0021-972X/04/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 89(6):2526–2539 Printed in U.S.A. Copyright © 2004 by The Endocrine Society doi: 10.1210/jc.2004-0276 Insulin Resistance Syndrome in Children

The insulin resistance syndrome (syndrome X, metabolic syndrome) has become the major health problem of our times. Associated obesity, dyslipidemia, atherosclerosis, hypertension, and type 2 diabetes conspire to shorten life spans, while hyperandrogenism with polycystic ovarian syndrome affect the quality of life and fertility of increasing numbers of women. Whereas a growing number of single genetic diseases affecting satiety or energy metabolism have been found to produce the clinical phenotype, strong familial occurrences, especially in racially prone groups such as those from the Indian subcontinent, or individuals of African, Hispanic, and American Indian descents, together with emerging genetic findings, are revealing the polygenetic nature of the syndrome. However, the strong lifestyle factors of excessive carbohydrate and fat consumption and lack of exercise are important keys to the phenotypic expression of the syndrome. The natural history includes small for gestational age birth weight, excessive weight gains during childhood, premature pubarche, an allergic diathesis, acanthosis nigricans, striae compounded by gynecomastia, hypertriglyceridemia, hepatic steatosis, premature atherosclerosis, hypertension, polycystic ovarian syndrome, and focal glomerulonephritis appearing increasingly through adolescence into adulthood. Type 2 diabetes, which develops because of an inherent and/or an acquired failure of an insulin compensatory response, is increasingly seen from early puberty onward, as is atheromatous disease leading to coronary heart disease and stroke. A predisposition to certain cancers and Alzheimer's disease is also now recognized. The looming tragedy from growing numbers of individuals affected by obesity/insulin resistance syndrome requires urgent public health approaches directed at their early identification and intervention during childhood. Such measures include educating the public on the topic, limiting the consumption of sucrose-containing drinks and foods with high carbohydrate and fat contents, and promoting exercise programs in our nation's homes and schools.

R EAVEN (1) FIRST DESCRIBED syndrome X to comprise central obesity, hyperinsulinemia, hyperuricemia, hypertriglyceridemia, and a propensity to coronary heart disease (CHD) and stroke. The insulin resistance syndrome (IRS) has since been expanded from this core phenotype to become increasingly recognized by physicians, especially in the highly prone racial groups. A recent American College of Endocrinology position statement on IRS indicated that one in three or four U.S. adults have IRS, and 90% of diabetics are insulin resistant (IR), whereas one in 10 women have polycystic ovarian syndrome (PCOS).
The purpose of this review is to summarize the natural history of IRS, especially as it impacts children. We argue herein that attention must be urgently given to the children who are becoming more obese and more IR with time. In them, effective public health measures must be found to identify those affected as early as possible and treat them, if we are to prevent the burgeoning associated morbidities and mortalities that accumulate with their passage into adulthood.

U.S. epidemiology of obesity and type 2 diabetes
The increasing prevalence of obesity in the U.S. is alarming, with 34% of the adult population being overweight ]body mass index (BMI) ranging from 25-29.9 kg/m 2 [, and another 27% are obese (BMI, Ն30 kg/m 2 ) (2). Thus, more than 45 million Americans are obese, a 74% increase in prevalence rates from 1991. Over the same time, diabetes rates have increased by 61% to affect at least 16 million (7.7%) Americans. Adults with a BMI greater than 40 have been found to be 7.4 times more likely to develop diabetes, 6.4 times more likely to have hypertension, and 1.9 times more likely to have hypercholesterolemia and to have increased death rates from all cancers combined that are 52% higher for men and 62% higher for women than those with BMIs less than 24.9 kg/m 2 (3,4).
Insulin resistance (IR) alone is responsible for 46.8%, 6.2%, and 12.5% of the annual CHD events in type 2 diabetics, nontype 2 diabetics, and in the total U.S. population, respectively. The annual total cost of IR-attributable events in the U.S. was estimated to be $12.5 billion in 1999, of which $6.6 billion were direct medical costs. The annual cost of diabetes in medical expenditures and lost productivity climbed from $98 billion in 1997 to $132 billion in 2002. The direct medical costs of diabetes more than doubled in that time, from $44 billion in 1997 to $91.8 billion in 2002 (9). As mentioned, most diabetics have underlying IRS.
However, recent studies suggest that type 2 diabetes can be prevented. When 522 obese Finns with impaired glucose tolerance (IGT) were randomized to receive an intensive exercise and diet program, there was a 58% reduction in their progression to diabetes over a mean of 3.2 yr (10). The Diabetes Prevention Program trial (11), which involved 3234 subjects with IGT, showed a 58% reduction in progression to diabetes in the lifestyle group treatment group and a 31% decrease with metformin treatment from placebo-treated controls. Metformin was more effective in younger subjects (11). In the Troglitazone in the Prevention of Diabetes study of 235 Hispanic women with a history of gestational diabetes, a 56% reduction in progression to diabetes was observed after a median follow-up of 30 months (12). Metformin is a safe and effective agent to improve IR in pediatric patients (13)(14)(15)28). It follows that as IRS is the constant precursor of type 2 diabetes, and IRS begins in childhood, then the earlier an intervention can be initiated in the natural history of the disease, the more effective it will be.

