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Objective: Compared with Caucasians, obese African-American adolescents have a higher risk for type 2 diabetes. Subclinical inflammation and reduced glucagon-like peptide 1 (GLP-1) concentration are linked to the pathogenesis of the disease. We determined the relationship between insulin resistance, beta-cell activity, and subclinical inflammation with GLP-1 concentrations and whether racial disparities in GLP-1 response were present in 49 obese adolescents (14 +/- 3 years; 76% African American; 71% female)., Research Design and Methods: Subjects underwent physical examination and an oral glucose tolerance test. We measured levels of high-sensitivity CRP (CRP(hs)), fibrinogen, glucose, GLP-1(total), GLP-1(active), and insulin. Insulin and glucose area under the curve (AUC), insulinogenic index (DeltaI30/DeltaG30), and composite insulin sensitivity index (CISI) were computed. Subjects were categorized by race and as inflammation positive (INF+) if CRP(hs) or fibrinogen were elevated., Results: No racial differences were seen in mean or relative BMI. Thirty-five percent of subjects had altered fasting or 2-h glucose levels (African American vs. Caucasian, NS), and 75% were INF+ (African American vs. Caucasian, P = 0.046). Glucose and insulin, CISI, and DeltaI30/DeltaG30 values were similar; African Americans had lower GLP-1(total) AUC (P = 0.01), GLP-1(active) at 15 min (P = 0.03), and GLP-1(active) AUC (P = 0.06) and higher fibrinogen (P = 0.01) and CRP(hs) (NS) compared with Caucasians., Conclusions: African Americans exhibited lower GLP-1 concentrations and increased inflammatory response. Both mechanisms may act synergistically to enhance the predisposition of obese African Americans to type 2 diabetes. Our findings might be relevant to effective deployment of emerging GLP-1-based treatments across ethnicities.

The prevalence and severity of childhood obesity have increased steadily over the past three decades. The human species evolved to rigorously defend its lower limit for weight and adiposity but is tolerant of the upper limit, which, until recent times, was rarely approached. Neuroendocrine mechanisms within the limbic core of the brain prevent starvation (ventromedial hypothalamus), heighten reward (ventral tegmental area and nucleus accumbens), and attenuate stress (amygdala), in order to promote food-seeking and ingestive behavior and to conserve energy output. In a stressful modern environment with ready access to calorie-dense, highly palatable foods and limited venues for activity, normal, reflexive responsiveness to these three drives makes weight gain all but inevitable. The obesity that ensues often engenders insulin resistance, which undermines the ability of normal hunger and satiety signals to accurately modulate energy intake versus expenditure. Obesity interventions that rely on cognitive information alone cannot free children from this "limbic triangle." Integrated multidisciplinary family- and community-based education, effective stress reduction, and a societal commitment to alter the food and built environments are all necessary components to battle the global obesity epidemic.

Obesity is the most serious long-term health risk currently facing America's adolescents. Weight gain during adolescence carries a higher risk for adult obesity and the metabolic syndrome. This review highlights early adolescence as a particularly high-risk time for weight gain due to the synergy of naturally occurring metabolic changes along with increasing behavioral risk factors. One of the first potential health effects of abnormal weight gain during this period is earlier puberty, usually manifested as thelarche. The obesity epidemic is clearly implicated in the national trend toward earlier thelarche, although the data are not as strong in relation to menarche. Leptin activation of the hypothalamic-pituitary axis, combined with insulin resistance, and increased adiposity may result in the higher estrogen levels that are linked to breast development. Young adolescents also experience a sharp decline in their level of physical activity, worsening nutritional habits, and other important psychosocial and developmental risk factors that may contribute to obesity and estrogen-dependent disease in later life, including polycystic ovary syndrome and breast cancer. Unfortunately, the very psychosocial factors that contribute to abnormal weight gain during early adolescence make prevention and treatment in this population particularly challenging. Therefore, intervening prior to pubertal onset becomes even more important given the risk factors present once puberty begins.

