a single fasting blood sample drawn as part of an ongoing study (San Diego Study of Children's Activity and Nutrition). Parents gave written permission, and children assented to measurement. The study was approved by the Institutional Review Board. This study began when children were approximately 4 years of age, and they are currently age 11 years on average. The original study population was a convenience sample of 149 White (non-Hispanic) and 202 Mexican-American 4-year-old children and their mothers who were recruited from state-funded preschools. Attendance at the preschool was conditional upon a low-income criterion that all families met. The socioeconomic status scale, based upon finer divisions of income and education, revealed the Mexican-American population to have a significantly lower socioeconomic status score. The study has investigated physical parameters of growth, as well as dietary and physical activity habits among the children and adults. No interventions were performed. Methods and health behavior results to date have been previously published.²⁸ For the first time in the study, blood lipids were examined. All fasting blood samples were obtained in the morning in the homes of the subjects. Historical information and morphometric measurements were also obtained by a trained assessor at this time.

Height

Standing height was measured with subjects standing erect with shoes removed on a hard, level surface, with heels, buttocks and upper back in contact with a vertical wall, and arms hanging by their sides. The assessor positioned the subject's head in the Frankfort Horizontal Plane, and instructed the subject to inhale deeply while maintaining this position and looking straight ahead.³⁴ The assessor then slid a wooden headboard down the vertical wall until it made firm contact with the vertex of the subject's head, and made a level mark on the wall at the base of the headboard with a pencil. Height was then recorded as the vertical distance from the floor to the level mark on the wall, which was measured using a steel carpenter's tape to the nearest 0.25 inches and converted to centimeters for data analysis.

Weight

Weights were obtained using portable floor scales with digital display to the nearest 0.5 pound. Subjects wore ordinary clothing and removed their shoes for the weighing procedure. Scales were calibrated weekly at 25-pound increments up to 200 pounds using certified calibration weights. Recorded weights were converted to kilograms for data analysis. Body mass index (BMI) was calculated as weight/height² (kg/m²).

Skinfolds

The triceps and subscapular skinfolds were measured on the subject's right side using Lange skinfold calipers, which exert a constant pressure of 10 g/mm². The triceps skinfold was measured along a raised vertical fold of skin 1 cm below the mid-acromiale radiale line on the mid-line of the posterior surface of the right arm.³⁴ The subscapular skinfold was raised just below and to the right of the inferior angle of the right scapula, with the measurement taken 1 cm below the site along the oblique fold.³⁴ Skinfolds were recorded to the nearest 1.0 mm, 2 seconds after maximum jaw pressure was applied. The anthropometric protocol for skinfold and girth measures was completed from start to finish three consecutive times to allow compressed adipose tissues to resume their normal state before subsequent measures. A fourth measurement was taken when there was an extreme difference between any two of the original three skinfolds, with the average of the three closest skinfolds used for data analysis. Skinfold calipers were calibrated weekly at 10-mm increments to 50 mm using a certified calibration block.

Waist-Hip Circumferences

Each subject's waist and hip girth were measured with the subject standing erect with feet together using a 1.5-m flexible plastic anthropometric tape applied without undue pressure. Waist girth was measured as the horizontal circumference at the slimmest portion of the waist where it indents slightly at the sides approximately halfway between the lower rib cage and the iliac crest.³⁴ In subjects where the waist was not apparent, an arbitrary measurement was made at this level. Waist girth was recorded to the nearest 0.1 cm with the subject at normal expiration. Hip (gluteal) girth was measured horizontally at the level of the greatest posterior protuberance of the buttocks and approximately the level of the symphysis pubis anteriorly, and recorded to the nearest 0.1 cm.³⁴ Three measures of both the waist and hip girth were obtained from each subject, with a fourth measure taken only when no two of the original three were within 0.5 cm of each other. The average of the three closest values was calculated for the purpose of data analysis. Training and field reliabilities were acceptable and reflected rigorous adherence to protocol. Criterion to trained assessor reliability for circumference and skinfold measures was 0.86. Intra-observer reliabilities ranged from 0.94 to 0.96 (percent agreement statistic of the same assessor with the same subject).

Blood Pressure

All participants were asked to void, then sit quietly for at least 5 minutes in a comfortable setting before blood pressure measurement. Blood pressure was measured three times at 1-minute intervals with the arm supported and at heart level. Systolic and diastolic blood pressure were measured using the Hawksley Random Zero Sphygmomanometer (Hawksley & Sons Limited, Sussex, England). Assessors received extensive blood pressure measurement training that included lectures, demonstration testing, and proficiency testing and certification. Inter-assessor reliabilities performed on the same subject simultaneously, with two stethoscopes on the same arm, were acceptable; (adultsystolic: 0.87, diastolic: 0.79; childrensystolic: 0.64, diastolic: 0.61), with diastolic blood pressure being less reliably measured often attributable to the inherent variability of diastolic blood pressure at a young age.

