Adipotoxicity and the insulin resistance syndrome

During the last decades, nutritional fat intake has continuously inflated in parallel with an enormous rise in the prevalence of obesity and type-2 diabetes in adults but increasingly also in adolescents and even children. Augmented fat intake is associated with an increased mass of adipose tissue which releases free fatty acids (FFA) but also hormones and cytokines such as leptin, adiponectin, resistin, tumor necrosis factor-a and interleukin-6. In particular, FFA decrease insulin-mediated glucose transport/ phosphorylation in skeletal muscle and impair suppression of glucose production by the liver, indicating insulin resistance. In addition, ectopic lipid storage in both liver and skeletal muscle has recently been related to reduced insulin sensitivity. In conclusion, increased fat intake and expanded body fat are now held responsible for increased FFA availability and hormonal changes which may lead to insulin resistance and type- 2 diabetes.     

Does obesity cause type 2 diabetes mellitus (T2DM)? Or is it the opposite?

Obesity is believed to be a promoter of type 2 diabetes mellitus (T2DM). Reports indicate that severe obesity in childhood and adolescence increases the risk of T2DM in youth and young adults. T2DM, which is commonly asymptomatic, frequently is not recognized until random blood glucose is measured. Screening blood glucose levels measured in obese individuals are more effective for identifying undiagnosed persons, than screening the general population and therefore introduces a selection bias for discovery. The following commentary will indicate why these observations do not indicate that obesity is the cause of T2DM. Also, it will be shown that the insulin resistance of T2DM occurs primarily in the muscles of lean individuals predisposed to diabetes before they become obese. This insulin resistance is not secondary to, but instead, is the cause of the excessive fat accumulation associated with T2DM. Moreover, this early muscle insulin resistance is the etiology of the hyperlipidemia and excess fat accumulation characteristic of T2DM.     

肥胖儿童伴良性黑棘皮病与胰岛素抵抗19例分析

目的　探讨肥胖儿童伴良性黑棘皮病与胰岛素抵抗及 2型糖尿病的关系。方法2 0 0 3年 6月～ 2 0 0 3年 9月 ,在我院内分泌门诊及病房就诊的体重指数 (BMI)≥ 2 5的肥胖儿童共 76例 ,对其中伴黑棘皮病皮肤改变的 19例 ( 2 5 % )均行皮肤病理活检以明确诊断 ,同时对这些患儿行空腹血糖、空腹血胰岛素水平、空腹血糖 /胰岛素比值 (FGIR)及人体测量学参数 [腰围 /臀围比值(WHR) ,全身体脂含量 (FM)、体脂百分数 (BF % )、体重指数 (BMI) ]等的检测 ,并行葡萄糖耐量试验(OGTT试验 ) ,以探讨肥胖儿童伴良性黑棘皮病与胰岛素抵抗及 2型糖尿病的关系。结果　 19例良性黑棘皮病患儿人体测量学参数包括腰围 /臀围比值 ,全身体脂含量 (FM)、体脂百分数 (BF % )、体重指数 (BMI)及空腹血胰岛素水平明显高于正常对照组 (P <0 0 1) ,空腹血糖 /胰岛素比值 (FGIR) ( 4 2 7± 0 5 3)小于 7,存在明显的胰岛素抵抗 ,其中 1例诊断为 2型糖尿病 ,10例有糖耐量异常。结论　儿童良性黑棘皮病与肥胖、高胰岛素血症 ,胰岛素抵抗及 2型糖尿病密切相关 ,是临床胰岛素抵抗的皮肤标志     

Postprandial hyperlipidemia after a fat loading test in minority adolescents with type 2 diabetes mellitus and obesity

