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Disease in the Young) and the Diabetes Committee (Council on Nutrition, factors in childhood to diabetes and cardiovascular disease …

Obesity, Insulin Resistance, Diabetes, and Cardiovascular Risk in Children: An American Heart Association Scientific Statement From the Atherosclerosis, Hypertension, and Obesity in the Young Committee Council on Cardiovascular Disease in the Young and the Diabetes Committee Council on Nutrition, Physical Activity, and Metabolism Julia Steinberger and Stephen R Daniels Circulation 2003;107;1448-1453 DOI: 101161/01CIR000006092307573F2
Circulation is published by the American Heart Association 7272 Greenville Avenue, Dallas, TX 72514 Copyright 2003 American Heart Association All rights reserved Print ISSN: 0009-7322 Online ISSN: 1524-4539

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AHA Scientific Statement
Obesity, Insulin Resistance, Diabetes, and Cardiovascular Risk in Children
An American Heart Association Scientific Statement From the Atherosclerosis, Hypertension, and Obesity in the Young Committee Council on Cardiovascular Disease in the Young and the Diabetes Committee Council on Nutrition, Physical Activity, and Metabolism
This statement was reviewed by the American Diabetes Association The recommendations contained herein are consistent with the American Diabetes Associations Clinical Practice Recommendations
Julia Steinberger, MD; Stephen R Daniels, MD, PhD
therosclerotic cardiovascular disease is the No 1 killer in the adult population of Western societies,1 but the pathological processes and risk factors associated with its development have been shown to begin during childhood2 Obesity plays a central role in the insulin resistance syndrome, which includes hyperinsulinemia, hypertension, hyperlipidemia, type 2 diabetes mellitus, and an increased risk of atherosclerotic cardiovascular disease The incidence of type 2 diabetes reported in
children has increased alarmingly3,4 Resistance of the body to the actions of insulin results in increased production of this hormone by the pancreas and ensuing hyperinsulinemia Obesity beginning in childhood often precedes the hyperinsulinemic state Other components of the insulin resistance syndrome are also present in children and adolescents5,6 An association between obesity and insulin resistance has been reported in the young, as has the link between insulin resistance, hypertension, and abnormal lipid profile There is an increasing amount of data showing that being overweight during childhood and adolescence is significantly associated with insulin resistance, dyslipidemia, and elevated blood pressure in young adulthood Weight loss by obese youngsters results in a decrease in insulin concentration and improvement in insulin sensitivity Moreover, it has been determined that increased left ventricular mass, which is an independent risk factor for cardiovascular disease in adults, is present in childhood Recent research has found that left ventricular hypertrophy is related to other risk factors, including obesity and insulin resistance in children and adolescents7 The
specifics of the transition from risk

A

factors in childhood to diabetes and cardiovascular disease are not clear, but compelling evidence points to their association with overt disease in adults On the basis of current knowledge and extrapolation from studies in adults, it is reasonable to suggest that lifestyle modification and weight control in childhood could reduce the risk of developing the insulin resistance syndrome, type 2 diabetes mellitus, and cardiovascular disease

Obesity and the Insulin Resistance Syndrome
Obesity increases the risk of cardiovascular disease in adults and has been strongly associated with insulin resistance in normoglycemic persons and in individuals with type 2 diabetes8,9 Data from the Framingham study have established an increased incidence of cardiovascular events with increasing weight in both men and women10 Body weight and mortality were directly related in the Harvard Alumni Health Study,11 and weight gain was a significant risk factor for development of diabetes mellitus in women12 The association of obesity with the insulin resistance syndrome and cardiovascular risk is not only related to the degree of obesity but also seems to be
critically dependent on body fat distribution Thus, individuals with greater degrees of central adiposity develop this syndrome more frequently than do those with a peripheral body fat distribution13 Studies in obese adults have shown sustained improvement in cardiovascular risk in association with a 10 to 15 weight loss maintained over time14 One other report, however, suggested that a weight loss of 16 resulted in a

The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on December 27, 2002 A single reprint is available by calling 800-242-8721 US only or writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX 75231-4596 Ask for reprint No 71-0251 To
purchase additional reprints: up to 999 copies, call 800-611-6083 US only or fax 413-665-2671; 1000 or more copies, call 410-528-4426, fax 410-528-4264, or e-mail klbradle@lwwcom To make photocopies for personal or educational use, call the Copyright Clearance Center, 978-750-8400 Circulation 2003;107:1448-1453 2003 American Heart Association, Inc Circulation is available at http://wwwcirculationahaorg DOI: 101161/01CIR000006092307573F2