The functions of the pituitary hormones have been relatively well studied; however, understanding the regulation of their synthesis and release have been an ongoing subject of intense research. This review provides an overview of the pituitary cell types and their hormone products. Current understanding of the expression and regulation of the pituitary hormone genes, control of the synthesis and release of the corresponding hormones, and developmental changes are reviewed. This review concludes with a discussion of several of these genes and the genetic disorders with which they are associated.

In this review, the mechanism of our "toxic environment's" effects on insulin and weight gain in the genesis of obesity is elaborated. The composition of our diet is highly insulinogenic. The insulin drives energy into fat, and interferes with leptin signaling in the VMH. This results in weight gain and the sense of starvation, which results in decreased SNS activity, reducing energy expenditure and physical activity; and increased vagal activity, which promotes yet further insulin release and energy storage. Thus, hyperinsulinemia turns the leptin negative feedback system into a "vicious cycle" of obesity (see Figure 3, page 905). Externally, this appears as "gluttony and sloth" but it is biochemically driven. How does this work? A thin, insulin-sensitive, 13-year-old boy might consume a daily allotment of 2,000 kcal, and burn 2,000 kcal daily (or 50 kcal/kg fat-free mass) in order to remain weight-stable, with a stable leptin level. However, if that same 13-year-old became hyperinsulinemic and/or insulin resistant, perhaps as many as 250 kcal of the daily allotment would be shunted to storage in adipose tissue, promoting a persistent obligate weight gain. Due to the obligate energy storage, he now only has 1,750 kcal per day to burn. The hyperinsulinemia also results in a lower level of leptin signal transduction, conveying a CNS signal of energy insufficiency. The remaining calories available are lower than his energy expenditure; the CNS would sense starvation. Through decreased SNS tone, he would reduce his physical activity, resulting in decreased quality of life; and through increased vagal tone, he would increase caloric intake and insulin secretion, but now at a much higher level. Thus, the vicious cycle of gluttony, sloth, and obesity is promulgated. Is this personal responsibility, when a kid's brain thinks it's starving? Is it personal responsibility when the American Academy of Pediatrics still recommends juice for toddlers? Is it personal responsibility when the Women, Infant and Children program subsidizes fruit juice but not fruit? Is it personal responsibility when the first ingredient in the barbecue sauce is high-fructose corn syrup? Is it personal responsibility when high-fiber fresh produce is unavailable in poor neighborhoods? Is it personal responsibility when the local fast food restaurant is the only neighborhood venue that is clean and air-conditioned? Is it personal responsibility when in order to meet the criteria for No Child Left Behind, the school does away with physical education class? Is it personal responsibility when children are not allowed out of the house to play for fear of crime? We must get the insulin down. Fixing the "toxic environment" by altering the food supply and promoting physical activity for all children can't be done by government, and won't be done by Big Food. This will require a grassroots, bottom-up effort on the part of parents and community leaders. We as pediatricians must lead the way.

Childhood obesity has become epidemic over the past 30 years. The First Law of Thermodynamics is routinely interpreted to imply that weight gain is secondary to increased caloric intake and/or decreased energy expenditure, two behaviors that have been documented during this interval; nonetheless, lifestyle interventions are notoriously ineffective at promoting weight loss. Obesity is characterized by hyperinsulinemia. Although hyperinsulinemia is usually thought to be secondary to obesity, it can instead be primary, due to autonomic dysfunction. Obesity is also a state of leptin resistance, in which defective leptin signal transduction promotes excess energy intake, to maintain normal energy expenditure. Insulin and leptin share a common central signaling pathway, and it seems that insulin functions as an endogenous leptin antagonist. Suppressing insulin ameliorates leptin resistance, with ensuing reduction of caloric intake, increased spontaneous activity, and improved quality of life. Hyperinsulinemia also interferes with dopamine clearance in the ventral tegmental area and nucleus accumbens, promoting increased food reward. Accordingly, the First Law of Thermodynamics can be reinterpreted, such that the behaviors of increased caloric intake and decreased energy expenditure are secondary to obligate weight gain. This weight gain is driven by the hyperinsulinemic state, through three mechanisms: energy partitioning into adipose tissue; interference with leptin signal transduction; and interference with extinction of the hedonic response to food.

