Fibroblast Growth Factor-21 to Adiponectin Ratio: A Potential Biomarker to Monitor Liver Fat in Children With Obesity.

Background: There is a pressing need for effective and non-invasive biomarkers to track intrahepatic triglyceride (IHTG) in children at-risk for non-alcoholic fatty liver disease (NAFLD), as standard-of-care reference tools, liver biopsy and magnetic resonance imaging (MRI), are impractical to monitor the course disease. Objective: We aimed to examine the association between serum fibroblast growth factor (FGF)-21 to adiponectin ratio (FAR) and IHTG as assessed by MRI in children with obesity. Methods: Serum FGF21 and adiponectin levels and IHTG were measured at two time points (baseline, 6 months) in obese children enrolled in a clinical weight loss program. The association between percent change in FAR and IHTG at final visit was examined using a multiple linear regression model. Results: At baseline, FAR was higher in the subjects with NAFLD (n = 23, 35.8 ± 41.9 pg/ng) than without NAFLD (n = 35, 19.8 ± 13.7 pg/ng; p = 0.042). Forty-eight subjects completed both visits and were divided into IHTG loss (≥1% reduction than baseline), no change (within ±1% change), and gain (≥1% increase than baseline) groups. At 6 months, the percent change in FAR was different among the three groups (p = 0.005). Multiple linear regression showed a positive relationship between percent change in FAR and the final liver fat percent in sex and pubertal stage-similar subjects with NAFLD at baseline (slope coefficient 6.18, 95% CI 1.90-10.47, P = 0.007), but not in those without NAFLD. Conclusions: Higher value in percent increase in FAR is positively associated with higher level of IHTG percent value at 6 months in children with baseline NAFLD. FAR could be a potential biomarker to monitor the changes in IHTG in children with NAFLD.

Metabolic syndrome is a sequela of radiation exposure in hypothalamic obesity among survivors of childhood brain tumors.

Survivors of childhood brain tumors may be at risk for early onset of metabolic syndrome, possibly secondary to surgery and/or radiation exposure. This study examines effects of radiation exposure to hypothalamus-pituitary-adrenal axis (HPA) on metabolic risk among survivors of childhood brain tumors. One hundred forty-two met inclusion criteria; 60 had tumor surgery plus radiation exposure (>1 Gray (Gy)) to HPA. The second subgroup of 82 subjects had surgery only and were not exposed to radiation. Both subgroups had survived for approximately 5 years at the time of study. All had clinical evaluation, vital signs, anthropometry, measurement of body composition by dual X-ray absorptiometry and fasting laboratory assays (metabolic panel, insulin, C-peptide, insulin-like growth factor-1, leptin and adiponectin). Body composition data for both subgroups was compared with the National Health and Nutrition Survey (NHANES) subgroup of similar age, gender and body mass index. Cranial surgery was associated with obesity of similar severity in both subgroups. However, survivors exposed to radiation to the HPA also had increased visceral fat mass and high prevalence of growth hormone deficiency and metabolic syndrome. Fat mass alone did not explain the prevalence of the metabolic syndrome in radiation exposure subgroup. Other factors such as growth hormone deficiency may have contributed to metabolic risk. We conclude that prevalence of metabolic syndrome among subjects exposed to hypothalamic radiation was higher than expected from hypothalamic obesity alone. Radiation exposure may exert untoward endocrinopathies due to HPA exposure that worsens metabolic risk. Early screening for metabolic syndrome in this population is indicated.

Effects of residential summer camp on body mass index and body composition in type 1 diabetes.

BACKGROUND: Body mass index (BMI) and fat mass may be higher in children with diabetes compared to healthy peers. It is not certain how diabetic children respond to exercise and diet interventions. OBJECTIVE: To investigate the effect of summer camp on BMI and body composition in children with type 1 diabetes. METHODS: Five hundred eighty-six children (5-19 years, 518 with type 1 diabetes, 68 without diabetes) were followed while attending camp. BMI z-scores (BMIz) and body composition (bioelectrical impedance analysis) were measured at the beginning and end of each 19-day session. Diet and activity were directly supervised, blood glucose closely monitored. A nested diabetic/non-diabetic sib pair analysis was also conducted. Changes in BMIz and percent fat mass (%FM) were the primary outcomes. Findings were confirmed by analysis of data from 612 campers (549 with diabetes) the following summer. RESULTS: At entry, campers with diabetes had higher BMIz and %FM. They tended to gain BMIz (0.04 ± 0.01) whereas non-diabetic campers lost (-0.16 ± 0.11, P < .0001). BMIz increases were positively correlated with precamp hemoglobin A1c values. The differences in initial values and changes in BMIz remained when campers with diabetes were compared to their siblings. All experienced a similar reduction in %FM. Similar results were obtained the following summer. CONCLUSIONS: Children with diabetes may, therefore, accrue more lean body tissue with increased exercise and a healthy diet than those without diabetes. This effect is greatest in those with initially poor metabolic control.