Serum Lipids, Lipoproteins, Insulin

Total cholesterol, triglycerides, and HDL cholesterol were measured on plasma samples, drawn on subjects who had fasted overnight, by enzymatic techniques with an ABA-200 bichromatic analyzer (Abbott Laboratories, Irving, TX). If triglycerides were <400 mg/dL, LDL cholesterol was calculated by the Friedewald formula. In plasma samples with triglycerides >400, the sample underwent ultracentrifugation to float up lipoproteins with a density 1.006. Total cholesterol was then measured on the infranate, and HDL cholesterol was then subtracted from this value to calculate LDL cholesterol.³⁵ The LDL cholesterol/apolipoprotein B (apo B)-100 ratio was used as a marker of LDL size.^36,37 Insulin levels were performed by a double-antibody radioimmunoassay method (Linco RIA Insulin Kit; Sigma Diagnostics, St Louis, MO) and apolipoprotein B (apo B) levels were measured using immunopreciptin analysis (Incstar Corp, Stillwater, MN).

Statistical Methods

Log values of insulin and triglycerides were used to more closely approximate a Gaussian distribution. Comparisons of the distributions of lipid values for Mexican-Americans and Anglo-Americans used Mann-Whitney U test and Kolmogorov-Smirnov tests. In addition to computing the Pearson correlation coefficients of lipid and lipoprotein values, we also computed rank correlation coefficients to assure that significant results were not attributable to a few outlying values. Likewise, the linear regressions involving the lipid values were performed on the ranked lipid values. For the correlation analyses between mother-child pairs, each pair represented one point of the regression analysis for each different parameter evaluated. A syndrome X score was calculated by summing the rank scores for each individual for the variables insulin, systolic blood pressure, triglycerides, HDL cholesterol, LDL cholesterol/apo B. Rank scores were assigned in ascending order (from 1 for the lowest values to n for the highest) for insulin, systolic blood pressure, triglycerides; and, in descending order (from 1 for the highest values to n for the lowest values) for HDL cholesterol and LDL cholesterol/apo B.

	RESULTS

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The mean age of mothers (Anglo-American, 39.2; Mexican-American, 38.0 years) and of children (Anglo-American, 11.3; Mexican-American, 11.5 years) did not differ between ethnicities. Slightly more Mexican-American mothers reported a history of diabetes in the family (59.8%) compared with Anglo-American mothers (46.2%).

Mexican-American mothers and children both had greater BMI and sum of skinfolds measurements than did their Anglo-American counterparts. The waist-to-hip ratio was also greater in the Mexican-American mothers than in the Anglo-American mothers. The waist-to-hip ratio was also slightly greater in Mexican-American children, although this difference did not reach statistical significance. These data are summarized in Table 1.

Levels of lipids, lipoproteins, blood pressure glucose and fasting insulin for adults and children of both ethnic groups are shown in Table 2. Means are contrasted between ethnic groups. The following variables did not differ between ethnic groups in either adults or children: total cholesterol (TC), LDL cholesterol, lipoprotein(a) Lp(a), glucose, LDL cholesterol/apo B ratio (an estimate of LDL particle size). In contrast, triglyceride, fasting insulin, and TC/HDL ratio were higher, while HDL cholesterol was lower in both Mexican-American adults and children compared with their Anglo-American counterparts (P < .05 in all cases). Additionally, plasma apolipoprotein B levels and an estimate of VLDL cholesterol (triglycerides/5, calculated after excluding all participants with triglycerides >400 mg/dL) were significantly higher in Mexican-American adults than in Anglo-American adults.

To determine whether the differences in the amount and type of obesity between these ethnic groups influenced lipid and insulin values, we adjusted for BMI, the sum of skinfold thickness, or waist-to-hip ratio in separate analyses. After adjusting for any one of these measures of obesity, the differences in triglycerides, apo B, insulin levels and TC/HDL ratio were no longer statistically significant between adult Mexican-Americans and Anglo-Americans. However, HDL cholesterol levels remained significantly lower in Mexican-Americans. Similarly, obesity also appeared to contribute substantially to differences in values between Mexican- and Anglo-American children. Although Mexican-American children still had a trend toward to have a worse metabolic profile (lower HDL, higher triglycerides, higher TC/HDL ratio, and higher syndrome X score) after adjustment for either BMI, skinfolds or waist-to-hip ratio, only fasting insulin levels remained statistically higher in the Mexican-American children (data not shown).

