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(Circulation. 1996;93:54-59.)
© 1996 American Heart Association, Inc.

Articles

Persistent Elevation of Plasma Insulin Levels Is Associated With Increased Cardiovascular Risk in Children and Young Adults

The Bogalusa Heart Study

Weihang Bao, PhD; Sathanur R. Srinivasan, PhD; Gerald S. Berenson, MD

From the Tulane National Center for Cardiovascular Health, Tulane School of Public Health and Tropical Medicine, New Orleans, La.

Correspondence to Gerald S. Berenson, MD, Tulane National Center for Cardiovascular Health, Tulane School of Public Health and Tropical Medicine, 1501 Canal St, 14th Floor, New Orleans, LA 70112-2824.

	Abstract

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Background Hyperinsulinemia has been considered to be a potent cardiovascular risk factor. The present investigation examines persistently elevated fasting insulin levels from childhood to young adulthood and its influence on cardiovascular risk factors.

Methods and Results A longitudinal cohort was constructed from two cross-sectional surveys in a community-based population over an 8-year period: 1606 individuals (39% were black) aged 5 to 23 years participated in the first survey. Stability in rankings (persistence) of insulin levels was shown by the presence of significant correlations between year 1 and year 8 values (r=.23 to .36, P<.0001), with a greater magnitude in older subjects. Compared with subjects with levels of insulin consistently in the lowest quartile, those with levels always in the highest quartile showed higher (P<.001) levels of body mass index (+9 kg/m²), triglycerides (+58 mg/dL), LDL cholesterol (+11 mg/dL), VLDL cholesterol (+8 mg/dL), glucose (+9 mg/dL), systolic blood pressure (+7 mm Hg), and diastolic blood pressure (+3 mm Hg); lower (P<.001) levels of HDL cholesterol (-4 mg/dL); and higher (P<.05) prevalence of parental history of diabetes (3.3-fold) and hypertension (1.2-fold). There were 739 young adults aged 20 to 31 years at follow-up. As adults, individuals with consistently elevated insulin versus those with consistently decreased insulin had increased (P<.05) prevalence of obesity (36-fold), hypertension (2.5-fold), and dyslipidemia (3-fold), which was attributed to both baseline insulin and change of insulin from baseline to follow-up. In addition, clustering of these risk factors was stronger (P<.05) in adults with persistent insulin elevation.

Conclusions Elevated insulin levels persist from childhood through young adulthood, resulting in a clinically relevant adverse cardiovascular risk profile in young adults.

Key Words: insulin • follow-up studies • risk factors

	Introduction

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Elevated levels of plasma insulin are common in adults and are often associated with coronary heart disease.^{1 2 3 4} This association may be direct or indirect in that higher insulinemia is a cardiovascular risk factor, or it is correlated with other established cardiovascular risk factors. Many cross-sectional studies in both children and adults have shown that hyperinsulinemia is associated with an adverse pattern of cardiovascular risk factors, including obesity, dyslipidemia, and hypertension.^{5 6 7} The clustering of these risk factors along with hyperinsulinemia, called syndrome X or insulin resistance syndrome, has been well established.^{9 10 11}

Elevated plasma insulin levels have been shown to persist (track) over time in children.^{12 13 14} However, information is lacking regarding the effect of persistently increased levels of insulin over the long term on cardiovascular risk in children and young adults. Such information obtained from young individuals who do not have overt clinical abnormalities in childhood may help obtain a better understanding of the role of insulinemia in the development of cardiovascular diseases. The objective of the present study was to examine the long-term persistence (tracking) of insulin levels in children and young adults in a community-based population and to observe the effect of persistently elevated insulin levels on adult cardiovascular risk.

	Methods

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Population
The Bogalusa Heart Study, which started in 1973, is a long-term epidemiological study of cardiovascular disease risk factors in a biracial (65% white and 35% black) population of children and young adults.¹⁵ Until 1988 through 1991, cross-sectional surveys were conducted approximately every 3 years in this population. Beginning with the 1981-1982 cross-sectional survey, fasting insulin was measured in the total survey population. Therefore, for simplicity of analysis, we selected the survey subjects (1606) who participated in both the 1981-1982 (baseline) and the 1988-1991 (the most recent measurement as follow-up) surveys. At baseline, these selected subjects were 5 to 23 years of age. Of the study population, 33% were black and 55% were female. At baseline, these subjects were similar to other participants examined at the same survey in weight, height, and plasma insulin levels (data not shown).