The continuing increase in the incidence of type 2 diabetes mellitus (DM2) and obesity in children and adolescents is attributable to excessive caloric intake. Abnormal lipid metabolism in the postprandial state leads to long exposure of the vasculature to hyperlipidemia. Most children and adolescents with DM2 are obese, and many have fasting hypertriglyceridemia. Clustering of hyperlipidemia, DM2 and obesity increases the risk for cardiovascular disease. We therefore studied lipids, insulin, C-peptide, and glucose in response to an oral fat load simulating the fat content of a high-fat, fast-food meal in 12 type 2 diabetic obese, 15 non-diabetic obese, and 12 non-diabetic non-obese (control) adolescents (aged 10-19 yr; 87% African-Americans). All three groups were age-, sex-, and sexual maturation-matched. Mean body mass indices were similar in the diabetes and obese groups (32.7 +/- 1.1 vs 35.8 +/- 1.6 kg/m2). All patients with DM2 had fasting C-peptide > 0.2 nmol/l (0.7 ng/ml) and negative diabetes-associated autoantibodies. Serum total cholesterol, triglyceride, high- and low-density lipoprotein cholesterol, insulin, C-peptide, and plasma glucose levels were measured at 0, 2, 4, and 6 h after the fat load. The area under the curve (AUC) was calculated by trapezoidal estimation. Triglyceride AUC was significantly greater in the diabetes group than in the other two groups (15.7 +/- 2.9 vs 9.2 +/- 0.7 and 7.5 +/- 0.7 mmol x h/l [1389 +/- 258 vs 819 +/- 60 and 663 +/- 62 mg x h/dl]; p < 0.02 and <0.004, respectively), as were insulin, C-peptide, and glucose AUCs. Incremental triglyceride response (delta triglyceride = peak - fasting) in the diabetes group was significantly higher than that in the control group (2.1 +/- 0.7 vs 0.8 +/- 0.1 mmol/l 189.7 +/- 58.4 vs 71.2 +/- 11.1 mg/dl]; p < 0.04). Insulin resistance was estimated using the homeostasis model assessment (HOMA), which was greater in the diabetes group than in the obese and control groups (14.4 +/- 2.8 vs 5.2 +/- 0.8 and 3.2 +/- 0.4; p < 0.001 and < 0.0001, respectively). The diabetes group was divided into subgroups of high and normal fasting triglycerides on the basis of triglyceride levels above and below the 95th percentile. The delta triglyceride in the subgroup with high fasting triglycerides was substantially greater than in the subgroup with normal fasting triglycerides (3.4 +/- 1.1 vs 0.8 +/- 0.2 mmol/l [305.2 +/- 96.8 vs 74.2 +/- 18.0 mg/dl]; p < 0.001). Total cholesterol and triglyceride AUCs were much greater in the high vs normal fasting triglycerides subgroup (33.0 +/- 2.9 vs 24.2 +/- 1.9 and 23.6 +/- 3.5 vs 7.8 +/- 0.6 mmol x h/l [1274 +/- 113 vs 934 +/- 72 and 2085 +/- 309 vs 692 +/- 49 mg x h/dl]; p < 0.02 and <0.0001, respectively), as were insulin and C-peptide AUCs. HOMA was greater in the high vs normal fasting triglycerides subgroup (20.8 +/- 4.0 vs 8.0 +/- 1.6; p < 0.0001). In addition to elevated plasma glucose levels, there were no significant differences in either insulin or lipid parameters among the diabetes subgroup with normal fasting triglycerides, the obese group, and controls. Our data suggest that postprandial hyperlipidemia in response to a fat loading test is present in adolescents with DM2 who already have fasting hypertriglyceridemia. The degree of insulin resistance as an underlying abnormality--not DM per se--determines the degree of postprandial lipemia.     

Insulin resistance and cardiovascular risk in the pediatric patient

The insulin resistance syndrome, a cluster of potent risk factors for atherosclerotic cardiovascular disease and type 2 diabetes in adults, is composed of hyerinsulinemia, obesity, hypertension and hyperlipidemia. In addition, left ventricular hypertrophy and its precursor increased left ventricular mass, is known to be a powerful predictor of adverse cardiovascular events, both as an independent risk factor and by association with the insulin resistance syndrome. Obesity appears to have a major role in the relations between the components of the insulin resistance syndrome, and their association with increased heart mass. Of significant impact in the adult population, atherosclerotic cardiovascular disease and death are rarely seen in the young, but the pathologic processes and risk factors associated with its development have been shown to begin during childhood. Recent studies revealed the presence of components of the insulin resistance syndrome also in children and adolescents, however, their associations are not well understood. A direct link between obesity and insulin resistance has also been reported in the young, as has the link between insulin resistance and abnormal lipid profile. There is an increasing amount of data to show that being overweight during childhood and adolescence is significantly associated with insulin resistance, abnormal lipids and elevated blood pressure in young adulthood. Weight loss in these situations results in a decrease in insulin concentration and an increase in insulin sensitivity toward normalcy. Moreover, it has been determined that increased left ventricular mass is present in childhood, and is related to other risk factors, namely obesity and insulin resistance. Based on current knowledge, it is reasonable to suggest that weight control, and lifestyle modification, could alter the incidence of the syndrome of insulin resistance, and improve the risk profiles for cardiovascular disease as children make the transition toward adolescence and young adulthood.     