Objective: To assess the use of oral glucose tolerance testing (OGTT) to predict efficacy of insulin sensitization (metformin) or suppression (octreotide) because insulin resistance and insulin hypersecretion may impact pharmacotherapeutic efficacy in obese children., Study Design: Forty-three and 24 obese children, with and without central nervous system (CNS) insult, underwent OGTT. Insulin sensitivity was expressed as composite insulin sensitivity index (CISI), and secretion as corrected insulin response (CIRgp). Those without CNS insult received metformin (weight-based dosing) for 6 to 16 months. Those with CNS insult received octreotide SQ 15 microg/kg/d for 6 months. Body mass index (BMI) and z-score responses were modeled using CIRgp and CISI., Results: Metformin: With CIRgp and CISI = 1, BMI z-score in white children declined by 0.23 over the first 4 months (P < .001), and by 0.14 over the next year (P = .33). Each 2-fold increase in CIRgp or CISI attenuated BMI z-score reduction, but with wide uncertainty (P = .24). Black children exhibited little response. Octreotide: With CIRgp and CISI = 1, BMI z-score decreased by 0.23 in the first 4 months (P = .052). Efficacy was dependent on an interaction between CIRgp and CISI (P = .051)., Conclusions: Efficacy of metformin was predicted by pretreatment insulin resistance. Efficacy of octreotide was predicted by insulin hypersecretion and sensitivity.

Background: Adrenocorticotropin deficiency (ACTHD) can be clinically subtle, but life-threatening if not recognized. We assessed the prevalence of ACTHD in survivors of childhood cancer according to tumor diagnosis/therapy., Procedure: Chart review of endocrine/oncology history was performed in 310 childhood cancer survivors. Patients were referred to endocrine clinic because of slow growth, fatigue, or abnormal pubertal timing. Evaluation of growth hormone (GH), thyrotropin (TSH), ACTH, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) was performed. Low response to metyrapone and/or low dose ACTH test defined ACTHD., Results: ACTHD was identified in 56 (18%), [44 of 182 (24%) central nervous system (CNS) tumors, 3 of 18 (17%) non-CNS cranial tumors, 9 of 97 (9%) hematologic malignancies]. Of the 56 with ACTHD, 53 (95%) had received cranial irradiation (mean 45.5 Gy, range 14-70 Gy); three had not: one each with craniopharyngioma, hypothalamic astrocytoma, and brain stem glioma. All but one also had GH deficiency and/or central hypothyroidism., Conclusions: Childhood cancer survivors with greatest risk for ACTHD had craniopharyngioma, other suprasellar tumor, or medulloblastoma or > or =24 Gy cranial irradiation. We recommend annual testing for ACTHD for 10-15 years and continued lifelong surveillance after CNS tumor or cranial irradiation, in patients with other hypothalamic-pituitary deficiencies or symptoms of ACTHD., ((c) 2005 Wiley-Liss, Inc.)

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatremia. We describe two infants whose clinical and laboratory evaluations were consistent with the presence of SIADH, yet who had undetectable arginine vasopressin (AVP) levels. We hypothesized that they had gain-of-function mutations in the V2 vasopressin receptor (V2R). DNA sequencing of each patient's V2R gene (AVPR2) identified missense mutations in both, with resultant changes in codon 137 from arginine to cysteine or leucine. These novel mutations cause constitutive activation of the receptor and are the likely cause of the patients' SIADH-like clinical picture, which we have termed "nephrogenic syndrome of inappropriate antidiuresis.", (Copyright 2005 Massachusetts Medical Society.)

Objectives: To assess insulin dynamics to oral glucose tolerance testing in obese children, denoting individual contributions of insulin hypersecretion versus resistance to racial and etiopathogenetic specificity., Study Design: We performed 3-hour oral glucose tolerance testing in 113 nondiabetic obese children (age 13.6 +/- 3.1 years; 41 male, 78 female; 37 black, 41 white; 35 with central nervous system [CNS] insult). The corrected insulin response (CIRgp; measuring beta-cell secretion) and the composite insulin sensitivity index (CISI) were computed and log-transformed, and each was modeled in terms of the other, plus race/etiology, age, sex, body mass index z score, glucose tolerance, pubertal status, and geographic location., Results: A scatterplot of logCIRgp versus logCISI showed that racial and etiopathogenetic groups plotted in different areas. CISI (controlled for CIRgp and other variables) was only 13% lower in blacks than in whites ( P = .32). Conversely, CIRgp (controlled for CISI and other variables) was 49% higher in blacks ( P = .028). CNS insult exhibited a 40% higher CIRgp ( P = .054) and 11% higher CISI ( P = .42) than intact white subjects., Conclusions: Insulin hypersecretion and resistance are distinct phenomena in childhood obesity. Insulin hypersecretion appears to be the more relevant insulin abnormality both in obese blacks and in CNS insult.