General Physical Examinations
All examinations followed the same protocols.¹⁵ All subjects were instructed to fast for 12 hours before the screening. Compliance was determined by an interview on the morning of the examination. Blood was drawn by antecubital venipuncture to obtain serum and plasma. All subjects included in the study had fasting blood samples taken.

Height was measured to within 0.1 cm, weight to within 0.1 kg, and subscapular and triceps skinfolds to within 1.0 mm. As a measure of overall adiposity, the body mass index ([BMI] weight in kilograms divided by height in meters squared) was calculated. Blood pressure levels were measured on the right arm with subjects in a relaxed, sitting position. The cuff size used for blood pressure determination was based on measurements of right arm length and circumference. The blood pressure level reported was the mean of six replicate readings taken by two randomly assigned, trained nurses.

Parental history of cardiovascular diseases, including heart attack, diabetes, and hypertension, was obtained through a questionnaire administered before the date of examination. Parents of school-aged children filled out the questionnaire along with permission forms for the examination. Post–high school young adults filled out the questionnaire by themselves. Parental history of disease was defined as positive if one or both parents had the disease. During an interview for young adults, the subjects were asked if they had ever been treated for hypertension or dyslipidemia.

Laboratory Measurements
Serum cholesterol and triglycerides were measured by following enzymatic procedures^{16 17} with the Abbott VP instrument (Abbott Laboratories). The procedures met the performance requirements of the Lipid Standardization Program of the Centers for Disease Control and Prevention (CDC). The Laboratory has been monitored by the CDC's surveillance program. Serum VLDL, LDL, and HDL cholesterol levels were analyzed by a combination of heparin-calcium precipitation and agar-agarose gel electrophoresis procedures.¹⁸ Plasma immunoreactive insulin levels were measured with a commercial radioimmunoassay kit (Phadebas, Pharmacia Diagnostics). Plasma glucose was determined as part of a multiple chemistry profile (SMA20).

Statistical Analysis
The Statistical Analysis System was used.¹⁹ Insulin and triglycerides were log-transformed so that they were more normally distributed. Longitudinal changes in insulin over time were evaluated by a paired t test. Stratified by age, race, and sex, Spearman correlations were calculated to examine the association during baseline and follow-up levels of insulin. The study subjects were ranked according to age-, race-, and sex-specific quartiles of insulin at baseline and follow-up. Subjects whose insulin levels were persistently in the highest or lowest quartile during both surveys were then identified. Thus, the study subjects were categorized as having persistently elevated insulin or persistently low insulin or none of the above (other) groups. Age, height, weight, and BMI of these groups were compared. After checking the interactions between the effect of insulin and the effects of age, race, and sex, differences in levels of other risk factor variables among these groups were examined, correcting for age, race, and sex with and without adjustment for BMI. Parental history of heart attack, hypertension, and diabetes mellitus were also compared between subjects with persistently high or low insulin levels.

To study clinically evident abnormalities in adults, further analyses were performed on a subset of the study cohort that consisted of subjects who were adults at follow-up (aged 20 to 31 years). These adults were considered to be obese if their BMI was above the 85th percentile value reported by NHANES I survey.^{20 21} They were classified as clinically hypertensive if they had systolic blood pressure above 140 mm Hg or fifth phase diastolic blood pressure above 90 mm Hg or had been treated for hypertension. Based on the guidelines from the National Cholesterol Program,²² these adults were diagnosed as having dyslipidemia if their level of total cholesterol was above 240 mg/dL, of LDL cholesterol was above 160 mg/dL, of HDL cholesterol was below 35 mg/dL, or of triglycerides was above 250 mg/dL or they were being treated for dyslipidemia. The prevalence of these risk factors was compared with the use of a ² analysis between subjects with and without persistent elevation of insulin levels. A multiple logistic regression was also performed, using the presence or absence of a risk factor as the dependent variable. The independent variables included age, race, sex, baseline insulin, and change of insulin from baseline to follow-up. Clustering of these risk factors was also examined.

	Results

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Longitudinal Changes of Plasma Insulin
Baseline and follow-up mean levels of fasting plasma insulin are given by age, race, and sex in Fig 1. Regardless of race and sex, significant increases of insulin over an 8-year period were observed in the youngest age group (aged 5 to 9 years at baseline). The increases in this age group were more dramatic in females than in males, regardless of race.

View larger version (35K): [in this window] [in a new window]   Figure 1. Bar graphs of longitudinal changes of fasting insulin in children and young adults over an 8-year period in the Bogalusa Heart Study (1606). Regardless of race and sex, significant increases of insulin were observed in the 5- to 9-year-old age group 8 years later.