Definitions
IR is defined as an impaired ability of plasma insulin at usual concentrations to adequately promote peripheral glucose disposal, suppress hepatic glucose, and inhibit very low density lipoprotein (VLDL) output, but it can be inferred on strong clinical evidence and confirmed by insulin and glucose measurements made by fasting insulin/glucose screening, oral glucose tolerance tests (OGTT), the minimal model frequently sampled iv glucose tolerance test (FSIVGTT), and insulin/glucose clamp studies.

Biochemical definitions
Fasting levels of insulin greater than 15 U/ml, or insulin peak (post-OGTT) levels of more than 150 U/ml and/or more than 75 U/ml at 120 min of OGTT are hyperinsulinemic levels, which infer IR (16).
Insulin sensitivity from OGTT can also be assessed by numerous indexes (Table 1). Such approaches are simple, albeit insensitive, have been validated for epidemiological studies (17,18), and correlate with the indexes of insulin sensitivity obtained from glucose clamp studies and minimal model analysis (19). The minimal model FSIVGTT is a more accurate method of quantifying insulin sensitivity (Si), acute insulin response (AIR) and disposition indexes (DI) (30). The AIR characterizes the first phase of insulin secretion that is a marker of early ␤-cell compensation (30). In nonobese children, the normal AIR range was recently reported by Gower et al. (31) to be 747 Ϯ 122 U/ml in Caucasians, 1210 Ϯ 116 U/ml in African-Americans, and 938 Ϯ 38 U/ml in Hispanic children at Tanner stages 1-3.
The DI characterizes the relationship of insulin secretion to the degree of IR. The DI calculated by (AIR ϫ Si) describes the hyperbolic relationship between insulin secretion (AIR) and Si from FSIVGTT, which is sensitive to detect even latent ␤-cell defects. Gower et al. (31) reported DI from AIR (minutes Ϫ1 ) to be in the range of 0.29 Ϯ 0.07 in Caucasian, 0.45 Ϯ 0.07 in African-American, and 0.35 Ϯ 0.05 in Hispanic children at Tanner stages 1-3.
Hyperglycemic and euglycemic-hyperinsulinemic clamp studies are well established for assessing ␤-cell function and Si, but these are relatively invasive procedures that are difficult to perform. Well accepted normal values for children with any of the described methods are still needed.

Clinical definitions
The clinical phenotype of IRS includes centrally biased obesity; characteristic skin involvements ]acanthosis nigricans (AN), skin tags, striae, acne, hirsutism, and frontal balding[; an allergic diathesis, especially as manifest by asthma; hypertension; an atherogenic dyslipidemia ]increased VLDL with raised triglycerides (TG) and reduced levels of the protective high density lipoprotein (HDL) cholesterol[; early atherosclerosis, tall stature and pseudoacromegaly (with suppressed GH levels); focal segmental glomerulosclerosis; hepatic steatosis; and adrenal and ovarian hyperandrogenism (Table 2). Importantly, IR is not infrequent in the absence of obesity, whereas even considerably obese persons can be insulin sensitive.
Obese patients thus represent heterogeneous subgroups of metabolic and phenotypical expressions of IR, whereas individuals with the same BMI can have very different degrees of IR and metabolic (insulin) compensation. However, most individuals with BMIs more than 35-40 kg/m 2 are IR. Children with BMIs higher than the 85th percentile for age and gender are classified as overweight, whereas those that are higher than the 95th percentile are designated obese (34). Adolescents and adults with BMIs of 25 kg/m 2 or more are at risk for adiposity-related morbidity, whereas those with BMI greater than 30 kg/m 2 are obese according to the World Health Organization panel.

Pathogenesis
Nature vs. nurture. The dramatic rise in obesity-associated IRS reflects environmental increased availability and consumption of food with high carbohydrate and fat contents together with decreased physical activities. Genetic predispositions to obesity favor selection of metabolically advantaged (energy thrifty) traits resulting in an enhanced ability to store excess calories in tissues as fat and to spare protein breakdown for gluconeogenesis, favoring survival in times of hunger. Genotypic factors influence the ability to use food energy efficiently through mechanisms of intraabdominal fat distribution, resting metabolic rate, changes in energy expenditure, body composition to overfeeding, feeding behavior (includ- ing food preferences), adipose tissue lipoprotein lipase activity, and the basal rate of lipolysis.
Genetic IR. The pathogenesis of IR is multifactorial (Table 3). Thus, several molecular pathways in energy homeostasis, lipid metabolism, insulin receptor signaling pathway, cytokines, hormone-binding proteins including those that are serine protease inhibitors (SERPINS), and other protease regulators are responsible for the development of IR, obesity, or lipodystrophy ( Fig. 1  Lipodystrophy associated with HIV protease inhibitors; acquired generalized lipodystrophy-Lawrence syndrome is caused by antibodies against adipocyte-membrane antigens Barraquer-Simons' syndrome (partial acquired cephalothoracic lipodystrophy) have accelerated complement activation and a serum IgG, called C3 nephritic factor, that is thought to cause lysis of adipose tissue expressing adipsin (Table 3B). In practice, however, steroid-induced IR in a person who happens to be genetically prone to IR is the most commonly encountered, especially when the obese child also has IR-associated asthma. We find this a frequent occurrence in our clinical practices. GH therapy can provoke transient IR also, but this therapeutic issue needs further study. In the small for gestational age (SGA) disorders without catch-up growth, such as the Russell-Silver syndrome, IR may develop even before GH is given.
Birth weight and length. A continuum of increased risk of adulthood diseases, such as cardiovascular diseases, type 2 diabetes, and hypertension, based upon SGA at birth is now established (38). In our African American and Hispanic IR patients, moderate SGA has been startlingly common. Experimental utero-placental insufficiency in rats to provoke intrauterine growth retardation induced an impaired oxidative phosphorylation in skeletal muscle with a diminished uptake of glucose (39). In humans, the risk of IR is particularly apparent when an SGA newborn undergoes rapid postnatal weight gains to obesity. The Early Bird Study suggested that IR at 5 yr was related not to birth weight, but, rather, to weight catch-up growth, especially in girls (40). Such growth patterns following fetal growth restraint are associated with maternal-uterine factors such as primiparity, smoking, restrictions in the maternal diet, maternal IRS, and gestational diabetes. Alternatively, if an inherited IR state was manifested in utero, then diminished fetal growth with SGA might be anticipated, because insulin is a powerful prenatal GH. In many of the families we have studied in whom we have documented members with IRS, some 50% of the siblings also develop IRS, and these subjects tend to have been SGA compared with those who do not. Curiously, large for gestational age children are at risk of IR as well. A U-shaped relation between birth weight and fasting insulin was shown in Pima Indian children with both low and high birth weights (41). The same U-shaped relation between birth weight, BMI, and fat mass was demonstrated recently in adolescents (42).
Gestational diabetes per se significantly increases the subsequent risk of obesity and type 2 diabetes (43), with the children of mothers with type 1 diabetes being more predisposed to type 2 diabetes as adults compared with children born to fathers with type 1 diabetes (44).