Purpose: We conducted a phase II trial of conformal radiation therapy (CRT) for localized childhood ependymoma to determine whether the irradiated volume could be reduced to decrease CNS-related side effects without diminishing the rate of disease control., Patients and Methods: Between July 1997 and January 2003, 88 pediatric patients (median age, 2.85 +/- 4.5 years) received CRT in which doses (59.4 Gy to 73 patients or 54.0 Gy after gross-total resection to 15 patients younger than 18 months) were administered to the gross tumor volume and a margin of 10 mm. Patients were categorized according to extent of resection (underwent gross total resection, n = 74; near-total resection, n = 6; subtotal resection, n = 8), prior chemotherapy (n = 16), tumor grade (anaplastic, n = 35), and tumor location (infratentorial, n = 68). An age-appropriate neurocognitive battery was administered before and serially after CRT., Results: The median length of follow-up was 38.2 months (+/- 16.4 months); the 3-year progression-free survival estimate was 74.7% +/- 5.7%. Local failure occurred in eight patients, distant failure in eight patients, and both in four patients. The cumulative incidence of local failure as a component of failure at 3 years was 14.8% +/- 4.0%. Mean scores on all neurocognitive outcomes were stable and within normal limits, with more than half the cohort tested at or beyond 24 months., Conclusion: Limited-volume irradiation achieves high rates of disease control in pediatric patients with ependymoma and results in stable neurocognitive outcomes., (Copyright 2004 American Society of Clinical Onocology)

Hypothalamic obesity is a devastating complication in children surviving brain tumors and/or cranial irradiation. These subjects are thought to exhibit autonomic dysregulation of the beta-cell, with insulin hypersecretion in response to oral glucose tolerance testing (OGTT). We report the results of a randomized, double-blind, placebo-controlled trial of octreotide therapy for pediatric hypothalamic obesity. Eighteen subjects [weight, 100.6 +/- 5.6 kg; body mass index (BMI), 37.1 +/- 1.3 kg/m(2)] received octreotide (5-15 microg/kg x d s.c.) or placebo for 6 months. With octreotide, Delta weight (mean +/- SEM) was +1.6 +/- 0.6 vs. +9.1 +/- 1.7 kg for placebo (P < 0.001). Delta BMI was -0.2 +/- 0.2 vs. +2.2 +/- 0.5 kg/m(2), respectively (P < 0.001). OGTT documented Delta insulin response (peak - basal) of -417 +/- 304 pM after octreotide vs. +216 +/- 215 pM after placebo (P = 0.034). Improvement in physical activity by parent report was noted with octreotide, but not placebo (P = 0.03). For the octreotide group, changes in quality of life positively correlated with changes in insulin response (P = 0.041). Complications and adverse events were mild and self-limited. These data demonstrate the beneficial effects of octreotide in pediatric hypothalamic obesity. Octreotide suppressed insulin, and stabilized weight and BMI. Improved quality of life correlated with the degree of insulin suppression. Octreotide was safe and well tolerated.