Persistence of Plasma Insulin Levels Over Time
Subjects with relatively high/low fasting plasma insulin levels tended to have retained such levels 8 years later. Corrected for race and sex, the partial correlation between baseline and follow-up insulin levels was .23 (P=.0001) for the age groups of 5 to 9 or of 10 to 16 and .36 (P=.0001) for the age group of 17 to 23. Furthermore, when subjects were grouped into quartiles according to age-, race-, and sex-specific rankings of insulin level, a higher-than-expected number of individuals who ranked high (>75th percentile) or low (<25th percentile) in insulin levels at baseline maintained these respective ranks at follow-up. Of subjects who had insulin levels above the 75th percentile at baseline, 40% remained so after 8 years. Overall, about 10% (162) of the study cohort had levels of insulin consistently in the highest quartile. In contrast, only 7% (115) of the population had levels of insulin consistently in the lowest quartile.

Characteristics Associated With Persistent Elevation of Insulin Levels
Follow-up characteristics of subjects with persistently elevated (>75th percentile) levels of insulin were compared with those whose insulin levels remained persistently low (<25th percentile). Data on those who did not belong to either category (other) are also included for comparison (Table 1). Subjects with elevated insulin levels had significantly adverse levels of risk factor variables, regardless of age, race, or sex. On average, they had higher (P<.0001) body weight and BMI than their counterparts with low insulin levels. In addition, they had higher levels of systolic and diastolic blood pressure, glucose, total cholesterol, triglycerides, VLDL cholesterol, and LDL cholesterol (all P<.0001) and lower levels of HDL cholesterol (P<.001). These differences still existed after adjusting for BMI, except for diastolic blood pressure, LDL cholesterol, and HDL cholesterol. Among subjects who did not belong to either category in terms of insulin levels, intermediate levels of risk factor variables were observed. Similar results were obtained when the above comparisons were made within each age group (5 to 9 years, 10 to 17 years, or 18 to 23 years old at baseline; data not shown).

View this table: [in this window] [in a new window]   Table 1. Follow-up Characteristics Associated With Persistent Elevation of Fasting Insulin Over an 8-Year Period: The Bogalusa Heart Study

The prevalence of parental history of heart attack, diabetes mellitus, and hypertension is presented in Fig 2, according to insulin levels of the study subjects. Among the subjects with persistently elevated insulin levels, parental diabetes occurred 3.3-fold more often than in those with low levels (20% versus 6%, P<.05). Parental hypertension was 1.2-fold greater (56% versus 47%, P<.05). However, the prevalence of parental history of heart attack was not significantly different between the groups.

View larger version (33K): [in this window] [in a new window]   Figure 2. Bar graph of prevalence of parental history of cardiovascular disease and diabetes in children and young adults according to fasting insulin status over an 8-year period. Among the subjects with consistently elevated insulin, parental diabetes and hypertension were significantly more prevalent.

There were 739 young adults aged 20 to 31 years at follow-up (aged 12 to 23 years at baseline). The prevalence of obesity, hypertension, and dyslipidemia among these young adults is shown in Table 2 according to insulin status over the 8-year period. The prevalence of obesity was 72% in subjects with persistently elevated insulin levels versus 2% in those with persistently low insulin levels. Similarly, hypertension and dyslipidemia were 2.5-fold and 3-fold, respectively, higher among those with persistently elevated insulin levels. This association between persistent insulin elevation and risk factors was also demonstrated in a logistic regression analysis. As shown in Table 3, both baseline insulin and change of insulin from baseline to follow-up predicted the emergence of adulthood risk factors. A 6-µU/mL higher level of baseline insulin was associated with 4.8-fold risk of obesity, 1.4-fold risk of hypertension, and 1.7-fold risk of dyslipidemia. Similarly, a 6.8-µU/mL higher increase from baseline to follow-up was associated with 4.8-fold risk of obesity, 1.2-fold risk of hypertension, and 1.6-fold risk of dyslipidemia. Expected race, sex, or age effect on risk factors was also apparent.

View this table: [in this window] [in a new window]   Table 2. Prevalence of Cardiovascular Risk Factors in Young Adults According to Fasting Insulin Status Over an 8-Year Period: The Bogalusa Heart Study

View this table: [in this window] [in a new window]   Table 3. Predicting Cardiovascular Risk Factors in Young Adults by Levels of Fasting Insulin Over an 8-Year Period: The Bogalusa Heart Study

Significant clustering of two or three risk factors occurred in subjects with persistent elevation of insulin levels (Fig 3). Clustering of obesity/hypertension, obesity/dyslipidemia, hypertension/dyslipidemia, and obesity/hypertension/dyslipidemia occurred in 10%, 30%, 11%, and 7%, respectively, of the individuals with persistently elevated insulin levels.