Association of Non-High-Density Lipoprotein Cholesterol with Psychosocial Dysfunction in Children and Adolescents with Obesity.

BACKGROUND: Children with obesity have worse psychosocial functioning compared to their non-overweight peers. Adult studies suggest that several metabolic factors may participate in the etiology of depression in obesity. METHODS: We evaluated the association of several metabolic parameters with psychosocial dysfunction in children with obesity, through a retrospective review of electronic medical records in patients ages 6-17. All parents were asked to complete the Pediatric Symptom Checklist (PSC) questionnaire, a validated measurement of psychosocial dysfunction in children. RESULTS: PSC scores were available in 618 patients. Overall, 11.2% of patients had a PSC score ≥28, suggestive of psychosocial dysfunction. Non-high-density lipoprotein (HDL) cholesterol was associated with a higher PSC score (p = 0.02), after adjusting for age, sex, race, socioeconomic status, and BMI z-score. CONCLUSIONS: Consistent with adult studies, in children and adolescents with obesity, non-HDL cholesterol may play a role in the etiology of psychosocial dysfunction. Further studies are warranted.

Management of pediatric obesity: a lifestyle modification approach.

Over the last decades, pediatric obesity has become a global epidemic with worldwide estimates as high as 43 million children and adolescents affected, and this number is rising at an exponential rate. With pediatric obesity comes a host of co-morbidities including impaired glucose tolerance, dyslipidemia, hypertension, and impaired liver function. Treatment of this population has proven to be challenging for many reasons. For patients, a new baseline exists consisting of an increasingly sedentary lifestyle as well as a lack of availability of affordable healthy alternatives. In addition, there is an overwhelming presence of energy-dense foods. For physicians, there are many issues including lack of time, training, and reimbursement. The most efficacious and reliable way to treat this population and its co-morbidities is with a healthy, balanced lifestyle consisting of a realistic diet plan and exercise regimen. The is the cornerstone of therapy in the Center for Obesity And its Complications in Health (COACH) clinic which is Children's Medical Center's (Dallas, TX) strategy to combat and treat pediatric overweight and obesity. Lifestyle changes of diet and exercise plans are tailored to each individual's interests and metabolic needs in COACH which is a multi-disciplinary clinic. Additionally, co-morbidities are screened for and treated aggressively to help prevent long-term complications of overweight and obesity. If others do similar interventions in their communities, this global epidemic has the possibility of more positive outcomes than those currently projected.

Vitamin D deficiency in obese children and its relationship to glucose homeostasis.

OBJECTIVES: The aim of the study was to compare the prevalence of vitamin D deficiency in obese and non-overweight children in North Texas, to examine relationships between dietary habits and 25-hydroxyvitamin D [25(OH)D] level in obese children, and to examine the relationship between 25(OH)D level and markers of abnormal glucose metabolism and blood pressure. PATIENTS AND METHODS: Using a cross-sectional design, systolic and diastolic blood pressure, dietary information, serum 25(OH)D, fasting glucose and insulin, 2-h glucose from oral glucose tolerance test, hemoglobin A1c, and homeostasis model assessment of insulin resistance were recorded for 411 obese subjects (6-16 yr old) at an obesity referral clinic. 25(OH)D was also obtained from 87 control non-overweight subjects (6-16 yr old). RESULTS: Ninety-two percent of obese subjects had a 25(OH)D level below 75 nmol/liter, and 50% were below 50 nmol/liter. Among non-overweight subjects, these frequencies were 68 and 22%, respectively (both P < 0.01 compared with obese subjects). 25(OH)D was negatively associated with soda intake (P < 0.001), juice intake (P = 0.009), and skipping breakfast (P < 0.001). 25(OH)D was negatively correlated with homeostasis model assessment of insulin resistance (r = -0.19; P = 0.001) and 2-h glucose (r = -0.12; P = 0.04) after adjustment for body mass index and age but was not correlated with hemoglobin A1c, systolic blood pressure Z score, or diastolic blood pressure Z score. CONCLUSIONS: Vitamin D deficiency is common in children in this southern United States location and is significantly more prevalent in obese children. Lower 25(OH)D level is associated with risk factors for type 2 diabetes in obese children.

Stimulated growth hormone concentrations in obese pediatric patients with mild and severe insulin resistance: a pilot study.

