Faculty Bibliography

Background: ALL maintenance therapy (MT) has been occasionally associated with symptomatic hypoglycemia (SH) [1], attributed to purine analogue (mercaptopurine; 6-MP).[2] 6-MP has been hypothesized to affect substrate utilization of gluconeogenic precursor alanine in the liver.[3] Even though thousands of children in the US are currently on 6-MP, the actual prevalence rate of 6-MP induced hypoglycemia has not been reported.Case report: 5 year overweight (weight 67^th percentile, BMI 90^th percentile for his age) male with ALL was evaluated for SH (lethargy and vomiting) which occurred 8-10 hours after fasting while receiving daily 6-MP. Hypoglycemic episodes (capillary blood glucose levels (BGs) were 35-65mg/dL), >20 episodes/ month, occurred predominantly around mid morning, but not during the 5-day dexamethasone pulse. Cortrosyn test yielded a normal cortisol response (0 min: 13 and 60 min: 25.9mug/dL) which ruled out pituitary adrenal suppression. A 12 hour overnight fasting glucose was 49 mg/dL, with suppressed insulin response < 2 muIU/mL, low C-peptide of 0.5ng/mL (0.8-3.5ng/mL), high IGF BP1 >160ng/mL (20-105ng/mL), high free fatty acid 2.64mmol/L (0.5-0.9mmol/L) and negative glucagon stimulation test ({Delta} BG <5mg/dL). These results ruled out hyperinsulinism and the diagnosis of ketotic hypoglycemia was made. The patient was placed on cornstarch therapy 5 hours prior to dose of 6-MP. This treatment reduced the SH events to <2 episodes/month. To study the efficacy of cornstarch, patient was placed on iPro professional CGM (Medtronic Diabetes) with a preset low alarm at 70mg/dL, was worn for a period of 5 days while patient was on cornstarch. With 1000 sensor readings the BG range was 65-158mg/dL. Mean absolute difference (MAD%) between sensor and finger stick BG readings (parent monitored patient's BG 4 times/day) was 9.4%. There was only one episode of asymptomatic hypoglycemia down to 65 mg/dL detected in the CGM.Conclusion: CGM technology helped us devise an effective management plan for our patient. CGM proved useful as an adjunct to characterize the pattern of hypoglycemia and validate the benefit of cornstarch in hypoglycemia associated with 6MP treatment of ALL

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