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Steinberger and Daniels
differential risk factor response, including a dramatic reduction in the incidence of type 2 diabetes but not in the 8-year incidence of hypertension15 An association between adiposity and insulin resistance has been reported in adults and children16,17 Weight loss is associated with a decrease in insulin concentration and an increase in insulin sensitivity in adults18 and adolescents19 In a study of 122 adolescents, obese individuals were significantly more insulin resistant and had an abnormal lipid profile when compared with lean subjects5; in this study, insulin resistance was significantly related to an abnormal lipid profile in heavy children but not in
thin children, and insulin resistance varied directly with the degree of adiposity Obesity and insulin resistance have also been shown to be associated with other risk factors, such as elevated blood pressure Ethnic and sex differences occur in the insulin resistance syndrome in the United States, with a greater prevalence demonstrated in men and in African Americans20

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Hypertension and the Insulin Resistance Syndrome
Essential hypertension is the clinical expression of a disordered interaction between the genetic, physiological, and biochemical systems that under usual conditions maintain cardiovascular homeostasis The multifactorial nature of essential hypertension has made it difficult to completely isolate the action of any one of these systems from the actions of the others The relation between insulin metabolism/resistance and essential hypertension has the potential to provide insight into the mechanisms that operate this complex interaction2125 Insulin increases renal sodium retention26 29 while increasing free water clearance Insulin resistance is also associated with increased sympathetic nervous system activity30 and stimulation of
vascular smooth muscle growth31 Insulin levels have been found to be significantly higher in adult patients with essential hypertension3234 and borderline hypertension35 than in normotensive control patients This is true whether insulin is measured in the fasting state3234,35 or in response to the oral glucose tolerance test,3234 the insulin suppression test, or the euglycemic insulin clamp technique33,35 Moreover, these differences have been reported to be independent of age, sex, and ethnic group3235 A confounding factor in the insulin hypertension link is obesity In most of the worlds populations, blood pressure is directly correlated with body weight Numerous studies have confirmed the association between weight gain, percent body fat, and insulin resistance21,36 39 Other studies, however, have indicated that an interaction exists between insulin and hypertension that is independent of their interaction with obesity40 The Coronary Artery Risk Development In young Adults CARDIA study of 4576 young adults reported a weight-independent association between fasting insulin concentration and hypertension41 Thus, it is clear that several questions about the association between blood
pressure and the syndrome of insulin resistance remain unanswered Although the prevalence of essential hypertension in children is low, the precursors of this disease are present long before clinically accepted levels of hypertension are recognized Substantial evidence from genetic and epidemiological studies confirms that blood pressure tracks over

time and that the roots of essential hypertension extend into the first and second decades of life42,43 There is a strong genetic influence on blood pressure that in some can be identified early in childhood44 and that is intensified in the presence of other risk factors45 Several studies have addressed the association between insulin and blood pressure in children and adolescents Interactions similar to those identified in adults also may be found at a young age The Bogalusa Heart Study has shown a positive correlation between blood pressure and fasting insulin, even after adjustment for body mass index, as early as 5 years of age46 Insulin resistance has been found in young black men early twenties with only borderline hypertension, independent of body mass index35 Several mechanisms through which blood pressure may be linked with
insulin resistance have been proposed In adolescents, the resistance to insulin has been associated with chronic sodium retention47 and sodium sensitivity,48 and this is reversible with weight loss and exercise18 Moreover, obese, insulin-resistant adolescents have increased forearm vascular resistance that is reversible with weight loss49 Of particular interest, normotensive adolescent offspring mean age of 13 years of hypertensive parents were found to have significantly higher serum insulin levels after an overnight fast and an intravenous glucose load, which suggests that insulin resistance predates an increase in blood pressure in subjects with a genetic predisposition to hypertension50 Because multiple mechanisms contribute to the development of hypertension, it is difficult to isolate the contribution of obesity and/or hyperinsulinemia

Lipid Abnormalities and the Insulin Resistance Syndrome
Insulin resistance has been hypothesized to play a major role in dyslipidemia in individuals with normal glucose tolerance, as well as in those with impaired glucose tolerance and type 2 diabetes51,52 Lipid abnormalities have also been reported in obese adults, who have elevated
triglycerides and LDL cholesterol and low levels of HDL cholesterol53,54 Similar lipid profiles have been reported in obese and nonobese adults with type 2 diabetes, in obese normoglycemic adults, and in nonobese adults with impaired glucose tolerance5557 The association between obesity and dyslipidemia observed in adults also has been documented also in children and adolescents In the Lipid Research Clinics Population Studies Data Book, obese adolescents had an abnormal atherogenic lipid profile consisting of elevated LDL cholesterol and triglycerides and low HDL cholesterol In more recent studies in children, insulin resistance was also implicated in the association between obesity and dyslipidemia In a study of insulin resistance and lipids that compared 82 normoglycemic, obese adolescents with 40 lean adolescents, abnormalities consistent with an atherogenic lipid profile were present in the obese subjects The dyslipidemia correlated with the degree of insulin resistance in the obese children, and it was shown that the degree of insulin resistance explained a significant portion of the variance in the levels of triglycerides, LDL cholesterol, and HDL cholesterol5 Investigators
from the Bogalusa Heart Study reported that overweight schoolchildren, in comparison with their lean counterparts,