BACKGROUND: GH excess predisposes to insulin resistance (IR). Obese patients have blunted responses to GH stimulation and decreased spontaneous secretion. GH secretion has not been studied in the context of IR.rr OBJECTIVE: To determine whether varying degrees of IR effects GH dynamics in obese children. PATIENTS/DESIGN: Patients (all > 10 y) were categorized according to gender and HOMA-IR to have either mild or severe IR. Twenty patients (10 female) with mild IR completed the study, as did 18 (9 female) in the severe group. Each patient underwent a GH stimulation test with GHRH. GH peak and area under the curve (AUC) were compared between the groups. RESULTS: Severe IR females had higher peak GH (mean +/- SD, 9.5 +/- 4.4 vs. 5.8 +/- 3.7 ng/dl, p = 0.04) and trended toward higher GH AUC (356 +/- 207 vs. 221 +/- 128, p = 0.06) than mild IR females. There were no differences in GH response in males, CONCLUSIONS: There may be a positive relationship between severity of IR and peak GH in obese girls.

Screening for type 2 diabetes in obese youth.

OBJECTIVE: To assess available blood tests as potential screening tools for impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM). METHODS: We studied 468 obese (BMI mean: 34.4 kg/m(2)) children, including a subgroup with serum fasting insulin levels of >15 microIU/mL. Fasting laboratory tests included measurements of serum glucose and insulin, hemoglobin A1c (HbA1c), and 1,5-anhydroglucitol (insulin-resistant subgroup only) levels. An oral glucose-tolerance test was performed on each patient, and 2-hour postload serum glucose and insulin levels were obtained. Fasting blood glucose (BG), Homeostasis Model of Assessment for Insulin Resistance (HOMA-IR), HbA1c, and 1,5-anhydroglucitol values were used as predictors for exceeding various 2-hour BG cut-offs. Receiver operator characteristic curves were fitted to determine area-under-the-curve values as measures of screening efficacy. RESULTS: In the insulin-resistant subgroup, 3 (2%) patients had T2DM and 23 (12%) had IGT. Optimal sensitivity and specificity to detect T2DM were, respectively, 99% and 96% at HbA1c >or= 6.0%, and 96% and 88% at 1,5-anhydroglucitol < 17.0 microg/mL, with lower values for fasting BG and the HOMA-IR. In the entire study group, 9 (2%) patients had T2DM and 44 (9%) had IGT. Optimal sensitivity and specificity to detect T2DM were, respectively, 86% and 85% at HbA1c levels of 5.7%, 88%, and 93% at a fasting BG level of 104 mg/dL, and 62% and 70% at an HOMA-IR of 7.9. CONCLUSIONS: HbA1c, 1,5-anhydroglucitol, and fasting BG levels are good predictors of T2DM in obese children, whereas HOMA-IR values are not. HbA1c and 1,5-anhydroglucitol are excellent predictors of T2DM in insulin-resistant obese children.

Neonatal thyrotoxicosis and persistent pulmonary hypertension necessitating extracorporeal life support.

We report a case of neonatal Graves' disease involving an infant with severe persistent pulmonary hypertension (PPHN) associated with neonatal thyrotoxicosis that necessitated extracorporeal membrane oxygenation. Hyperthyroidism, although uncommon in the newborn period, has been associated with pulmonary hypertension among adults. The exact mechanisms responsible for this effect on pulmonary vascular pressure are not well understood. Recent studies have provided evidence that thyrotoxicosis has direct and indirect effects on pulmonary vascular maturation, metabolism of endogenous pulmonary vasodilators, oxygen economy, vascular smooth muscle reactivity, and surfactant production, all of which may contribute to the pathophysiologic development of PPHN. Therefore, because PPHN is a significant clinical entity among term newborns and the symptoms of hyperthyroidism may be confused initially with those of other underlying disorders associated with PPHN (eg, sepsis), it would be prudent to perform screening for hyperthyroidism among affected newborns.

Roles of the lactogens and somatogens in perinatal and postnatal metabolism and growth: studies of a novel mouse model combining lactogen resistance and growth hormone deficiency.