IR, leptin resistance, ghrelin, and satiety
The insulin/leptin-arcuate nucleus of the hypothalamus axis regulates energy homeostasis through control of appetite and energy expenditure. Both hormones rise in direct proportion to adipose mass; they cross the blood-brain barrier and have receptors in the arcuate nucleus. Leptin acts on POMC expression and ␣MSH release. ␣MSH, in turn, interacts with MC3/4R to reduce food intake and increase energy expenditure by activating the sympathetic nervous system. Leptin down-regulates anabolic NPY, agouti-related peptide (AGRP), orexins, and melaninconcentrating hormone in the hypothalamus. The central melanocortin system is a key mediator of the catabolic effects of insulin in the brain. Gastric secretion of ghrelin is increased by fasting and increases pituitary GH release, thereby stimulating lipolysis to provide energy substrates. Ghrelin stimulates NPY-AGRP to antagonize ␣MSH. The resultant lack of anorexic pressure on MC4Rs results in increased feeding behavior and energy efficiency (with reduced fat oxidation) to store energy as fat. Conversely, in the fed state, insulin and leptin levels are increased, which increases the synthesis and processing of hypothalamic POMC to its component peptides, including ␣MSH, which, together with its colocalized neuromodulator cocaine/amphetamine-regulated transcript, acts at the MC4R to decrease appetite. Insulin and leptin also directly inhibit NPY-AGRP, further limiting feeding and providing for unantagonized MC4R occupancy. Therefore, ghrelin, insulin, and leptin represent afferent hormonal links between peripheral energy metabolism and central feeding behavior and tie together the gut, pancreas, adipocyte, hypothalamus, and pituitary to form a coordinated growth and energy regulatory system (45,46). Genetic defects at many of these steps have been described.

Natural history of the clinical IRS
The natural history of IRS begins in childhood, from the interplay of genetic and environmental factors ( Fig. 2 and 3). Although it is generally unclear whether a primarily genetically encoded state of IR and/or satiety disorder appears first, IR results in hyperinsulinism and precocious development of atherosclerosis and type 2 diabetes (47). A contemporary diet from early childhood replete with large amounts of saturated fats and excess carbohydrates is probably important to the development of hyperinsulinemia and obesity. The epidemic of obesity and diabetes follows U.S. commercially driven drink and food sources, with consumption of large amounts of sodas and fruit juices, and foods with a high glycemic index. Dietary carbohydrates (and fats) induce hyperinsulinism, a reduction in fatty acid (FA) oxidation, and hypertryglyceridemia. Diets rich in saturated FAs add a strong insulinotropic effect. In children, obesity and IR precede the development of hyperinsulinism. The hyperinsulinemia can thus be seen a compensatory mechanism for the preexisting, genetically programmed IR, which represents a mechanism for protection against the development of IGT and diabetes.
Insulin hypersecretion (especially portal) leads to increased FA synthesis, especially in the liver and adipose tissue. A compensatory increase in glucose oxidation and increased malonyl coenzyme A (CoA) signaling in the face abundant FAs direct an FA diversion away from ␤-oxi-dation to compensatory increases in long-chain CoA and TG synthesis in the liver. TG in the blood is a marker of intracellular hepatic long-chain CoA accumulation and increased VLDL synthesis. Normally appetite can be suppressed by both leptin and insulin; however, diets high in fat stimulate appetite directly. The liver, in turn, becomes insensitive to compensatory leptin signaling to increase ␤-oxidation, which is blocked in IR because of high levels of malonyl CoA. Elevated levels of malonyl CoA block FA ␤ oxidation, leading to TG accumulation in muscle and liver, with impaired serine phosphorylation of insulin receptor substrate-1, decreased GLUT4 translocation, and thereby decreased glucose oxidation. In the islets, these events lead to activation of caspases and increased ceramide levels inducing apoptosis of ␤-cells. Type 2 diabetes thus results when there is insufficient insulin secretion to counter preexisting IR. This is consistent with the United Kingdom Prospective Diabetes Study findings of progressive deterioration of ␤-cell function over time in both obese and nonobese patients with type 2 diabetes (48).
In experimental rats and human patients, IR is correlated with total muscle TG, as measured in biopsy samples, especially when intramyocellular fat is the measured variable. Also, tight positive correlations were found between the TG content of skeletal muscle, liver, and whole pancreas and variables such as the plasma insulin concentration, ␤-cell function, and IR in a variety of rat models with very different fat contents (49).