View larger version (30K): [in this window] [in a new window]   Figure 3. Clustering of obesity (BMI: >85 percentile value reported by NHANES I), hypertension (systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg, or on medication for hypertension), and dyslipidemia (total cholesterol >240 mg/dL, LDL cholesterol >130 mg/dL, HDL cholesterol <35 mg/dL, or triglycerides >250 mg/dL) in 20- to 31-year-old adults by fasting insulin status over an 8-year period. Coexistence of two or more abnormalities existed only in the subjects with persistent insulin elevations.

The observed association between insulin and risk factors or parental history of disease was reexamined in a subset of the study cohort. Among the 739 study subjects who were young adults at follow-up, 447 participated in another cross-sectional survey between baseline and follow-up with an additional fasting insulin measurement. This sample was similar to the rest of the 739 adults in age, weight, height, and insulin. A portion of these 447 individuals may have had up to three insulin elevations (>75th percentile). As shown in Table 4, prevalence of obesity, dyslipidemia, or parental diabetes was clearly higher in subjects with two or three insulin elevations than in subjects with no or one insulin elevation. The prevalence of hypertension or parental hypertension was also higher in subjects with persistent insulin elevation, but the difference was not significant, which could be due in part to the smaller sample size.

View this table: [in this window] [in a new window]   Table 4. Prevalence of Cardiovascular Risk Factors by Insulin Status in Young Adults Who Participated in Three Cross-sectional Surveys Over an 8-Year Period: The Bogalusa Heart Study

	Discussion

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In the current community-based study, insulin was obtained at multiple times as part of cardiovascular risk factor surveys on children and young adults. Previously, tracking of insulin for periods of 3 and 6 years was reported in a subpopulation of a cross-sectional survey.¹² Relations between fasting insulin and cardiovascular risk factor variables were also observed cross-sectionally in this population of children and young adults.^{5 12 23} Based on a much larger population, spanning from young children to young adults, the current study revealed that insulin levels track over an 8-year period, especially in older subjects. In addition, the present study showed that compared with their counterparts, subjects with persistently high levels of insulin had adverse levels of BMI, blood pressure, total cholesterol, triglycerides, and lipoprotein cholesterols, and they were more likely to develop hypertension, dyslipidemia, and obesity in young adulthood. These findings support studies relating higher insulinemia to the risk of coronary heart disease in adults.^{2 3 4}

The link between obesity and insulin resistance and the attendant hyperinsulinemia is well documented in adults.^{24 25} In children, obesity, especially truncal obesity, has been shown to associate with both fasting and postglucose insulin response.^{23 26 27} The present study shows that the persistence of insulin levels at the highest or the lowest quartile relates to a 50% difference in body weight and a 45% difference in BMI, a measure of overall adiposity. Whether the observed increases in overall adiposity reflect truncal obesity is not clear, although hyperinsulinemia is often associated with increased abdominal and subscapular fat deposits.^{24 25} Earlier observations clearly showed a strong relation of subscapular skinfold as an index of central obesity, associated with risk factors and insulin levels.²³

The relation between insulin and blood pressure has been investigated in various cross-sectional^{6 8} and longitudinal studies.^{28 29 30 31} In some of these studies,³¹ obesity is a determining factor for the insulin–blood pressure relation. In the present study, the relation between insulin and blood pressure was readily apparent, especially for systolic blood pressure. This positive association between insulin and blood pressure was further supported by the 2.5-fold higher prevalence of hypertension noted in the young adults with persistently elevated insulin levels.

The association between elevated insulin and adverse levels of lipoproteins has been documented in several studies.^{7 32 33} Results from the present study are consistent with these findings. It is of interest that dyslipidemia was three times as prevalent in young adults with persistent insulin elevation.

Of particular interest is the significantly higher prevalence of parental history of diabetes mellitus and hypertension in the cohort with persistently high levels of insulin. This increased prevalence is important in showing the potential significance of differences in insulin metabolism in children and adolescents as determinants of the development of cardiovascular disease as they mature into adulthood. Parental history can be used as a surrogate measure of future risk of morbidity in this relatively young adult cohort, given the familial aggregation of cardiovascular diseases. Studies have suggested that adverse levels of serum lipoproteins, insulin, and blood pressure precede the onset of diabetes mellitus.^{34 35} Unexpectedly, there was no increase in the prevalence of heart attacks in parents of the cohort with persistently high levels of insulin. The young age of parents may limit this association. Furthermore, the multifactorial nature of coronary artery disease³⁶ might obscure the association.