Impaired glucose tolerance and risk factors for progression to type 2 diabetes in youth

Abstract:  Impaired glucose tolerance and impaired fasting glucose represent two potentially reversible prediabetes conditions. Previous reports from various regions across the globe indicate that both conditions may be relatively common in obese children and adolescents. The major factor driving the development of compromised glucose metabolism in obese youth is severe insulin resistance. This severe insulin resistance has been strongly associated with specific patterns of lipid partitioning. Severe obesity along with continued weight gain, specifically in obese youth belonging to ethnic minorities, have been shown to be associated with deterioration of glucose tolerance over short periods of time. As obesity-related insulin resistance in the pediatric age-group is associated with the development of altered glucose metabolism and other elements of the metabolic syndrome, severely obese youth are a high-risk group for the development of type 2 diabetes and may benefit most from preventive interventions such as environmental changes that promote increased physical activity.     

Aerobic fitness, fatness and the metabolic syndrome in children and adolescents

The paediatric obesity epidemic is well documented. Recently, there has also been the emergence of type 2 diabetes and the metabolic syndrome (MetS) among children and adolescents. Although it is well known that obesity is linked to the metabolic syndrome in youth, the role of physical activity and fitness on the metabolic syndrome is unclear. The purpose of this review was to examine the concepts of and associations between fitness, fatness and the MetS in children and adolescents. In general, the association between fatness and the MetS (or components of the MetS) is stronger than those for fitness. Furthermore, the correlation between fatness and the MetS remains significant after controlling for fitness, whereas the correlation between fitness and MetS does not remain significant after controlling for fatness. When subjects are cross-tabulated into categories (fat-fit, etc.), there is good evidence that fitness attenuates the MetS score among fat children and adolescents. The reasons for these observations possibly involve genetics, adipocytokines and mitochondrial function. Further study is needed to understand the role of physical activity and other environmental factors on this phenomena. In addition, longitudinal studies of the fat-fit phenotype are required and should include measurements of the hormonal mileau, adipokines and the oxidative capacity of skeletal muscle during childhood and adolescence.     

Intramyocellular lipid, adiposity, and muscle oxygen supply in prepubertal type 1 diabetes

Abstract:  Background: In the non-diabetic population, intramyocellular lipid (IMCL) accumulation is associated with obesity and poor muscle oxygen supply. IMCL levels are increased in type 1 diabetes, but their significance is less clear.
Methods:  We studied a group of 16 prepubertal boys (age 6.4–9.9 yr) with type 1 diabetes and a range of glycemic control [hemoglobin A1c (HbA1c) 6.4–10.2%]. Children's adiposity was assessed by anthropometry, muscle oxygen supply by near-infrared spectroscopy (NIRS), abdominal and IMCL content by magnetic resonance imaging (MRI), and magnetic resonance spectroscopy (MRS).
Results:  IMCL content did not associate with muscle reoxygenation rate, abdominal adiposity, duration of diabetes, or recent glycemic control. Muscle reoxygenation rate correlated with percentage body fatness (r² = 0.46, p = 0.004), visceral (r² = 0.45, p = 0.007) and abdominal subcutaneous fat volume (r² = 0.63, p = 0.0004), and dietary fat intake (r² = 0.27, p = 0.03) but not with the duration of diabetes nor HbA1c. HbA1c was significantly related to dietary fat intake only (r² = 0.28, p = 0.03).
Conclusion:  While causality cannot be inferred, interventions aimed at improving muscle oxygen supply, or preventing its deterioration, might reduce the development of adiposity in children with type 1 diabetes.     

