Faculty Bibliography
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54
Efficacy of vitamin D on glucose homeostasis in obese adolescents [Meeting Abstract]
Background: The childhood obesity epidemic had led to an exponential rise in the prevalence of pre diabetes and /or Type 2 diabetes. Vitamin D deficiency results in decreased insulin sensitivity (ability of insulin to promote peripheral glucose uptake) and fasting hyperglycemia has been correlated with Vitamin D deficiency in obese adolescents and children.1,2 Aims: To study insulin sensitivity and secretory indices derived from an oral glucose tolerance test (OGTT) in obese adolescents with vitamin D deficiency before and immediately after normalization of serum 25(OH) vitamin D levels. Methods: In a single blinded randomized placebo controlled study (cross over design with planned sample size= 20) obese adolescents with vitamin D deficiency; 25 (OH) vitamin D < 20 ng/dl (50 nmol/L) were recruited. Adolescents were assigned to receive 50,000 IU of ergocalciferol (group A) once weekly or placebo (group B) for 6 weeks. At week 7, subjects were reassigned to receive vitamin D if they were in group B or placebo if they were in Group A. Study subjects had an OGTT and screening labs (25 (OH) Vitamin D, PTH, CMP, calcium, phosphorous and urine calcium/ creatinine ratio) at baseline, week 7 and then again at week 12 on the completion of study. Indices derived from OGTT were: 1) Whole body sensitivity index (WBISI):10,000/(fasting glucose(mg/dL)x fasting insulin(uIU/mL)x(mean glucose (mg/dL) x mean insulin (uIU/mL) 2) Insulinogenic index: 30 min insulin- fasting insulin (uIU/mL) / 30 min glucose- fasting glucose (mg/dL) Results: To date four subjects have completed the study: Hispanic females (mean +/- SD) age 16.1+/- 1years, BMI 34.5+/- 4.5. Baseline labs were: HbA1c 5.3+/- 0.2, fasting glucose 81+/- 5.1, and fasting insulin 16.5+/- 5.3uIU/ml. PTH 48.5+/- 13.8 ng/dl (15- 75), calcium 9.1+/- 0.1 mg/dl (8.3- 10.3), phosphorous 4.3+/- 0.2mg/dl ( 2.7- 4.5), alkaline phosphatase 95+/- 19 mg/dl (39- 390) and urine calcium/creatinine were normal at baseline and on completion as we monitored for hypercalcemia. Mean 25 (OH) Vit D was 19.4+/- 1.4 ng/dl before treatment. In 3 of 4 subjects vit D did not normalize to >30 ng/dl (23+/- 6.7 mg/dl) on completion of the study, while it did in one patient (30.2 ng/dl). The mean insulin during OGTT (total of six levels during OGTT) decreased by 57% from 88+/- 36 to 51+/- 10 IU/L from start to completion of the study, while mean glucose values and HbA1c remained unchanged. WBISI improved significantly from 2.2+/- 0.3 to 4.3+/- 0.6, a 51% increase in this sensitivity index. Conclusions: These results, though preliminary, suggest that even marginal increases in the Vitamin D levels in deficient insulin resistant obese adolescents appears to improve their hyperinsulinemia. More intriguing is that insulin sensitivity index WBISI improved after 6 weeks of vitamin D treatment, which if confirmed at study completion could have important therapeutic implications for insulin resistance
EMBASE:72338295
ISSN: 0163-769x
CID: 2187872
Comparison of oral and intravenous glucose tolerance test derived sensitivity and secretory indices in obese adolescents
Background. Insulin resistance increases type 2 diabetes risk in obese adolescents. Thus, quantitative tools measuring insulin sensitivity and secretion are important for risk assessment. Methods. Forty-four obese pubertal adolescents underwent oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIGT). We correlated OGTT-derived whole body sensitivity index (WBISI) with FSIGT-derived insulin sensitivity index (Si). Insulinogenic index (IGI) from OGTT was compared with acute insulin response to glucose (AIRg) from FSIGT. Results. Fasting insulin (r = -.64, P < .0005) and glucose (r = -.39 P
PMID: 23418053
ISSN: 0009-9228
CID: 249512
Continuous glucose monitoring: a valuable monitoring tool for management of hypoglycemia during chemotherapy for acute lymphoblastic leukemia
Abstract Background: Acute lymphoblastic leukemia (ALL) maintenance therapy (MT) has been occasionally associated with symptomatic hypoglycemia (SH), attributed to purine analog (mercaptopurine [6-MP]). This hypoglycemia has been hypothesized to affect substrate utilization of gluconeogenic precursor alanine in the liver. Case Report: An overweight 5-year-old boy with ALL was evaluated for SH (lethargy and vomiting) that occurred 8-10 h after fasting while receiving daily 6-MP. Hypoglycemic episodes (>20 episodes per month) occurred predominantly around midmorning but not during the 5-day dexamethasone pulse. The adrenocorticotropic hormone test yielded a normal cortisol response, which ruled out pituitary adrenal suppression. A 12-h overnight fasting glucose was 49 mg/dL, with suppressed insulin response <2 IU/mL, low C-peptide of 0.5 ng/mL, high insulin-like growth factor-binding protein >160 ng/mL, high free fatty acid of 2.64 mmol/L, and negative glucagon stimulation test (change in blood glucose [BG] <5 mg/dL). These results ruled out hyperinsulinism. The patient was placed on cornstarch therapy 5 h prior to dosing with 6-MP. This treatment reduced the SH events to fewer than two episodes per month. To study the efficacy of cornstarch, the patient was fitted with the iPro professional continuous glucose monitoring system (CGMS) (Medtronic MiniMed, Northridge, CA) with a preset low alarm at 70 mg/dL, which was worn for a period of 5 days while the patient was on cornstarch. With 1,000 sensor reading the BG range was 65-158 mg/dL, and the percentage mean absolute difference between sensor and finger-stick BG readings (the parent monitored his BG four times a day) was 9.4%. There were no hypoglycemic episodes detected by the CGMS while the patient was on cornstarch. After the cessation of chemotherapy, a 15-h fasting study was performed, and the CGMS was placed. Results showed resolution of hypoglycemia. Conclusions: The CGMS helped us devise an effective management plan for our patient. CGMS proved useful as an adjunct to characterize the pattern of hypoglycemia and to validate the benefit of cornstarch in hypoglycemia associated with 6-MP treatment of ALL.