The present study demonstrates that significant clustering of obesity, hypertension, and dyslipidemia occurs primarily among young individuals with persistently elevated levels of insulin. Ubiquitous association of these clinical conditions seen among middle-aged adults has been called syndrome X,⁹ insulin resistance syndrome,¹¹ or deadly quartet.³⁷ Insulin resistance is considered to play a pathophysiological role in this multiple metabolic disorder.^{9 10 11} Although several prospective studies have suggested that plasma insulin relates to subsequent coronary artery disease,^{4 38 39} the role of insulinemia as a direct risk factor for development of atherosclerosis is far from settled.^{40 41}

The presence of multiple cardiovascular risk factors and parental cardiovascular diseases among young individuals with persistently high insulin levels points to the need for preventive measures early in life. Universal adoption of a healthy lifestyle, including prudent diet and exercise, if undertaken early in life, may have a long-term salutary effect with respect to the early onset of coronary heart disease, hypertension, and diabetes mellitus.

	Acknowledgments

 
This research was supported by grant HL-38844 from the National Heart, Lung, and Blood Institute of the US Public Health Service. The Bogalusa Heart Study is a joint effort of the many investigators and staff members, whose cooperation is gratefully acknowledged. We thank the Bogalusa Heart Study field staff and the Core Laboratory staff. We especially thank the Bogalusa schools, teachers, parents, and, particularly, children and young adults from Bogalusa, La.

Received January 1, 1995; revision received June 12, 1995; accepted August 25, 1995.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Stout RW. Insulin and atheroma: 20-year perspective. Diabetes Care. 1990;13:631-654. [Abstract]
   
2. Welborn TA, Wearne K. Coronary heart disease incidence and cardiovascular mortality in Busselton with reference to glucose and insulin concentrations. Diabetes Care. 1979;2:154-160. [Abstract]
   
3. Ducimetiere P, Eschwege E, Papoz L, Richard JL, Claude JR, Rosselin G. Relationship of plasma insulin levels to the incidence of myocardial infarction and coronary heart disease mortality in a middle-aged population. Diabetologia. 1980;19:205-210. [Medline] [Order article via Infotrieve]
   
4. Pyörälä K, Savolainen E, Kaukola S, Haapakoski J. Plasma insulin as coronary heart disease risk factor: relationship to other risk factors and predictive value during 9-1/2 year follow-up of the Helsinki Policeman Study population. Acta Med Scand Suppl. 1985;701:38-52. [Medline] [Order article via Infotrieve]
   
5. Jiang X, Srinivasan SR, Bao W, Berenson GS. Association of fasting insulin with blood pressure in young individuals: the Bogalusa Heart Study. Arch Intern Med. 1993;153:323-328. [Abstract]
   
6. Manolio TA, Savage PJ, Burke GJ, Liu KA, Wagenknecht LE, Sidney S. Association of fasting insulin and blood pressure and lipids in young adults: the CARDIA adults. Arteriosclerosis. 1990;10:430-436. [Abstract/Free Full Text]
   
7. Orchard TJ, Becker DJ, Bates M, Kuller LH, Drash AL. Plasma insulin and lipoprotein concentrations: an atherogenic association? Am J Epidemiol. 1983;118:326-337. [Abstract/Free Full Text]
   
8. Modan M, Halkin H, Fuchs Z, Lusky A, Chetrit A, Eshkol A, Segal P, Almog S, Shefi M. Hyperinsulinemia: a link between hypertension, obesity, and glucose intolerance. J Clin Invest. 1985;75:809-817.
   
9. Reaven GM. Role of insulin resistance in human disease: Banting Lecture 1988. Diabetes. 1988;37:1595-1607. [Abstract]
   
10. DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 1991;14:173-194. [Abstract]
    
11. Haffner SM, Valdez RZ, Hazuda HP, Mitchess BD, Morales PA, Stern MP. Prospective analyses of the insulin-resistance syndrome (syndrome X). Diabetes. 1992;41:716-722.
    