Tangled relationship between insulin resistance and microalbuminuria in children with obesity

Childhood obesity represents a complex disease with a well-known cardiometabolic burden including fatty liver, type 2 diabetes, metabolic syndrome, and cardiovascular disease. From a pathogenic point of view, insulin resistance (IR) represents the key factor underlying the spectrum of these obesity consequences. As observed in adults, recent data supported the occurrence of microalbuminuria (MA) as marker of early kidney dysfunction and its potential link with cardiometabolic factors also in children with obesity. In fact, a well-documented pathophysiological hypothesis both in adults and children supported an intimate correlation with the major feature of obesity such as IR through the influence of insulin on renal hemodynamics. Based on the clinical and prognostic relevance of this relationship in daily practice (including an increased risk of chronic kidney disease development overtime), more scientific attention needs to be paid to the evaluation of early kidney damage in children with obesity. In this paper, we attempt to address three debated questions regarding the intriguing liaison between IR and MA in children with obesity: (1) What is the prevalence of pediatric MA? (2) What is the state of art of MA in children with obesity? and (3) Is there a link between IR and MA in children with obesity?     

Circulating adipocyte fatty acid-binding protein, juvenile obesity, and metabolic syndrome

Adipocyte fatty acid-binding protein (A-FABP) links obesity and metabolic syndrome (MetS) and might be targeted in future therapies. Its utility as a MetS biomarker has been suggested in adults but has not been examined in children/adolescents. Our objectives were to identify metabolic parameters associated with A-FABP elevation in children and adolescents and to evaluate the effect of obesity intervention and A-FABP diagnostic utility. A-FABP and anthropometric, metabolic, and inflammatory indices were measured in 31 lean and 114 overweight/obese children and adolescents and reassessed after obesity intervention (1 year; diet and enhanced physical activity, with or without metformin). A-FABP was significantly higher in overweight/ obese than lean individuals, where it correlated with insulin, waist circumference (WC), and 2-h glucose independent of body mass index (BMI), age, gender, and developmental stage. The pattern of A-FABP associations differed between sexes. As a MetS indicator, A-FABP had 68% accuracy. The weight reduction program was effective in reducing A-FABP, BMI%, WC, triglycerides, and cholesterol. In conclusion, elevation in A-FABP is associated with MetS components independent of BMI status and can be reduced by diet and enhanced physical activity. A-FABP as a single MetS biomarker has a moderate accuracy.     

Type 2 diabetes mellitus in adolescents

Type 2 diabetes mellitus, a significant cause of adult morbidity and mortality, is being diagnosed more frequently in children and adolescents. Genetic predisposition and environmental factors are important determinants for the expression of this disease. Blacks, Hispanic Americans, and Native Americans are known to be at higher risk for type 2 diabetes mellitus as adults and there appears to be increased prevalence of the disease in adolescent members of these groups. Obesity, sedentary lifestyle, and high-fat diet are associated with type 2 diabetes mellitus. A combination of peripheral insulin resistance and relative insulin deficiency results in chronic hyperglycemia. The onset of hyperglycemia is usually slow and symptoms such as polyuria and polydipsia are often subtle and may go unrecognized by the patient. The treatment of children and adolescents with type 2 diabetes mellitus is an area of active study. Programs targeting diet modification and increased physical activity are being developed in hopes of delaying or preventing the onset of disease. This paper examines risk factors for the development of type 2 diabetes mellitus, reviews diagnostic criteria, and discusses newly established screening criteria for type 2 diabetes mellitus in children and adolescents.     

Type 2 diabetes,polycystic ovary syndrome and the insulin resistance syndrome in adolescents: Are they one big iceberg?

Obesity in children may cause overt clinical disease in childhood. The complex endocrine and metabolic changes of obesity and insulin resistance in adolescents result in hyperinsulinemia, dyslipidemia, hypertension, steatohepatitis, glucose intolerance, type 2 diabetes, acanthosis nigricans and ovarian hyperandrogenemia, commonly known as polycystic ovarian syndrome (PCOS). Type 2 diabetes and PCOS in adolescents are new endocrine diseases in this age group that require unique approaches to diagnosis and treatment. The direct correlation between duration of disease and control of the disease, and subsequent long term complications of these two diseases, predict serious morbidity in young adult life for the affected adolescents. Pediatricians have an important role in the prevention, diagnosis and treatment of obesity, insulin resistance syndrome, type 2 diabetes and PCOS.     