Because it is recognized in adults that many of these metabolic parameters are related to hyperinsulinemia and insulin resistance, we evaluated the relationship between quartiles of fasting insulin levels and selected lipid and blood pressure measurements for the adults and children as shown in Table 3. For both adults and children, higher insulin levels were associated with significantly higher triglycerides, blood pressure and lower HDL cholesterol, and LDL cholesterol/apo B levels. To investigate the relationship of insulin to these variables within ethnic groups we performed correlational analyses (Table 4). As expected, in Mexican-American and Anglo-American adults, insulin was positively associated with triglycerides, VLDL cholesterol, blood pressure, and inversely correlated with HDL cholesterol levels and LDL size (LDL cholesterol/apo B-100). In Mexican-American adults, all these correlations reached statistical significance, while in Anglo-Americans the inverse correlations between insulin and HDL cholesterol or LDL size did not. Even among the children there were significant correlations between insulin and these same variables. This was particularly impressive in Mexican-American children where insulin was positively correlated with triglycerides and inversely correlated with HDL cholesterol and LDL size.

To further study the relationship of insulin with other cardiovascular risk factors, we generated a new variable (described in "Methods") that was based on the sum of rankings for risk factors present in syndrome X.^21,22 Overall, both Mexican-American adults and children had a significantly higher score than their Anglo-American counterparts, demonstrating a greater tendency to develop the metabolic abnormalities present in syndrome X. This difference between ethnic groups was not attributable to a few Mexican-American individuals with more extreme values, but appeared attributable to slightly higher values throughout the Mexican-American cohort (data not shown). This new variable representing a sum of risk factors correlated well with measures of obesity and with fasting insulin levels (Table 5).

Many studies have documented that some cardiovascular risk factors appear to occur more frequently in related family members than in unrelated individuals. This also appears true for insulin resistance and diabetes.^38,39 Thus, it seems reasonable that risk factors frequently associated with insulin resistance may show familial patterns of inheritance as well. The design of this study also provided us the opportunity to examine the relationship of selected metabolic variables between mother and child. Pearson correlations for cardiovascular risk factors for Anglo- and Mexican-American mother-child pairs are shown in Table 6. As expected, significant correlations were noted for standard risk factors such as plasma cholesterol, LP(a), as well as TC/HDL ratio for both groups. Of note, fasting insulin levels and LDL size were correlated between mother-child pairs in both ethnic groups and HDL and triglyceride levels were significantly correlated for Anglo-American pairs, but not for Mexican-American pairs. Systolic and diastolic blood pressure values were significantly correlated in Mexican-American pairs but not in Anglo-American pairs. In general, the strength of the relationships between mother-child pairs appeared stronger in Anglo-Americans than in Mexican-Americans, although this difference was only statistically significant for the variables HDL and LP(a). Because obesity appeared to have an important impact on the levels of many of the risk factors, and measures of obesity were significantly correlated between mother-child pairs in both ethnic groups, we reevaluated the mother-child relationships after adjustment for BMI. Only the correlation of insulin levels between mother and child was significantly reduced.

	DISCUSSION

To establish cardiovascular disease prevention programs for the young, it is important to more fully characterize the risk factors that are present in younger age groups as well as identify those children at unique risk. Although there has been a recent surge in interest regarding the association of hyperinsulinemia with a variety of cardiovascular risk factors in adults, few studies have evaluated this relationship in children and none have performed so in both Anglo- and Mexican-American groups. The current study population is unique in its ethnic diversity and its inclusion of both parents and children, allowing us to evaluate for the possibility of an early onset of ethnic differences in insulin-cardiovascular risk factor associations.

In this study, individuals with higher insulin levels had higher levels of triglycerides, systolic blood pressure, and lower levels of HDL cholesterol and LDL cholesterol/apo B. This was true for both adults and children, suggesting that the relationship between insulin and these cardiovascular risk factors is consistent across these age groups. As noted by other investigators,^12,21 total cholesterol and LDL cholesterol were not related to insulin levels (Table 4). Compared with their Anglo counterparts, Mexican-American adults had greater levels of fasting insulin, and had a potentially more atherogenic risk profile. Although fasting insulin levels are not a direct measure of insulin resistance, they are strongly correlated (.6 to .8), and higher plasma insulin levels in Mexican-Americans are consistent with greater degrees of insulin resistance.^40,41 These findings confirm those of previous studies in Mexican-American adults.⁴² Higher levels of triglycerides, plasma insulin, blood pressure, small dense LDL, and lower HDL levels have all been associated with an increased risk of cardiovascular disease.^21,45 VLDL cholesterol, as estimated by the Friedewald formula, was also elevated in Mexican-American adults and has also been associated with coronary artery disease.^45,47 Higher levels of these risk factors place Mexican-Americans at greater risk for developing atherosclerotic disease. Although it is currently unclear whether the prevalence of coronary artery disease among Mexican-Americans is different than among Anglo-Americans, the relationships between insulin resistance and atherosclerosis appears to be similar between these groups.⁵⁰ Surprisingly, Mexican-American children also had evidence for greater insulin resistance, with higher fasting insulin levels, as well as higher triglycerides and lower HDL cholesterol than Anglo-American children. This indicates that the predisposition to develop a worse cardiovascular risk profile may be detectable early in life in Mexican-Americans.