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index, waist circumference [a measure of central adiposity], or other methods and determination of blood pressure and cholesterol should become part of the evaluation of any child with the risk profile described above Insulin resistance is measured by an accurate but rather complicated method: the euglycemic insulin clamp This technique involves the continuous intravenous administration of insulin and glucose over 3 hours and the calculation of insulin sensitivity the inverse of insulin resistance by measuring the amount of glucose required to maintain normal glucose levels euglycemia66 The euglycemic clamp currently is used for research purposes only Although less accurate than the euglycemic clamp method, assessment of hyperinsulinemia from fasting plasma insulin levels and estimation of insulin resistance from indices based on fasting glucose and insulin levels have been proposed as reasonable alternative methods for evaluating insulin resistance

were 24 to 71 times more
likely to have elevated total cholesterol, LDL cholesterol, and triglycerides, and 126 times more likely to have hyperinsulinemia58 Several mechanisms whereby insulin resistance could cause an alteration in lipid metabolism have been described Hyperinsulinemia is known to enhance hepatic very-lowdensity lipoprotein synthesis and thus may directly contribute to the increased plasma triglyceride and LDL cholesterol levels59 Resistance to the action of insulin on lipoprotein lipase in peripheral tissues may also contribute to elevated triglyceride and LDL cholesterol levels60,61 It has been suggested that insulin resistance may be responsible for the reduced levels of HDL cholesterol observed in type 2 diabetes patients and that despite enhanced HDL cholesterol synthesis, the plasma HDL cholesterol concentration was significantly reduced in patients with type 2 diabetes versus control subjects; this decrease in plasma HDL cholesterol was accounted for entirely by an increase in the rate of apolipoprotein A1/HDL cholesterol degradation, which exceeded the enhanced rate of its synthesis62 Other intrinsic metabolic factors, such as apolipoproteins, lipoprotein A, and homocysteine, are
known to influence the development of cardiovascular disease; their potential relationship to the insulin resistance syndrome remains to be clarified

Type 2 Diabetes Mellitus in Children and Adolescents
Type 2 diabetes mellitus has long been considered a disease of adults, in whom it is the most prevalent form of diabetes 90 and is associated with increased risk of cardiovascular disease morbidity and mortality67 During the past 10 years, however, an increasing frequency in the occurrence of type 2 diabetes mellitus has been reported in adolescents3 There are now reports in the literature of type 2 diabetes in Native American, Hispanic, African-American, South Asian, and white youth4 This increase in frequency of type 2 diabetes seems to parallel the increase in prevalence and severity of obesity in children and adolescents68 Type 2 diabetes is often asymptomatic in its early stages This makes the diagnosis difficult without an awareness of the subtle characteristics that should prompt further work-up Some patients are diagnosed with the typical symptoms of polyuria and polydipsia, and some develop ketoacidosis69 Others are asymptomatic or may have nonspecific findings, such as
vaginal moniliasis3 Some patients are identified when glycosuria is found on routine testing for sports, school, or employment examinations4 Obesity, acanthosis nigricans, and a positive family history of diabetes are common in adolescents with type 2 diabetes At diagnosis, the fasting C peptide and insulin concentrations are often elevated, and antibodies to pancreatic islet cells are generally absent70 Glycosylated hemoglobin concentrations may be elevated but variable according to how early in the course of the disease the diagnosis is made71,72 Children with type 2 diabetes are usually diagnosed after age 10 years This may be in part due to the physiological insulin resistance seen with the hypersomatotropic state of puberty, which may contribute to the exacerbation of the disease Adolescents with type 2 diabetes mellitus are almost always obese The mean body mass index in clinical series has ranged from 26 to 38 kg/m24 Patients with type 2 diabetes often have other risk factors for cardiovascular disease The prevalence of elevated blood pressure has ranged from 17 to 32 The prevalence of hypertriglyceridemia has ranged from 4 to 324 In one study, 6 had a clinical diagnosis of
sleep apnea3