儿童良性黑棘皮病与代谢异常

目的：观察儿童良性黑棘皮病与人体测量指标参数及代谢指标的关系,探讨儿童良性黑棘皮病与代谢性疾病的关系。方法：回顾性分析2007年2月至 2011年10月于我院诊治的29例良性黑棘皮病患儿的临床资料,以同年龄同性别同民族相匹配的32例正常儿童为对照组。比较两组儿童人体肥胖指标（体重指数、腰臀围比、体脂含量及体脂百分比）及代谢指标（血糖、胰岛素水平、血脂系列）等的不同。结果：29例良性黑棘皮病患儿体重指数、体脂含量、体脂百分数、腰臀围比、空腹血糖及胰岛素水平、甘油三酯均高于对照组（P<0.05）,而高密度脂蛋白低于对照组（P<0.05）。29例良性黑棘皮病患儿中,16例存在糖耐量异常,3例确诊为糖尿病（1例1型,2例2型）。结论：儿童良性黑棘皮病与肥胖、胰岛素抵抗及血脂异常密切相关。     

Altered glucose metabolism in obese youth

Altered glucose metabolism in obese youth is associated with defects in insulin sensitivity and insulin secretion. Peripheral insulin resistance in obese youth is an early phenomenon, strongly associated with a pattern of lipid partitioning characterized by increased deposition of lipid in the visceral and intramyocellular compartments. This metabolic phenotype is further characterized by a relatively reduced adiponectin level and elevation of inflammatory cytokines. A reduced sensitivity of the beta cell for first phase insulin secretion results in impaired glucose tolerance, while reduced first and second phase beta cell sensitivity for insulin secretion results in overt type 2 diabetes. Altered glucose metabolism in obese youth represents an element of the "insulin resistance syndrome", comprising obesity, dyslipidemia and hypertension. The dynamics of glucose tolerance status in these youngsters seems to be more rapid than in adults, thus representing a narrow window of opportunity for successful intervention to prevent diabetes.     

The inflammatory process of adipose tissue

Obesity and inflammation are highly integrated processes in the pathogenesis of insulin resistance, diabetes, atherosclerosis, and non-alcoholic fatty liver disease. The evidence that obesity can be regarded as an inflammatory disease comes from numerous studies showing a moderate increase of circulating inflammatory factors in obese patients and the identification of different types of immune cells infiltrating the human adipose tissue. Obesity may induce a pro-inflammatory state, which can cause or worsen insulin resistance in adipose tissue, skeletal muscle, and liver. The causative factors of this inflammation process in obesity are not entirely understood, but adipose tissue seems to play an important role in the relationship between obesity and chronic inflammation. Increased infiltration of adipose tissue with immune cells could cause adipose tissue insulin resistance via autocrine and paracrine cytokine/adipokine signalling, which contributes to systemically decreased insulin sensitivity via endocrine signalling. On the other hand, obesity-induced inflammation could represent a compensatory mechanism for increased adipose tissue turnover in obese states, which might protect obese individuals against deleterious effects of fat accumulation. A better understanding of the mechanisms and molecular components of obesity induced inflammatory response might lead to identifying novel therapeutic targets to prevent obesity-related complications.     

Glucose and insulin metabolism in obese youth

As the prevalence of childhood obesity increases, its health implications are becoming evident to pediatricians around the country. Most striking is the unprecedented epidemic of abnormalities in glucose metabolism, with the diagnosis of type 2 diabetes (T2DM) outnumbering the diagnosis of type 1 diabetes mellitus in many Pediatric Endocrine Clinics. Furthermore, the "Metabolic Syndrome" may be present in as many as 30% of obese adolescents and is manifested by the typical coexistence of central obesity, dyslipidemia, hypertension and impaired glucose tolerance or pre-diabetes. For the past ten years, our laboratory has focused on the metabolic consequences of obesity in youth. We have observed that alterations in the partitioning of fat in both muscle and abdominal tissues in these individuals is closely linked to insulin resistance and abnormalities in glucose homeostasis. Furthermore, we have been able to examine metabolic factors that predict the development of T2DM in obese children. We are currently examining the effect of impaired glucose tolerance on the vascular health of obese youth and have found that subtle shifts in glucose metabolism are associated with microalbuminuria, a surrogate marker of endothelial function and premature cardiovascular mortality.     

Characterisation of morbidity in a UK, hospital based, obesity clinic.