Loss of first phase insulin response to predict development of diabetes
Children affected by IRS are usually hyperinsulinemic individuals in whom carbohydrates can induce a delayed, but excessive, rise in insulin secretion. This may cause an excessive fall in glucose levels 3-4 h later, of sufficient severity to provoke symptoms of hypoglycemia (late reactive hypoglycemia). As the ability to secrete insulin declines, postprandial glucose intolerance appears, followed by fasting hyperglycemia and diabetes. On the basis of iv glucose testing, insulin release consists of two phases (50). In individuals with type 2 diabetes the second phase response is diminished, and the first phase response is almost absent. However, the first phase response decreases long before the development of type 2 diabetes. In the Insulin Resistance Atherosclerosis Study, subjects who were nondiabetic at baseline (n ϭ 903) were reexamined after 5 yr when 148 had developed diabetes. Individuals who had a low AIR combined with high proinsulin levels experienced the highest diabetes risk (51). Such data were supported by the United Kingdom Prospective Diabetes Study (52) and studies in Pima Indians (53), in whom it was shown that a low AIR predicts the development of diabetes at a time when many subjects still have normal glucose tolerance. The DI is an excellent method to detect latent ␤-cell defects, albeit hyperinsulinism documented by a high AIR is a predictor of the rate of increased fat mass.

Hyperinsulinism and IR are not benign, even without diabetes
The majority of persons with IR will not develop type 2 diabetes. The genetic backgrounds on which hyperinsulinism and IR develop strongly influence the adequacy of pancreatic ␤-cell compensation (54). The heritability of ␤-cell function, assessed in relation to insulin sensitivity (Si ϫ AIR glucose), demonstrated a heritability of 70% in 94 normal glucose-tolerant individuals (55). Pancreatic ␤-cell failure can represent independent genetic interactions that may be influenced by the human leukocyte antigen haplotype.
IRS individuals who can compensate by hyperinsulinemia may escape diabetes, but are still prone to other complications, such as early atherosclerosis, progression of obesity (especially central type), AN, increased skin tags, hypertension, dyslipidemia, hypercoagulation, PCOS, fatty liver infiltration, focal segmental glomerulosclerosis, and an increased cancer rate as well (4). Thus, IRS is not benign even when diabetes does not develop.

Hyperinsulinism-and IR-mediated pathologies (Tables 2 and 4)
Adipose tissue. It is widely believed that obesity itself, especially increased visceral fat accumulation, can lead to IR (56). Genetically induced IR can be the primary mechanism underling and evoking the progression of obesity. In contrast, nonobese, lean individuals can develop IR also. It has been shown that lean sisters and brothers of patients with obesity complicated by IR and PCOS can have IR, confirming that IR can be a primary mechanism. Generalized lipodystrophy can lead to IRS because of leptin deficiency and is dramatically reversible with leptin therapy.
Visceral fat. Visceral fat is a potent modulator of insulin action on hepatic glucose production (57). Central distribution of body fat (waist/hip ratio, Ͼ0.90 in females and Ͼ1.0 in males) is associated with an increased risk of stroke, CHD, diabetes, and early mortality and is a more sensitive indicator of impending morbidity than absolute fat mass. Waist circumference correlates with cardiovascular morbidity as well as BMI or percent body fat. Leptin levels are higher in sc fat and show greater correlations with sc adiposity than with visceral adiposity (58). Visceral fat tissue, through its portal drainage, is an important source of FFA that increase hepatic lipogenesis and decrease glucose oxidation (57). In vitro (isolated adipocytes) and in vivo studies in humans (labeled FA flux) showed that visceral FA flux was increased in obese patients.
In comparison with sc fat, visceral fat has more glucocorticoid receptors and higher local concentrations of glucocorticoids. Omental adipose tissue contains significantly more 11␤-hydroxysteroid dehydrogenase type 1 (11␤HSD1) activity than sc adipose tissue (59), promoting increased cortisol production from conversion of inactive cortisone. GH (and/or IGF-I) was suggested recently to inhibit 11␤HSD1, whereas in obesity, GH levels are decreased, leading to higher 11␤HSD1 activity (60). 11␤HSD1 activity correlates with IR (61). 11␤HSD1 knockout mice have been shown to resist diet-induced IR and hyperglycemia (62). A local increase in glucocorticoid hormone action in visceral fat may contribute to the pathogenesis of key features of the metabolic syndrome. Clinically, we observed increased abdominal striae and biochemically increased urinary free cortisol levels in obesity.
Patients with Cushing's syndrome have high levels of serum cortisol, and the patient with IRS has low to normal levels, albeit both have increased levels of urinary free cortisol. The explanation lies in the decreased levels of corticosteroid-binding globulin (CBG) found in IRS, where circulating cortisol is disproportionately free and bioactive, with increased conversion of cortisone to the metabolically active cortisol. The clinical distinction between patients with Cushing's and IRS is that the former is invariably growth retarded, in contrast to the child with IRS in whom linear growth is excessive. In the future, specific inhibitors of 11␤HSD1 to enhance insulin sensitivity and limit weight gain in obesity might have a place.
Fatty liver or hepatic steatosis. Hepatic steatosis is another complication of IR that may progress over years with inflammation and fibrosis (nonalcoholic steatohepatitis). At least 20% of such individuals eventually develop cirrhosis, liver failure, or hepatocellular carcinoma. Fatty liver affects 2.6% of children (63), and 22.5-52.8% of obese children and 10 -25% of adolescents (64). In adult patients with diabetes and obesity, 100% have mild steatosis, 50% have steatohepatitis, and 19% have cirrhosis (65). The disease is usually silent over many years. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase, alkaline phosphatase, and ␥-glutamyltransferase are elevated and have been proposed as surrogate markers of hepatic fat accumulation (66). The ratio of aspartate aminotransferase to ALT is usually less than 1, but this ratio increases as fibrosis advances.
Although there is no accepted pharmacological treatment that can reverse fatty liver disease, all patients should be given a low fat diet and TG-lowering agents and encouraged to exercise. Leptin injections have been proven efficient in patients with generalized lipodystrophy (67); antioxidant therapy has been proposed (68), but has not produced sustained improvement; and insulin sensitizers, such as metformin, have been efficient in mice (69), but there are few Hypertension. Hyperinsulinemia can increase blood pressure by several mechanisms: via its effect to increase renal sodium absorption, via increased activity of the sympathetic nervous system, and via FFA-induced sensitivity to adrenergic stimuli and antagonized nitric oxide vasorelaxation (71). Also, transgenic mice that overexpress leptin develop hypertension.