Our studies demonstrated significant correlations of cardiovascular risk factors between mothers and their children, supporting the possibility that these metabolic patterns may in part be inherited. Although this is not unexpected for risk factors such as total cholesterol, LDL cholesterol, and Lp(a) in which patterns of inheritance are well studied, it is of interest that risk factors such as triglycerides and insulin levels are also significantly correlated in mother-child pairs. This is consistent with the concept that insulin resistance is in part at least an inherited condition.^38,39,51 However, our study does not allow distinction between environmental and genetic influences.

After adjusting for differences in obesity between the two ethnic groups, many of the differences in cardiovascular risk factors were substantially reduced. This suggests that the apparently greater cardiovascular risk in the Mexican-American population, can be at least partly explained by greater obesity. This was true for both Mexican-American mothers and their children. Mexican-American children were substantially heavier than their Anglo-American counterparts, and this is consistent with recent data from the Child and Adolescent Trial for Cardiovascular Health (CATCH) multi-center study⁵² of 11-year-old children in four states: California, Louisiana, Minnesota, and Texas. Of note, whether cardiovascular risk factors, including insulin levels, in adults or in children were adjusted for estimates of overall fatness (BMI or skinfold thickness) or by a measure of abdominal obesity (waist-to-hip ratio), the effects were similar. This does not support the concept that abdominal obesity may be uniquely important to the development of insulin resistance. In adults it has been suggested that the waist-to-hip ratio may not measure abdominal obesity precisely enough to allow determination of its contribution and this may explain its diminished importance in this study. Although some studies have shown a unique relationship between abdominal obesity and insulin resistance,^53,54 recent studies using magnetic resonance imaging have failed to show a specific association of intraperitoneal or retroperitoneal fat with insulin resistance.^55,56 Moreover, the contribution of abdominal obesity to hyperinsulinemia and dyslipidemia is very likely decreased in children compared with adults. Abdominal obesity becomes more prominent with age, and as shown in this study did not differ significantly between Anglo- and Mexican-American children.

This study supports the concept that plasma insulin and/or insulin resistance influences the natural history of cardiovascular risk factor development, especially among Mexican-Americans. The mean value for the syndrome X score was significantly higher in both Mexican-American mothers and children, suggesting that there was a greater tendency for higher levels of multiple risk factors to occur in the Mexican-American subjects. This is consistent with the data from several recent studies that have demonstrated within Anglo-American populations that risk factors associated with insulin resistance are associated in young individuals just as they are in adults.^12,25,26 Moreover, this association of risk factors also appears to track into adulthood.²⁷

In summary, these results demonstrate that Mexican-Americans have a cardiovascular risk profile that is worse than their Anglo-American counterparts. Importantly, this study extends these findings to young children, demonstrating that this enhanced risk for cardiovascular disease begins early in life and suggests that this may result from the early development of obesity and insulin resistance. This is supported by the fact that the associations between insulin and other cardiovascular risk factors are apparent, even within the relatively normal ranges of insulin present among the healthy children in this study. Although the current findings are consistent with results from previous studies, it must be noted, however, that prospective studies are needed to confirm the role that hyperinsulinemia and/or insulin resistance play in the development of cardiovascular risk factors in children.

These findings suggest that early intervention to reduce risk factors in children may be particularly important to the Mexican-American population. Currently, the best approach to reducing insulin resistance is through weight loss and exercise, and several studies in children have demonstrated that interventions in these areas have resulted in benefits in behavior patterns and in some instances in improvement in risk factors.⁵⁷ Thus, encouraging appropriate nutrition and physical activity at early ages may be important modalities to slow or inhibit the development of weight gain, diabetes, and atherosclerosis.

	FOOTNOTES

Received for publication Jun 12, 1997; accepted Nov 11, 1997.

Reprint requests to (P.R.N.) Department of Pediatrics, Division of Community Pediatrics, University of California, San Diego, 9500 Gilman Dr, Dept 0927, La Jolla, CA 92093-0927.

	ACKNOWLEDGMENTS

This study was supported in part by National Institutes of Health Grant HL52449 (to P.R.N.); National Institutes of Health Grant HL-14197 (SCOR), a grant from the General Clinical Research Centers Program, Grant M01-RR00827 from the National Center for Research Resources/National Institutes of Health, and a Juvenile Diabetes Foundation/Veterans Administration Cooperative Diabetes Research grant (to P.R.).

	ABBREVIATIONS

LDL, low-density lipoprotein. HDL, high-density lipoprotein. VLDL, very low-density lipoproteins. BMI, body mass index. apo B, apolipoprotein B. TC, total cholesterol. Lp(a), lipoprotein(a).

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