AIM: To identify clinical features which predict those most at risk of co-morbidities within an obesity clinic. METHODS: Children attending an obesity clinic had fasting glucose, insulin, and lipids measured prior to a standard oral glucose tolerance test (OGTT). History and examination established birth weight, family history of type 2 diabetes/obesity, pubertal status, and presence of acanthosis nigricans. Central and total fat mass was estimated by bio-impedance. RESULTS: Of the 126 children evaluated, 10.3% (n = 13) had impaired glucose tolerance (IGT); the majority (n = 11) of these would not have been identified on fasting glucose alone. Those with IGT were more likely to have a parental history of type 2 diabetes (relative risk 3.5). IGT was not associated with acanthosis nigricans. Twenty five per cent (n = 19) of those evaluated (n = 75) had evidence of the "metabolic syndrome" (MS). HDL cholesterol and triglyceride levels were related to insulin sensitivity (HOMA-R); HDL cholesterol was also related to birth weight SDS. We observed a trend for those with MS to have a lower birth weight SDS. The severity of obesity did not influence the likelihood of IGT or MS. CONCLUSIONS: Significant numbers of obese children have associated co-morbidities. Analysis of fasting blood glucose samples alone is not satisfactory to adequately evaluate glucose homoeostasis. The overall level of obesity does not predict co-morbidities. Special attention should be given to those with parental diabetes and a history of low birth weight who are more likely to have IGT and abnormal lipid profiles respectively.     

IAP National Task Force for Childhood Prevention of Adult Diseases: insulin resistance and Type 2 diabetes mellitus in childhood

Type 2 diabetes mellitus (DM) has traditionally been considered a disease of adults. However, in the last 2 decades, it is increasingly being reported in children and adolescents. Obesity is a strong correlate, and the increasing prevalence of obesity and poor physical activity is precipitating type 2 DM at younger ages in the ethnic groups at risk.Indians and other South Asians are among the ethnic groups particularly prone to insulin resistance and type 2 DM, the other racial groups being some American Indian tribes like the Pima Indians, Mexican Americans,Pacific Islanders and African Americans,among others. The WHO has predicted that India will have the greatest number of diabetic individuals in the world by the year 2025.Type 2 DM starting during adolescence puts the individual at risk for major morbidity and even mortality right during the productive years of life. The microvascular complications of DM (nephropathy, retinopathy, neuropathy) are brought on at an early age. In addition, type 2 DM and obesity are two components of a metabolic syndrome of insulin resistance, the other features of which include hypertension, dyslipidemia and hypercoagulability of blood. All these conditions together increase the risk for cardiovascular and cerebrovascular mortality and morbidity (i.e., myocardial infarction and stroke). The resulting economic burden will be enormous.Type 2 DM and the insulin resistance syndrome are to a large extent preventable.Adoption of a healthy eating and physical activity pattern has resulted in decreasing the development of DM in a few recent studies from various parts of the world. A concerted,multi-pronged effort is needed, involving the general public, pediatricians and general physicians, teachers and schools, the media,the government and professional medical bodies, to generate a momentum towards the goal of prevention of type 2 DM and the insulin resistance syndrome in the young population of India.     

Insulin and insulin resistance index are not independent determinants for the variation in leptin in obese children and adolescents

Recent findings have questioned the independent influence of insulin on leptin. We studied whether insulin contributes to leptin in obese children, independent of confounding parameters, such as total adiposity, fasting insulin resistance index, and fat free mass. In 100 obese boys and 103 obese girls, blood levels of leptin, insulin, glucose, and triglycerides were determined. The fasting insulin resistance index (FIRI) was calculated, and body composition was assessed by means of impedance. Leptin and glucose were higher in girls, and all estimates of adiposity were significantly associated with leptin. However, when adjusted for adiposity, the relationship between insulin and leptin, and also between FIRI and leptin, remained significant in boys and girls (p<0.05). Although several regression models were tested, neither insulin nor FIRI were found to contribute significantly and independently to leptin. BMI together with triglycerides and FFM were the main determinants for the variation in leptin in boys (adj. R2=0.46, p<0.0001). In girls, BMI explained a great magnitude of the variation in leptin (adj. R2=0.60, p<0.0001). These findings indicate that in the state of childhood and adolescent obesity, total adiposity but not insulin or insulin resistance index is the main determinant for leptin. In contrast to obese girls, the fat free mass and triglycerides contribute significantly to the variation in leptin in obese boys. The biological significance for these findings should be elucidated in longitudinal studies.