Hypothalamic obesity, a syndrome of intractable weight gain due to hypothalamic damage, is an uncommon but devastating complication for children surviving brain tumors. We undertook a retrospective evaluation of the body mass index (BMI) curves for the St. Jude Children's Research Hospital brain tumor population diagnosed between 1965 and 1995 after completion of therapy to determine risk factors for the development of obesity. Inclusion criteria were: diagnosis less than 14 yr of age, no spinal cord involvement, ambulatory, no supraphysiologic hydrocortisone therapy (>12 mg/m(2) x d), treatment and follow-up at St. Jude Children's Research Hospital, and disease-free survival greater than 5 yr (n = 148). Risk factors examined were age at diagnosis, tumor location, histology, extent of surgery, hydrocephalus requiring ventriculoperitoneal shunting, initial high-dose glucocorticoids, cranial radiation therapy, radiation dosimetry to the hypothalamus, intrathecal chemotherapy, and presence of endocrinopathy. Analyses were performed both between groups within a risk factor and against BMI changes for age in normal children older than 5.5 yr (the age of adiposity rebound). Risk factors were: age at diagnosis (P = 0.04), radiation dosimetry to the hypothalamus (51-72 Gy, P = 0.002 even after hypothalamic and thalamic tumor exclusion), and presence of any endocrinopathy (P = 0.03). In addition, risk factors when compared with BMI slope for the general American pediatric population included: tumor location (hypothalamic, P = 0.001), tumor histology (craniopharyngioma, P = 0.009; pilocytic astrocytoma, P = 0.043; medulloblastoma, P = 0.039); and extent of surgery (biopsy, P = 0.03; subtotal resection, P = 0.018). These results verify hypothalamic damage, either due to tumor, surgery, or radiation, as the primary cause of obesity in survivors of childhood brain tumors. In particular, hypothalamic radiation doses of more than 51 Gy are permissive. These results reiterate the importance of the hypothalamus in energy balance, provide risk assessment criteria for preventative measures before the development of obesity in at-risk patients, and suggest therapeutic strategies to reduce the future development of obesity.

Purpose: To prospectively evaluate pediatric patients with localized primary brain tumors for evidence of endocrinopathy before radiotherapy (RT)., Methods and Materials: Seventy-five pediatric patients were evaluated with the arginine tolerance test and L-dopa test for growth hormone secretory capacity and activity; thyroid-stimulating hormone surge and thyrotropin-releasing hormone stimulation test for the hypothalamic-thyroid axis; the 1-microg adrenocorticotropin hormone (ACTH) and metyrapone test for ACTH reserve; and, depending on age, a gonadotropin-releasing hormone stimulation test to determine gonadotropin response. The study included 38 male and 37 female patients, age 1-21 years with ependymoma (n = 35), World Health Organization (WHO) Grade I-II astrocytoma (n = 18), WHO Grade III-IV astrocytoma (n = 10), craniopharyngioma (n = 7), optic pathway tumor (n = 4), and germinoma (n = 1). Seven patients receiving dexamethasone at the time of the evaluation were excluded from the final analysis., Results: Of 68 assessable patient, 45 (66%) had evidence of endocrinopathy before RT, including 15 of 32 patients (47%) with posterior fossa tumors. Of the 45 patients, 38% had growth hormone deficiency, 43% had thyroid-stimulating hormone secretion abnormality, 22% had an abnormality in ACTH reserve, and 13% had an abnormality in age-dependent gonadotropin secretion., Conclusion: The incidence of pre-RT endocrinopathy in pediatric brain tumor patients is high, including patients with tumors not adjacent to the hypothalamic-pituitary unit. These data suggest an overestimation in the incidence of radiation-induced endocrinopathy. Baseline endocrine function should be determined for brain tumor patients before therapy. The potential for radiation-induced endocrinopathy alone cannot be used as an argument for alternatives to RT for most patients. Pre-RT endocrinopathy may be an early indicator of central nervous system damage that will influence the functional outcome unrelated to RT.

Purpose: To review our institution's experience in the treatment of craniopharyngioma and assess the merits of initial therapy with limited surgery and irradiation., Methods and Materials: The data of 30 patients (median age 8.6 years) with a diagnosis of craniopharyngioma between April 1984 and September 1997 were reviewed. Their course of treatment, neurologic, endocrine, and cognitive function, and quality of life at last follow-up were compared., Results: Fifteen patients were initially treated with surgery (8 required irradiation after relapse) and 15 with limited surgery and irradiation (2 required additional treatment for tumor progression). Only 1 patient died of tumor progression. The surgery group lost a mean of 9.8 points in full-scale IQ, and the combined-modality group lost only 1.25 points (p <0.063). Patients in the surgery group who had relapses (n = 9) lost a mean of 13.1 points (p <0.067). A loss of 10 points was considered clinically significant. The surgery group also had more frequent neurologic, ophthalmic, and endocrine complications. The mean Health Utility Index (a functional quality-of-life index) was higher for the combined-modality group (0.85) than for the surgery group (0.71; p <0.063, one-sided t test)., Conclusions: The acute neurologic, cognitive, and endocrine effects of surgery often affect long-term function and quality of life. Our experience suggests that limited surgery and radiotherapy cause lesser or comparable sequelae. Diabetes insipidus was the only endocrine deficiency that differed substantially in frequency between the two groups. Newer radiation planning and delivery techniques may make a combined-modality approach a good initial option for most patients.

