Faculty Bibliography

Obese adolescents are at risk of cardiovascular disease (CVD). Our study aims to explore the links between insulin-like growth factor I (IGF-I), IGF binding protein 1 (IGFBP-1), and novel markers of CVD risk in this population.Low IGF-I is associated with impaired glucose tolerance and CVD, and low IGFBP-1 has been linked with metabolic syndrome. The IGF and inflammatory systems have close biological links, and pro-inflammatory markers like high sensitivity c-reactive protein (hsCRP) independently predict CVD and diabetes. Adipocytokines are also important markers. Adiponectin correlates inversely with insulin resistance (IR), and higher levels independently predict reduced risk of CVD. It also demonstrates anti-inflammatory and myocardial remodeling effects. Abnormal leptin signaling is implicated in obesity-related CVD.We hypothesize that IGF-I and IGFBP-1 are related to these proteins. Because the IGF family is linked to inflammation, we suspect that these proteins affect coronary vessels independent of insulin and body mass, and may serve as novel markers of CVD risk.We recruited 63 obese adolescents age 8-17yrs; 44% were male. Race: 1 Asian, 35 Black, 23 White. Ethnicity: 8 Hispanic. Blood was drawn at 8am fasting. Means (standard deviations) were: weight 101.3kg (21.7), BMI 36.7kg/m2 (6.7), IGF-I 316.4ng/mL (119.3), IGFBP-1 6.45ng/mL (11.3), hsCRP 5.32mg/L (5.18), adiponectin 4.5ug/mL (1.7), leptin 37.6ng/mL (17.9). Using Spearman bivariate correlations we saw strong correlation between IGF-I and hsCRP (r=-0.470, p<0.0005), and also between IGF-I and leptin (r=-0.297, p=0.028), but not between IGF-I and adiponectin (r=0.006, p=0.96). We also found significant correlation between IGFBP-1 and leptin (r=-0.274, p=0.045); however, following Spearman partial correlations controlling for BMI and fasting insulin the relationship was no longer significant. IGFBP-1 and adiponectin were strongly correlated (r=0.523, p<0.0005). Following Spearman partial correlations controlling for fasting insulin (r=0.456, p=0.0008) and for BMI z-score (r=0.526, p<0.0005) the relationship remained highly significant.Our findings show a strong relationship between IGFBP-1 and adiponectin independent of BMI and insulin, and between IGF-I and hsCRP/leptin. This supports our hypothesis that the IGF axis is related to markers of cardiovascular risk. Higher IGF-I levels in adults may serve as a vascular protective factor; further study is needed in youth at risk for CVD

Background: PA, traditionally considered a benign process, is now viewed as a harbinger for future aberration such as polycystic ovary syndrome (PCOS) (1, 2). PA is the presence of pubic hair before age 8 yrs in girls, with DHEAS being the predominantly elevated androgen (3). While the role of androgens in bone growth has been well established in vitro (4), correlations between the elevated androgens and advanced bone age (ABA) observed in girls with PA have not been well delineated. The goal of this study was to identify the predominant androgen in a multiethnic cohort of girls with PA and to determine if that androgen was associated with ABA. Methods: A retrospective chart review was conducted on girls aged 5-7 that presented to our clinic between 2002-2010. The review included anthropometric data, androgen profile, bone age (BA), growth velocity and Tanner stage. Age-matched controls were also identified. Hormone concentrations were determined by radioimmunoassay and chromatography following extraction in our institution's endocrine laboratory. Mann-Whitney U tests and Spearman Correlation tests were used for statistical analyses. Results: Our cohort of 40 girls with PA were mostly Hispanic (58%) and African-American (25%) with a mean age of 6.89 +/- 0.80 yrs, BA of 7.83 +/-1.27 yrs, BMI 19.83 +/- 0.75, BMI Z-score 1.26 +/- 0.20, and growth velocity 7.03+/- 0.45 cm/yr. Testosterone was elevated in 60% of girls with PA (defined as >=10ng/dl for pre-pubertal girls) with DHEAS being elevated only in 30% of girls (>=75mug/dl for girls aged 6-8; >=55 mug/dl for girls <5 yr). Girls in the PA group had significantly elevated testosterone (11.55 +/- 4.83 ng/dL; p=0.04) and DHEAS (65.52 +/- 41.84 mug/dl; p=0.04) levels when compared to age-matched controls (n=7). The 17-OHP values in the two groups were not significantly different. 48% girls had an ABA (defined as BA >=1 yr of chronological age). There was a significant correlation between BA and serum testosterone while controlling for BMI (r=0.51, p=0.05). There was no significant association between BA and DHEAS, androstenedione, and 17-OHP.Conclusion: In our cohort of girls, testosterone emerged as the predominant elevated androgen. The adverse long-term effect of hyperandrogenism and consequent PCOS have been well established. Therefore monitoring girls with PA, elevated testosterone and ABA for emergence of aberrations in the hypothalamic gonadal axis may be prudent

OBJECTIVE: Sleep deprivation is associated with increased risk of adult type 2 diabetes mellitus (T2DM). It is uncertain whether sleep deprivation and/or altered sleep architecture affects glycemic regulation or insulin sensitivity or secretion. We hypothesized that in obese adolescents, sleep disturbances would associate with altered glucose and insulin homeostasis. RESEARCH DESIGN AND METHODS: This cross-sectional observational study of 62 obese adolescents took place at the Clinical and Translational Research Center and Sleep Laboratory in a tertiary care children's hospital. Subjects underwent oral glucose tolerance test (OGTT), anthropometric measurements, overnight polysomnography, and frequently sampled intravenous glucose tolerance test (FSIGT). Hemoglobin A(1c) (HbA(1c)) and serial insulin and glucose levels were obtained, indices of insulin sensitivity and secretion were calculated, and sleep architecture was assessed. Correlation and regression analyses were performed to assess the association of total sleep and sleep stages with measures of insulin and glucose homeostasis, adjusted for confounding variables. RESULTS: We found significant U-shaped (quadratic) associations between sleep duration and both HbA(1c) and serial glucose levels on OGTT and positive associations between slow-wave sleep (N3) duration and insulin secretory measures, independent of degree of obesity, pubertal stage, sex, and obstructive sleep apnea measures. CONCLUSIONS: Insufficient and excessive sleep was associated with short-term and long-term hyperglycemia in our obese adolescents. Decreased N3 was associated with decreased insulin secretion. These effects may be related, with reduced insulin secretory capacity leading to hyperglycemia. We speculate that optimizing sleep may stave off the development of T2DM in obese adolescents