Assessment
Our understanding of the insulin resistance syndrome in children is evolving, and there is no general agreement about the overall assessment and treatment of this syndrome Although the end points for cardiovascular risk are not seen in childhood, the components of the insulin resistance syndrome obesity, hypertension, dyslipidemia, and hyperinsulinemia track from childhood into adulthood, which supports the conclusion that the precursors of cardiovascular disease are present early in life63,64 Because insulin resistance often is associated with type 2 diabetes, the first step in assessment is to identify children who would benefit from intervention Testing has been recommended for children at significant risk for the presence or development of type 2 diabetes65 These are children who in general: 1 are overweight; 2 have a family history of type 2 diabetes; 3 have a predisposition based on race/ethnicity American Indian, African American, Hispanic, Asian/Pacific Islander; and 4 have signs of insulin resistance or conditions associated with insulin resistance eg, acanthosis nigricans, hypertension, dyslipidemia, polycystic ovary syndrome The diagnosis of
diabetes can be made by using either the fasting plasma glucose or the 2-hour value on an oral glucose tolerance test The fasting glucose determination is preferred At this time, sufficient data are not available to support the use of the HbA1c in the diagnosis of diabetes It is important to remember that even in the face of a normal fasting glucose level, the child may have diabetes or remain at risk for developing type 2 diabetes Children who do not have elevated blood glucose concentrations may exhibit other features of the insulin resistance syndrome, such as obesity, hypertension, and high cholesterol, and they remain at risk for cardiovascular disease and diabetes Body size measurements expressed by body mass

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Because type 2 diabetes is a relatively recent problem in adolescents, few data on long-term follow-up exist One study of Pima Indians monitored 36 individuals for a mean of 10 years until they reached a median age of 26 years In this cohort, at baseline age 5 to 19 years, 85 were obese, 14 had hypertension, 30 had total cholesterol 200 mg/dL, and 55 had triglyceride concentrations 200
mg/dL Fiftyeight percent of the patients had microalbuminuria and 16 a urinary albumin/creatinine ratio 300 mg/g, which indicated that the renal effects of diabetes were already present at diagnosis After 10 years of follow-up, the number of patients with increased urinary albumin excretion was significantly increased, as was the magnitude of albuminuria73 Thus, these patients have a constellation of risk factors that place them at increased risk of cardiovascular disease at an early age The pathophysiology of the development of type 2 diabetes mellitus is complex and multifactorial It is believed that obesity leads to insulin resistance and increased circulating insulin concentrations over time It seems that at some point a loss of control of blood glucose begins to emerge, resulting in dietary glucose intolerance This ultimately results in type 2 diabetes It is known that obese individuals may develop different degrees of insulin resistance, and not all individuals develop glucose intolerance The factors that make some individuals more likely to progress to type 2 diabetes mellitus are not well understood at the present time A strong family predisposition is known to exist;
therefore, parental history is important in risk assessment In the future, genetic markers may help identify those offspring of diabetic parents who are greatest risk of developing diabetes The treatment of type 2 diabetes mellitus in adolescents is similar to the treatment in adults Because obesity is the major underlying factor, patients are counseled on an improved, calorie-restricted diet and increased physical activity to achieve better energy balance and weight loss It is not currently known what level of weight loss is necessary for adolescents to achieve improved glucose handling In adults, it seems that a 10 to 15 weight loss has substantial benefit Patients may also be treated with oral agents Future studies may answer questions about the safety and efficacy of oral agents in children in general, and specifically about the safety and efficacy of medications that increase insulin sensitivity, such as glitazones Some adolescents with type 2 diabetes mellitus may require administration of insulin to achieve control of their diabetes Type 2 diabetes mellitus seems to be emerging as a major public health problem for adolescents The early onset of type 2 diabetes suggests that
these patients will be at risk for the development of cardiovascular disease at a young age If the secular trend seen with increasing prevalence and severity of obesity in childhood and adolescence continues, it is likely that the problem of type 2 diabetes also will increase in the pediatric age group74

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the putative earliest point in the development of cardiovascular risk This may result in important information on the etiologic relations between early indicators of the insulin resistance syndrome, type 2 diabetes, and establishment of risk in young adulthood As more research evidence is accumulated, it is also important to deal with the problems of insulin resistance and type 2 diabetes in children and adolescents from a clinical standpoint The first approach should focus on prevention of obesity in childhood More attention should be paid to increasing physical activity and decreasing calorie consumption in this age group Once obesity is established in a child or adolescent, vigorous clinical efforts should be directed at treating it At present, this involves therapy directed at behavior change, but in the future it may include
pharmacological and surgical approaches in the appropriate patients Clinicians should watch vigilantly for the subtle signs that indicate the development of insulin resistance, glucose intolerance, and type 2 diabetes Early recognition of these problems can lead to better treatment On the basis of current knowledge, it seems that better control of blood glucose is likely to lead to improved long-term microvascular and macrovascular outcomes Thus, the best approach to prevention of future cardiovascular disease in these young patients is early recognition and aggressive therapy Without this, it is likely that this patient population is destined to develop cardiovascular complications and require substantial resources for future management

References
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Significance
In the face of the major impact that adult cardiovascular disease has in the westernized societies, it seems crucial to examine further the relationships among cardiovascular risk factors at the childhoodadolescenceadulthood transition, ie,

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KEY WORDS: AHA Scientific Statements diseases obesity diabetes mellitus

pediatrics

cardiovascular

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