12. Burke GL, Webber LS, Srinivasan SR, Radhakrishnamurthy B, Berenson GS. Fasting plasma glucose and insulin levels and their relationship to cardiovascular risk factors in children: Bogalusa Heart Study. Metabolism. 1986;35:441-446. [Medline] [Order article via Infotrieve]
    
13. Rönnemaa T, Knip M, Lautala P, Viikari J, Uhari M, Leino A, Kaprio EA, Salo MK, Dahl M, Nuutinen EM, Pesonen E, Pietikäien M, Akerblom HK. Serum insulin and other cardiovascular risk indicators in children, adolescents and young adults. Ann Med. 1991;23:67-72. [Medline] [Order article via Infotrieve]
    
14. Bao W, Srinivasan SR, Berenson GS. Persistence of multiple cardiovascular risk clustering related to syndrome X from childhood to young adulthood: the Bogalusa Heart Study. Arch Intern Med. 1994;154:1842-1847. [Abstract]
    
15. Berenson GS, McMahan CA, Voors AW, Webber LS, Srinivasan SR, Frank GC, Foster TA, Blonde CV. Cardiovascular Risk Factors in Children: The Early Natural History of Atherosclerosis and Essential Hypertension. New York, NY: Oxford University Press; 1980.
    
16. Allain CC, Poon LS, Chan CSG, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem. 1974;20:470-475. [Abstract]
    
17. Bucolo G, David H. Quantitative determination of serum triglycerides by the use of enzymes. Clin Chem. 1973;19:476. Abstract. [Abstract]
    
18. Srinivasan SR, Berenson GS. Serum lipoproteins in children and methods for study. In: Lewis LA, ed. CRC Handbook of Electrophoresis. Vol. III. Lipoprotein Methodology and Human Studies. Boca Raton, Fla: CRC Press; 1983:185-204.
    
19. SAS Institute Inc. SAS/STAT User's Guide, Version 6, Fourth Edition. Cary, NC: SAS Institute Inc; 1989.
    
20. Must A, Dallal GE, Dietz WH. Reference data for obesity: 85th and 95th percentiles of body mass index (wt/ht²) and triceps skinfold thickness. Am J Clin Nutr. 1991;53:839-846. [Abstract/Free Full Text]
    
21. Himes JH, Dietz WH. Guidelines for overweight in adolescent preventive services: recommendations from an expert committee. Am J Clin Nutr. 1994;59:307-316. [Abstract/Free Full Text]
    
22. Summary of the Second Report of the National Cholesterol Education Program (NCE) Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA. 1993;269:3015-3023. [Medline] [Order article via Infotrieve]
    
23. Freedman DS, Srinivasan SR, Burke GL, Smoak CG, Shear CL, Harsha DW, Webber LS, Berenson GS. Relation of body fat distribution to hyperinsulinemia in children and adolescents: the Bogalusa Heart Study. Am J Clin Nutr. 1987;46:403-410. [Abstract/Free Full Text]
    
24. Stern MP, Haffner SM. Body fat distribution and hyperinsulinemia as risk factors for diabetes and cardiovascular disease. Arteriosclerosis. 1986;6:123-130. [Abstract/Free Full Text]
    
25. Kissebah AH, Vydelingam N, Murray R, Evans DJ, Hartz AJ, Kalkhoff RK, Adams PW. Relation of body fat distribution to metabolic complications of obesity. J Clin Endocrinol Metab. 1982;56:254-260.
    
26. Garcia-Webb P, Bonser A, Wearne KL, Gracey M. Obesity and insulin secretion in fasting high school students. Diabetologia. 1980;19:194-197. [Medline] [Order article via Infotrieve]
    
27. Voors AW, Harsha DW, Webber LS, Radhakrishnamurthy B. Clustering of anthropometric parameters, glucose tolerance, and serumlipids in children with high and low ß- and pre-ß-lipoproteins: Bogalusa Heart Study. Arteriosclerosis. 1982;2:346-355. [Abstract/Free Full Text]
    
28. Mitchell BD, Haffner SM, Hazuda HP, Valdez R, Stern MP. The relation between serum insulin levels and 8-year changes in lipid, lipoprotein, and blood pressure levels. Am J Epidemiol. 1992;136:12-22. [Abstract/Free Full Text]
    
29. Flack JM, Liu K, Savage P, Jacobs DR Jr, Nelson E, Gardin J, Folsom AR, Sidney S. Baseline fasting insulin predicts 2 year blood pressure change in young adults: the CARDIA Study. Circulation. 1991;83:724. Abstract.
    