IR as an initiator of atherosclerosis. Studies of adults have
shown that there is an association between IR and atherosclerosis, Increased thickness of the arterial carotid wall and an atherogenic dyslipidemic profile that includes hypertriglyceridemia, low serum HDL cholesterol concentrations, and atherogenic low density lipoprotein (LDL) cholesterol particles compounded by low SHBG levels are factors for increased risk of atherosclerosis. Importantly, hyperinsulinemia is an independent cardiovascular risk factor (72). The Muscatine Study linked childhood coronary risk factors to atherosclerosis in asymptomatic adults. The most predictive childhood risk factor was increased BMI. Coronary artery calcifications were also associated with increased blood pressure and decreased HDL cholesterol levels measured during childhood (73). Fatty streaks can be found in the aorta inchildren older than 3 yr of age and in coronary arteries by adolescence (74). The Bogalusa Heart Study confirmed that the same risk factors that are important for adults, such as elevated BMI, systolic blood pressure, serum TG, and LDL lipoproteins, convey greater atherosclerosis risk in the aorta and coronary arteries in children (74). The Pathobiological Determinants of Atherosclerosis in Youth study confirmed the origin of atherosclerosis in childhood, showed that progression toward clinically significant lesions may occur in young adulthood, and demonstrated that the progression of atherosclerosis is strongly influenced by CHD risk factors (75).
The thickness of the carotid wall, a validated surrogate marker for atherosclerosis in teenagers and young adults, is sensitive to the intake of cholesterol, serum levels of cholesterol and TGs, BMI, smoking, hypertension, and fasting glucose (76).
Endothelial dysfunction is an early event preceding the formation of plaques, representing an early disease process of atherosclerosis that begins in childhood and is associated with IR and hyperinsulinemia (77).
Low hormone-binding proteins and SERPINS. Decreased levels of multiple binding proteins ]CBG, SHBG, IGF-binding protein-1 (IGFBP-1), thyroid binding globulin, and vitamin D-binding protein (VitD-BP)[ have been reported in patients with obesity and metabolic syndrome X, suggesting a common underlying regulatory mechanism. The binding activities of these proteins are believed to modulate the biodisposal of hormones at the level of target cells. Deficiencies of hormonal binding proteins are implicated in clinical hirsutism, PCOS, Cushing-like features, pseudoacromegaly, thrombosis, inflammation, and even increased cancer risk in cases of IRS.
SHBG has been found to be negatively correlated with BMI and fasting insulin levels. Decreased SHBG increases testosterone bioavailability, leading to the development of hyperandrogenism, even when serum levels of testosterone are normal.
IGFBP-1 is often strikingly depressed in IRS, producing an excessive of free IGF-I, albeit the total level of IGF-I is usually normal. IGFBP-1 levels are regulated principally by insulin and to a lesser extent by glucose levels. Decreased IGFBP-1 in the face of IR leads to the increased tissue bioavailability of IGF-I, such that it can enhance the glucose-lowering effect of insulin. This can lead to the development of microvascular complications and pseudoacromegaly. We found that low levels of IGFBP-1 are associated with the degree of IR, whereas IGFBP-3 correlates directly with the degree of hyperinsulinism.
The low levels of CBG found in IRS lead to disproportionately free and active circulating cortisol. That can lead to clinical and metabolic overlap between Cushing's syndrome and IR. Increased conversion of inactive cortisone to active cortisol by 11␤HSD1 in visceral fat compounds the effect. CBG secretion has been shown to be negatively regulated by both insulin and IL-6 (78).
Thyroid binding globulin levels in IRS are often depressed, leading to confusion as to the presence of hypothyroidism. Obese patients are thus often unnecessarily treated for hypothyroidism they do not have. They may, however, develop true hypothyroidism on the basis of associated Hashimoto's disease.
The low level of 25-hydroxyvitamin D 3 is associated with IR (79), and 1,25-dihydroxyvitamin D 3 is essential for normal insulin secretion. Although VitD-BP is known as a macrophage-activating factor, and polymorphism of VitD-BP is connected to diabetes risk in Pima Indians (80). Low levels of IGFBP-1 and 1,25-dihydroxyvitamin D were found in maternal and umbilical cord blood in preeclampsia (81).
CBG, thyroid binding globulin, and plasminogen activator inhibitor-1 (PAI-1) belong to a family of SERPINS, and insulin and cytokines levels in the case of IR can regulate their activity. These binding proteins (serine protease inhibitors) are substrates for elastase that is expressed at the surface of neutrophils. Therefore, the variability in circulating binding protein levels might be linked to their cleavage by activated neutrophils. Increased peripheral white blood cell count and neutrophils are usually found in both obesity and IR, which might facilitate serine protease availability and binding protein cleavage. This mechanism is likely to contribute to decreased serum binding globulins levels in obesity and IR.