To delineate the roles of the lactogens and GH in the control of perinatal and postnatal growth, fat deposition, insulin production, and insulin action, we generated a novel mouse model that combines resistance to all lactogenic hormones with a severe deficiency of pituitary GH. The model was created by breeding PRL receptor (PRLR)-deficient (knockout) males with GH-deficient (little) females. In contrast to mice with isolated GH or PRLR deficiencies, double-mutant (lactogen-resistant and GH-deficient) mice on d 7 of life had growth failure and hypoglycemia. These findings suggest that lactogens and GH act in concert to facilitate weight gain and glucose homeostasis during the perinatal period. Plasma insulin and IGF-I and IGF-II concentrations were decreased in both GH-deficient and double-mutant neonates but were normal in PRLR-deficient mice. Body weights of the double mutants were reduced markedly during the first 3-4 months of age, and adults had striking reductions in femur length, plasma IGF-I and IGF binding protein-3 concentrations, and femoral bone mineral density. By age 6-12 months, however, the double-mutant mice developed obesity, hyperleptinemia, fasting hyperglycemia, relative hypoinsulinemia, insulin resistance, and glucose intolerance; males were affected to a greater degree than females. The combination of perinatal growth failure and late-onset obesity and insulin resistance suggests that the lactogen-resistant/GH-deficient mouse may serve as a model for the development of the metabolic syndrome.

Insulin pump therapy in toddlers and preschool children with type 1 diabetes mellitus.

OBJECTIVE: To test whether glycemic control in young children could be achieved more effectively and safely by using continuous insulin infusions administered by insulin pumps. STUDY DESIGN: We analyzed the effects of pump therapy in nine toddlers in whom type 1 diabetes developed between the ages of 10 and 40 months. After a mean of 13.7 months of therapy with multiple daily injections, patients were treated with insulin pumps for periods ranging from 7 to 19 months (mean, 12.7 months). RESULTS: Before initiation of pump therapy, HbA1c levels averaged 9.5% +/- 0.4%, and patients had a mean of 0.52 episodes per month of severe hypoglycemia (uncontrolled shaking, inconsolable crying, disorientation, or seizures). After initiation of pump therapy, HbA1c levels declined to 7.9% +/- 0.3% (P <.001 vs prepump levels), and the incidence of severe hypoglycemia decreased to 0.09 episodes per month (P <.05). Normal linear growth and weight gain were maintained during pump therapy. There were no changes in the frequency of physician or emergency room visits for acute hyperglycemia or ketoacidosis. However, the frequency of parental contacts with health personnel declined by >80%, reflecting increasing parental confidence and independence in diabetic care. Subjective assessments revealed significant improvements in quality of life and high levels of satisfaction with pump therapy. CONCLUSIONS: Insulin pump therapy may provide an effective alternative for selected preschool children with type 1 diabetes.

Leptin in the newborn mouse. Plasma concentrations, characterization of the circulating hormone, and tissue source.

Previous studies suggested that brown adipose tissue (BAT) provides a source of circulating leptin in the newborn mouse. However, we detected no leptin mRNA in newborn BAT or in newborn liver or stomach. In contrast, leptin expression was detected readily in newborn white adipose tissue (WAT). Fasting plasma leptin concentrations in newborn mice were comparable to those in adult nonpregnant mice. In contrast to adult mice, however, the fasting leptin levels in newborn males were comparable to those in females. While leptin in the late-gestational pregnant mouse circulates as a complex with the leptin-binding protein, leptin in the newborn mouse circulates as the free hormone. Factors regulating the expression of leptin by newborn WAT remain to be elucidated.

Targeted deletion of the PRL receptor: effects on islet development, insulin production, and glucose tolerance.

PRL and placental lactogen (PL) stimulate beta-cell proliferation and insulin gene transcription in isolated islets and rat insulinoma cells, but the roles of the lactogenic hormones in islet development and insulin production in vivo remain unclear. To clarify the roles of the lactogens in pancreatic development and function, we measured islet density (number of islets/cm(2)) and mean islet size, beta-cell mass, pancreatic insulin mRNA levels, islet insulin content, and the insulin secretory response to glucose in an experimental model of lactogen resistance: the PRL receptor (PRLR)-deficient mouse. We then measured plasma glucose concentrations after ip injections of glucose or insulin. Compared with wild-type littermates, PRLR-deficient mice had 26-42% reductions (P < 0.01) in islet density and beta-cell mass. The reductions in islet density and beta-cell mass were noted as early as 3 wk of age and persisted through 8 months of age and were observed in both male and female mice. Pancreatic islets of PRLR-deficient mice were smaller than those of wild-type mice at weaning but not in adulthood. Pancreatic insulin mRNA levels were 20-30% lower (P < 0.05) in adult PRLR-deficient mice than in wild-type mice, and the insulin content of isolated islets was reduced by 16-25%. The insulin secretory response to ip glucose was blunted in PRLR-deficient males in vivo (P < 0.05) and in isolated islets of PRLR-deficient females and males in vitro (P < 0.01). Fasting blood glucose concentrations in PRLR-deficient mice were normal, but glucose levels after an ip glucose load were 10-20% higher (P < 0.02) than those in wild-type mice. On the other hand, the glucose response to ip insulin was normal. Our observations establish a physiologic role for lactogens in islet development and function.