30. Jiang X, Srinivasan SR, Bao W, Berenson GS. Association of fasting insulin with longitudinal changes in blood pressure in children and adolescents: the Bogalusa Heart Study. Am J Hypertens. 1993;6:564-569. [Medline] [Order article via Infotrieve]
    
31. Weinsier RL, Norris DJ, Birch R, Bernstein RS, Pi-Sunyer FX, Yang MU, Wang J, Pierson RN Jr, Van Itallie TB. Serum insulin and blood pressure in an obese population. Int J Obes. 1986;10:11-17. [Medline] [Order article via Infotrieve]
    
32. Zavaroni I, Bonora E, Pagliara M, Dall'Aglio E, Lucketti L, Buonanno G, Bonati PA, Bergonzani M, Grundi L, Passeri M. Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance. N Engl J Med. 1989;320:702-706. [Abstract]
    
33. Jiang X, Srinivasan SR, Webber LS, Wattigney WA, Berenson GS. Association of fasting insulin with serum lipids and lipoproteins in children, adolescents and young adults: the Bogalusa Heart Study. Arch Intern Med. In press.
    
34. Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK. Cardiovascular risk factors in confirmed prediabetic individuals: does the clock for coronary heart disease start ticking before the onset of clinical diabetes? JAMA. 1990;263:2893-2898. [Abstract]
    
35. McPhillips JB, Barrett-Connor E, Wingard DL. Cardiovascular disease risk factors prior to the diagnosis of impaired glucose tolerance and non-insulin-dependent diabetes mellitus in a community of older adults. Am J Epidemiol. 1990;131:443-453. [Abstract/Free Full Text]
    
36. Castelli WP. Epidemiology of coronary heart disease: the Framingham Study. Am J Med. 1984;76:4-12. [Medline] [Order article via Infotrieve]
    
37. Kaplan NM. The deadly quartet: upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med. 1989;149:1514-1520. [Abstract]
    
38. Fontbonne A, Charles MA, Thibult N, Richard JL, Claude JR, Warnet JM, Rosselin GE, Eschwege E. Hyperinsulinaemia as a predictor of coronary artery disease mortality in a healthy population: the Paris Prospective Study, 15 year follow-up. Diabetologia. 1991;34:356-361. [Medline] [Order article via Infotrieve]
    
39. Cullen K, Stenhouse NS, Wearne KL, Welborn TA. Multiple regression analysis of risk factors for cardiovascular disease and cancer mortality in Busselton, Western Australia: 13 year study. J Chron Dis. 1983;36:371-377. [Medline] [Order article via Infotrieve]
    
40. Jarrett RJ. Why is insulin not a risk factor for coronary heart disease? Diabetologia. 1994;37:945-947. [Medline] [Order article via Infotrieve]
    
41. Stern MP. The insulin resistance syndrome: the controversy is dead, long live the controversy! Diabetologia. 1994;37:956-958.[Medline] [Order article via Infotrieve]
    

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				J. A. Morrison, L. A. Friedman, and C. Gray-McGuire Metabolic Syndrome in Childhood Predicts Adult Cardiovascular Disease 25 Years Later: The Princeton Lipid Research Clinics Follow-up Study Pediatrics, August 1, 2007; 120(2): 340 - 345. [Abstract] [Full Text] [PDF]

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				H. M. Kim, J. Park, H.-S. Kim, D. H. Kim, and S. H. Park Obesity and Cardiovascular Risk Factors in Korean Children and Adolescents Aged 10-18 Years from the Korean National Health and Nutrition Examination Survey, 1998 and 2001 Am. J. Epidemiol., October 15, 2006; 164(8): 787 - 793. [Abstract] [Full Text] [PDF]

				A. R. Sinaiko, J. Steinberger, A. Moran, C.-P. Hong, R. J. Prineas, and D. R. Jacobs Jr Influence of Insulin Resistance and Body Mass Index at Age 13 on Systolic Blood Pressure, Triglycerides, and High-Density Lipoprotein Cholesterol at Age 19 Hypertension, October 1, 2006; 48(4): 730 - 736. [Abstract] [Full Text] [PDF]

				K. A. Waters, S. Sitha, L. M. O'Brien, S. Bibby, C. de Torres, S. Vella, and R. de la Eva Follow-up on Metabolic Markers in Children Treated for Obstructive Sleep Apnea Am. J. Respir. Crit. Care Med., August 15, 2006; 174(4): 455 - 460. [Abstract] [Full Text] [PDF]

				L. Pacifico, L. Di Renzo, C. Anania, J. F Osborn, F. Ippoliti, E. Schiavo, and C. Chiesa Increased T-helper interferon-{gamma}-secreting cells in obese children. Eur. J. Endocrinol., May 1, 2006; 154(5): 691 - 697. [Abstract] [Full Text] [PDF]