Inflammation, asthma, eczema, and impaired immunity. IRS and type 2 diabetes have increased markers of inflammation, such as C-reactive protein (CRP), erythrocyte sedimentation rates, and TNF␣ levels. Data from the National Health and Nutrition Examination Survey III cohort of 5305 children showed that 24.2% of boys and 31.9% of girls with BMI greater than the 95th percentile had elevated CRP levels (82). Bogolusa and Pathobiological Determinants of Atherosclerosis in Youth studies confirmed the significance of elevated CRP for future atherosclerosis development in children. BMI correlates with levels of CRP (83), and adiposity has been reported to be the major determinant of CRP levels in children. Among adults, those with baseline CRP in the top quartile were found to be twice as likely to develop diabetes over 3-4 yr of follow-up as those with lower levels (84). Our previous data revealed significantly elevated sTNF receptor type 2 in obese children compared with lean children, with significantly elevated levels in the group of obese children with IGT (Anhalt et al., personal communication).
Leptin has been shown to up-regulate the production of proinflammatory cytokines, including TNF-␣ and IL-6, to increase phagocytosis by macrophages, and to increase T helper cell type 1 (Th1) levels and suppression of Th2 cytokine production in mice (85).
A connection between leptin and autoimmunity was recently recognized in the light of understanding that leptin could favor proinflammatory cell responses and directly influence the development of autoimmune disease mediated by Th1 responses. Intraperitoneal injections of leptin accelerated autoimmune destruction of insulin-producing ␤-cells and significantly increased interferon-␥ (IFN␥) production in peripheral T cells in nonobese diabetic mice. Similar observations were documented by leptin injections given to C57BL/6J-ob/ob mice that converted these mice from disease resistant to susceptible to autoimmune encephalomyelitis. This switch was accompanied by a Th2 to Th1 pattern of cytokine release and consequent reversal of Ig subclass production (86). Thus, leptin resistance evident in IRS could bias to Th2-type responses.
The role that leptin plays in the immunosuppression of malnutrition is increasingly recognized. Seven of 11 children in the family with a leptin mutation died of infections in childhood (87). At the same time it was shown that leptin treatment of human lymphocytes during a mixed lymphocyte reaction in vitro enhanced IFN␥ production and blunted IL-4 production (85).
Significant association between asthma and obesity has been noted, especially during puberty. One of the possible mechanisms is that obesity represents a proinflammatory state, and leptin levels influence Th1 cytokine responses. Relationships between birth weight with adult BMI, and between obesity and asthma have been well recognized. BMI correlated with the prevalence of asthma in both boys and girls. It was noted that girls who became obese between ages 6 -11 yr were 7 times more likely to develop new asthmatic symptoms at ages 11-13 yr (88). At the same time intervention trials documented the beneficial effect of weight loss on improvements in forced expiratory volume in 1 sec, FVC, dyspnea, use of rescue bronchodilators, and the median number of asthma exacerbations in the treatment group compared with the control group (89).
Hypoventilation and sleep apnea. Excess body fat leads to a decline in the expiratory reserve volume, vital capacity, total lung capacity, and functional residual volume, probably due to the excess body mass per se, albeit others implicate excessive leptin levels (90).
Significance of AN. AN is a skin lesion that is widely used as a clinical surrogate of laboratory-documented IR/hyperin-sulinemia, denoting a subgroup with a high risk for type 2 diabetes. We suggest that AN should be documented in all children seen in practice, especially if they are obese or diabetic. Common sites of involvement include the axillae, posterior region of the neck, antecubital fossae, and groins. Less commonly, it involves the other flexural areas, umbilicus, submammary region, knuckles, elbows, and, in extreme cases, the entire skin. The severity of AN correlates well with the degree of insulin responses to IR. We find AN to precede IR documentable by OGTT or IVGTT. However, AN also persists into the decompensated phase of IR where insulin levels may be normal or low. Nearly 40% of Native American teenagers have AN, as do 13% of African American, 6% of Hispanic, less than 1% of white and non-Hispanic children, aged 10 -19 yr. In Caucasian patients, the acanthosis often appears a light yellow/gray color, emphasizing that the lesion represents a thickening of the stratum corneum that becomes pigmented in a racially dependent manner. Both insulin and IGF-I receptors have been identified in cultured human keratinocytes. High levels of insulin can activate both receptors (91). Additionally, TNF-␣ and IFN␥ cytokines that are often elevated in obesity, can induce up-regulation of PPAR␤/␦ and thereby keratinocyte proliferation (92,93).