Somatostatin (SMS) is a potent inhibitory molecule. It inhibits both exocrine and endocrine secretory functions of the pancreas, suppresses growth hormone secretion and reduces the level of insulin-like growth factor-1. Long-acting somatostatin analogues were currently investigated for potential clinical benefits in two settings: (a) control of hyperinsulinaemia in obesity and (b) control of an excess of pro-angiogenic factors in diabetes-associated retinal complications. In two randomized, controlled trials the long-acting somatostatin analogue octreotide retarded progression of the microvascular complications in pre-proliferative and advanced stages of diabetic retinopathy. Inhibition of the early phase of insulin secretion by use of octreotide in patients with hypothalamic obesity resulted in weight loss and improved quality of life. Efficacy of octreotide correlated to residual beta-cell activity prior to the treatment. Obesity and diabetes mellitus are the most common chronic metabolic disorders in the world. The use of somatostatin analogues addressing the various hormonal imbalances of these disorders may provide a novel concept for their pharmacological treatment., (Copyright 2002 Elsevier Science Ltd.)

Purpose: Growth hormone (GH) deficiency is a known consequence of central nervous system irradiation. The relationship between the dose to the hypothalamus and the time to onset of clinically significant GH deficiency is unknown. Conformal radiotherapy (CRT) techniques allow for a more accurate determination of hypothalamic dosimetry. We correlated the dosimetry of the hypothalamus and the peak GH value after CRT in children with localized primary brain tumors., Methods and Materials: The arginine tolerance/L-dopa test was performed before (baseline) and repeated 6 and 12 months after CRT in 25 children (median age 4.8 years) with ependymoma (n = 15) or low-grade (n = 8) or high-grade (n = 2) astrocytoma. None had evidence of GH deficiency (arginine tolerance/L-dopa peak GH level >10 ng/mL [10 microg/L]) at baseline. Peak GH levels were modeled as a function of time after CRT and volume of the hypothalamus receiving a dose within the specified intervals of 0-20 Gy, 20-40 Gy, and 40-60 Gy. The model was used to predict the change in the peak GH levels over time (0-12 months) and fit under the assumption that the integral effect of irradiation was a linear sum of the products of the volume receiving a particular dose and the impact of that dose., Results: The peak GH level declined during the 0-12 months after CRT (p < 0.0001). GH deficiency was observed in 11 children at 6 months and a total of 20 children at 12 months. As expected, the effect of the dose interval 0-20 Gy was smaller than the 20-40-Gy dose interval; the largest effect was noted with the dose interval 40-60 Gy. The peak GH level may be predicted using the following estimating equation within the time limit of 0-12 months: GH(t)=Exp[ln(bGH)-(0.00058V(0-20 Gy)+0.00106V(20-40 Gy)+0.00156V(40-60 Gy))x t], where bGH is the baseline peak GH level, V(0-20 Gy), V(20-40 Gy), and V(40-60 Gy) is the percent-volume of the hypothalamus irradiated from 0 to 20 Gy, 20 to 40 Gy, and 40 to 60 Gy, respectively, and t is time after irradiation. When included in the model, the rate of decline in the peak GH response also was influenced by hydrocephalus and tumor location., Conclusion: The peak GH response within 12 months after CRT depends on hypothalamic dose-volume effects and may be predicted on the basis of a linear model that sums the effects of the entire distribution of dose. The modeled effects may be used to optimize radiotherapy and minimize and treat GH deficiency.