				R. Tauman, L. M. O'Brien, A. Ivanenko, and D. Gozal Obesity Rather Than Severity of Sleep-Disordered Breathing as the Major Determinant of Insulin Resistance and Altered Lipidemia in Snoring Children Pediatrics, July 1, 2005; 116(1): e66 - e73. [Abstract] [Full Text] [PDF]

				A. Jessup and J. S. Harrell The Metabolic Syndrome: Look for It in Children and Adolescents, Too! Clin. Diabetes, January 1, 2005; 23(1): 26 - 32. [Full Text] [PDF]

				P. D. Reaven, T. Traustadottir, J. Brennan, and P. R. Nader Cardiovascular Risk Factors Associated With Insulin Resistance in Children Persist Into Late Adolescence Diabetes Care, January 1, 2005; 28(1): 148 - 150. [Full Text] [PDF]

				S. Cook, M. Weitzman, P. Auinger, M. Nguyen, and W. H. Dietz Prevalence of a Metabolic Syndrome Phenotype in Adolescents: Findings From the Third National Health and Nutrition Examination Survey, 1988-1994 Arch Pediatr Adolesc Med, August 1, 2003; 157(8): 821 - 827. [Abstract] [Full Text] [PDF]

				V. Biton, P. Levisohn, S. Hoyler, A. Vuong, and A. E. Hammer Lamotrigine Versus Valproate Monotherapy--Associated Weight Change in Adolescents With Epilepsy: Results From a Post Hoc Analysis of a Randomized, Double-Blind Clinical Trial J Child Neurol, February 1, 2003; 18(2): 133 - 139. [Abstract] [PDF]

				M. R. Denburg, M. E. Silfen, A. M. Manibo, D. Chin, L. S. Levine, M. Ferin, D. J. McMahon, C. Go, and S. E. Oberfield Insulin Sensitivity and the Insulin-Like Growth Factor System in Prepubertal Boys with Premature Adrenarche J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5604 - 5609. [Abstract] [Full Text] [PDF]

				A. M Tershakovec, A. F Jawad, N. O Stouffer, A. Elkasabany, S. R Srinivasan, and G. S Berenson Persistent hypercholesterolemia is associated with the development of obesity among girls: the Bogalusa Heart Study Am. J. Clinical Nutrition, October 1, 2002; 76(4): 730 - 735. [Abstract] [Full Text] [PDF]

				H. S. Randeva, K. C. Lewandowski, J. Drzewoski, K. Brooke-Wavell, C. O'Callaghan, L. Czupryniak, E. W. Hillhouse, and G. M. Prelevic Exercise Decreases Plasma Total Homocysteine in Overweight Young Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4496 - 4501. [Abstract] [Full Text] [PDF]

				P. Marques-Vidal, E. Mazoyer, V. Bongard, P. Gourdy, J.-B. Ruidavets, L. Drouet, and J. Ferrieres Prevalence of Insulin Resistance Syndrome in Southwestern France and Its Relationship With Inflammatory and Hemostatic Markers Diabetes Care, August 1, 2002; 25(8): 1371 - 1377. [Abstract] [Full Text] [PDF]

				G. S. Berenson, S. R. Srinivasan, W. Bao, W. P. Newman, R. E. Tracy, W. A. Wattigney, and The Bogalusa Heart Study Association between Multiple Cardiovascular Risk Factors and Atherosclerosis in Children and Young Adults N. Engl. J. Med., June 4, 1998; 338(23): 1650 - 1656. [Abstract] [Full Text] [PDF]

				P. Reaven, P. R. Nader, C. Berry, and T. Hoy Cardiovascular Disease Insulin Risk in Mexican-American and Anglo-American Children and Mothers Pediatrics, April 1, 1998; 101 (4): e12 - e12. [Abstract] [Full Text] [PDF]

				J W G Yarnell, C C Patterson, D Bainton, and P M Sweetnam Is metabolic syndrome a discrete entity in the general population? Evidence from the Caerphilly and Speedwell population studies Heart, March 1, 1998; 79(3): 248 - 252. [Abstract] [Full Text]

				W. H. Dietz Childhood Weight Affects Adult Morbidity and Mortality J. Nutr., February 1, 1998; 128(2): 411 - 411. [Abstract] [Full Text]

				E. Ferrannini, A. Natali, B. Capaldo, M. Lehtovirta, S. Jacob, and H Yki-Jarvinen Insulin Resistance, Hyperinsulinemia, and Blood Pressure : Role of Age and Obesity Hypertension, November 1, 1997; 30(5): 1144 - 1149. [Abstract] [Full Text]

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