Hyperandrogenism and reproductive abnormalities
IR can present with overt virilization or hirsutism, menstrual irregularity, persistent acne, scalp hair loss, hyperhydrosis, infertility, or precocious adrenarche in childhood. Menstrual irregularity and evidence of hyperandrogenism, whether clinical (hirsutism, acne, or male pattern balding) and/or biochemical (high serum androgen concentrations) are associated with the PCOS. Hyperinsulinemia potentates ovarian hyperandrogenism by enhancing pituitary LH secretion, potentiating ovarian 17-hydroxylase and 17,20-lyase activities, and suppressing blood SHBG and CBG level capacities and inhibits both estradiol-and T 4 -stimulated SHBG production (94). SHBG levels in the circulation are characteristically low, resulting in increased free and bioactive testosterone. Reducing IR by the administration of metformin, PPAR␥ agonists, d-chiro-inositol, or leptin lowers serum free testosterone concentrations, reduces cytochrome P450c17 (17-hydroxylase) activity, and normalizes SHBG levels, resulting in slowed bone maturation and adrenarche (94).
Pseudoacromegaly. Linear and acral growth is usually accelerated in IRS and may present as pseudoacromegaly. Hyperinsulinemia promotes linear growth by activating skeletal IGF-I receptors, whereas low levels of IGFBPs can promote IGF-I action by allowing it to be freely and metabolically available. Increased IGF-I/IGFBP-1 ratios are postulated to result in the development of AN and ovarian hyperplasia. Increased aromatization of androgens to estrogens secondary to obesity increases the propensity to adipo/gynecomastia in adolescent boys and enhances GH production (95). Estrogens affect longitudinal bone growth through their action on endochondral bone formation (96). Ghrelin is known to stimulate GH secretion, and in obesity ghrelin levels are decreased (97). However, Korbonits et al. (98) recently identified polymorphism in the ghrelin gene of 14 children who were tall and obese, suggesting a role of ghrelin in stature and BMI. MC4R gene mutations are present in up to 5.8% of obese children who are tall (Ͼ2 sd above the mean for age) (99). Direct action of leptin on bone growth can predispose to pseudoacromegaly (100). Pseudoacromegaly is seen in the face of low plasma GH levels secretion typical for obesity. Leptin decreases GHRH receptor gene transcription, thereby reducing GH levels and reduces responsiveness to GHRH (101).

Treatments
Decompensated and/or compensated patients. In children, IR is usually well compensated by hyperinsulinemia, whereas we find progressive failure of compensation through puberty with rising glucose and triglyceride levels. Weyer et al. (102) followed 48 Pima Indians, with normal glucose tolerance for 5 yr, and 17 progressed from normal glucose tolerance through IGT to diabetes. In these progressors, insulin secretion declined by 78%, whereas insulin sensitivity declined by 14%. In the 31 individuals who did not develop diabetes, a similar 11% decrease in insulin sensitivity was associated with a 30% increase in insulin secretion rather than a decrease. The latter 31 individuals had compensated IR. Compensated hyperinsulinism, however, can lead to numerous complications from fatty liver and atherosclerosis to increased cancer risk. It is thus increasingly obvious that this sequence of events will be most easily interrupted at the earliest phases of life, during childhood. The child with IRS should be aggressively treated by involvement in an exercise program, such as walking or swimming for 30 -40 min most days of the week, because exercise provokes glucose entry into muscle without the involvement of insulin. We use pedometers as an adjunct to monitor this. Calorie and especially carbohydrate restriction is the key to reduce weight. However, where there is also an increased level of triglycerides, restriction of animal fats should be imposed. Fibrates may be required, especially when TG levels exceed 500 mg/dl, at which point acute pancreatitis and gall bladder disease become real risks. In this regard, behavioral therapy and metformin have been proven safe and effective in improving insulin sensitivity in pediatric patients (13)(14)(15). Laparoscopic surgery as well has been shown to be effective in decreasing weight, dyslipidemia, and IR in adults (103).
Behavior modification. Family-based behavioral interventions for obese children are considered safe and useful treatments for pediatric obesity. These interventions have been associated with reductions in total cholesterol, increases in HDL cholesterol, reductions in IR, and return of ovulatory cycles (104). Metformin is approved for the treatment of type 2 diabetes in children, but is also the drug of choice for IRS. Some have suggested that it is the gastrointestinal side-effects of the drug that accounts for much of its action. However, the drug is effective in type 2 diabetes without weight loss, being found to reduce hepatic glucose output in particular. Met-formin has various mechanisms of action in IR. It enhances insulin binding to insulin receptor in case of its downregulation by insulin receptor autoantibodies (105,106), and it otherwise increases binding of insulin to its receptor, with augmented phosphorylation and tyrosine kinase activity of the receptor (107). It is effective even in cases of insulin receptor mutations (108). It increases peripheral utilization of glucose though potentiating the phosphoinositol 3-kinase after engagement of the insulin receptor, increasing translocation of the glucose transporters GLUT1 and GLUT4 isoforms to cell membrane in different tissues (107, 109 -112); increases the activity of adenosine monophosphate kinase in muscle and liver; and reduces cytochrome P450c17 activity (113). It is considered safe and effective in pregnant women to decrease extreme hyperandrogenemia (114,115). It increases IGFBP-1 (116); decreases endothelin-1, a marker of vasculopathy; and decreases hepatic glucose output. Metformin down-regulates TNF␣ expression and uncoupling protein-2 mRNA concentrations in liver, thus decreasing hepatic lipid biosynthesis (69). Metformin is safe for the treatment of IRS in pediatric patients (13)(14)(15)117). Our experience in treating obese children and adolescents with IRS or PCOS with metformin is likewise very positive. We treated 16 females, 15-28 yr of age, who had IR and hyperandrogenism with metformin (850 mg, three times daily) for a period of 8 months to 1 yr. Insulin sensitivity, area under the curve for insulin, SHBG, testosterone and androsterone levels, and levels of triglycerides improved significantly (118). When gradually increased doses were given to minimize gastrointestinal side-effects, this was a safe and affective agent.
The PPAR␥ agonists are a group of ligand-activated transcription factors that govern energy metabolism, cell proliferation, and inflammation (119). PPAR␥ agonists are effective at insulin sensitization, but are less useful in supporting weight loss. The PPAR␥ isotype is mainly expressed in adipose tissue, where it stimulates adipogenesis and lipogenesis. PPAR␥ agonists have been shown to decrease inflammatory proteins and adhesion molecules, decrease cytokine production, improve lipid oxidation, reduce FFA secretion from adipocytes, decrease 11␤HSD1, reduce intramyocellular lipids, and reduce muscle IR (120); decrease PAI-1 expression in endothelial cells (121); decrease testosterone levels in IR females (122); and markedly induce adipocyte glycerol kinase gene expression. By inducing glycerol kinase, thiazolidinediones markedly stimulate glycerol incorporation into triglycerides and reduce FFA secretion from adipocytes (123).
Lipid-lowering agents. Fibrates lower triglyceride levels, as mediated through the PPAR␣ transcription factor, mainly in liver, where it has an important role in FA oxidation, gluconeogenesis, and amino acid metabolism. Pretreatment of endothelial cells with a PPAR␣ agonist (fenofibrate) reduced markers of inflammation such as vascular cell adhesion molecule-1 expression, CRP, fibrinogen, PAI-1, and IL-6. In cases of combined triglyceride-LDL cholesterol elevations, some combinations of fibrates and statins have been reported to induce serious rhadomyelysis. The use of different combinations or of a cholesterol uptake inhibitor such as zetia may be indicated.
Statins inhibit 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme in the mevalonate pathway through which cells synthesize cholesterol. To compensate for decreased synthesis and to maintain cholesterol homeostasis, cells, particularly hepatocytes, increase the expression of LDL receptors, which increases the uptake of plasma LDL, the main carrier of extracellular cholesterol, resulting in lower plasma LDL concentrations. Decreased plasma LDL levels reduce the progression of atherosclerosis and may even lead to the regression of preexisting atherosclerotic lesions. Statins have important immunomodulatory effects as well and are able to decrease the recruitment of monocytes and T cells into the arterial wall and inhibit T cell activation and proliferation in vitro (124).
Low doses of aspirin inactivate the enzyme cyclooxygenase, which catalyzes the conversion of arachidonic acid to prostaglandins G 2 and H 2 . These prostaglandins are precursors of thromboxane, a potent platelet proaggregant and vasoconstrictor. Low doses of enteric coated aspirin (81 mg/d) are preferred. Aspirin should be used in diabetic individuals over the age of 30 yr who are at high risk for cardiovascular events and may have a place in dyslipidemic children with IRS prone to pancreatitis.
Surgery. Restrictive surgical procedures based on an adjustable silicone band placement around a stomach fundal pouch can create a functional partition of the stomach. This has been shown to be successful in adults. Whereas restrictive procedures are effective in reducing intake of solid foods, high consumption of more liquid high calorie foods may prevent weight loss (125). Intestinal bypass surgery in children should probably only be used only in cases of potentially life-threatening complications such as sleep apnea.

Summary
The U.S. obesity epidemic continues unabated, with ever increasing numbers of the nation's obese children becoming irreversibly obese adults, replete with the IRS in all of its burgeoning complications, notably progressive atheroslerotic disease, hypertension, and type 2 diabetes. The only rational long-term solution must lie in the realization that the epidemic has its genesis in childhood, and thus, the interventional focus should be placed in early life. IRS requires mass screening for physical and laboratory markers, whereas long-term therapeutic trials that can show the long-term benefits of aggressive prevention and intervention, initially targeting highly prone ethnicities, are urgently needed. New findings encourage the development of methods to block ghrelin or promote neuropeptide YY and may provide novel new therapies.