PMID: 23145966
ISSN: 1520-9156
CID: 211082
Endothelial dependent vasodilatation across glucose tolerance categories in obese adolescents [Meeting Abstract]
Background: Obese adolescent with T2DM and /or pre diabetes demonstrate endothelial dysfunction (ED), a key early event in atherogenesis. Flow mediated dilatation (FMD) of the brachial artery is a well validated surrogate for ED. Traditional cardiovascular risk factors (BMI, LDL-cholesterol, systolic blood pressure and smoking) have a deleterious effect on the vasculature in adolescents. Objective and hypotheses: We proposed to delineate the relationship between glucose tolerance categories and ED in obese adolescents. Methods: 25 adolescents with a mean age of 15.7 +/- 1.5 years, BMI 35+/- 6 (60% female and Hispanic) underwent a 75 gram oral glucose tolerance test (OGTT). Duplex ultrasound (11MHz transducer) measured endothelium dependent vasodilatation. Reference range in our vascular lab for FMD is 5.89+/- 2.88% (95% CI: 4.53- 7.23). Results: Based on OGTT results: 16 subjects had normal glucose tolerance (NGT: fasting glucose <= 99 mg/dl and/ or 2 hour post challenge glucose <= 139 mg/dl) and 6 subjects were diagnosed with pre diabetes(fasting glucose>= 100 and/ or 2 hour post challenge glucose >= 140 mg/dl). Adolescents with T2DM (n= 3) had lower FMD (3.2+/- 2.8%) compared to adolescents with NGT (6.5+/- 5.08%) and of those with NGT; five had an impaired FMD (<= 5.8%). Adolescents with pre diabetes had FMD values (9.8+/- 3.08%) higher than NGT group, though differences between the glucose tolerance categories did not reach statistical significance (NGT vs. pre diabetes vs. T2DM, p= 0.26). FMD did not correlate with CVS risk factors in these adolescents. In adolescents with NGT, FMD was negatively correlated with 2 hour glucose (r= -0.6, p= 0.03). Conclusions: Adolescents with prediabetes compared to those with T2DM appear to have preserved endothelium dependent vasodilatation. In adolescents with NGT, lower FMD predicts impaired glucose tolerance and accelerated vascular dysfunction. CVS risk factors did not appear to affect FMD in these obese adolescents
EMBASE:71247148
ISSN: 1663-2818
CID: 688302
Androgen profile and anti-Mullerian hormone levels in girls with premature adrenarche [Meeting Abstract]
Background: Premature adrenarche (PA), the presence of pubic hair before age eight years in girls, is considered a harbinger of polycystic ovary syndrome (PCOS). Anti-Mullerian hormone (AMH), a dimeric glycoprotein, reflects the amount of growing follicles in the ovaries and is considered a robust index of ovarian function. AMH levels are known to be elevated in patients with PCOS and also in pre pubertal daughters of women with PCOS. Objective and hypotheses: The goal of this study was to determine the androgen and AMH profile in a multiethnic cohort of girls with PA. Methods: Girls diagnosed with PA between 2002- 2012 were studied for BMI, bone age (BA), testosterone, dehydroepiandrosterone sulfate (DHEA-S) and 17-hydroxyprogesterone (17-OHP). Age matched girls were identified to serve as a comparison group. AMH levels were measured in stored sera of girls with PA as well in matched controls via the AMH Gen II ELISA assay from Quest Diagnostics, Nichols Institute (reference range< 18 years: 0.3- 11.2ng/ml). Results: Fifty-one patients with PA (58% Hispanic) with an average BMI (mean+/- SD) of 19.4+/- 4.1years, BA of 6.9+/- 3.2 years and chronological age (CA) 6.8+/- 0.8 years were compared to controls (n= 15) with BMI of 16.4+/-1.56 years, BA of 6.2+/-1.6 years and CA of 6.02+/- 1.3 years. Testosterone levels of 11.5+/- 4.1 ng/dl were elevated in 66% (<=10: pre pubertal) of girls of PA. DHEA-S levels of 67+/- 56 ug/dl (>=75: 6-8 yr >=55< 5 yr) were elevated in 21% of girls with PA, and 40% of all girls with PA had an advanced BA (defined as BA>= 1 year of CA). In girls with PA (n=14) AMH levels of 2.16+/-1.7 ng/dl were lower than in controls (n=6) 4.18+/- 2.58 ng/dl, though this difference did not reach statistical significance (p= 0.128). Conclusions: In our investigation we did not find PCOS related abnormalities in serum AMH levels in girls with PA. AMH levels cannot discriminate which girls with PA will go on to develop PCOS in the future
EMBASE:71247323
ISSN: 1663-2818
CID: 688292
Vitamin D intoxication in a toddler due to a dispensing error of an imported vitamin D supplement [Meeting Abstract]
Introduction: Vitamin D intoxication is a rare cause of hypercalcemia. There is a recent increase in reports of pediatric cases of hypercalcemia, secondary to vitamin D intoxication. This trend is attributable to the growing popularity of vitamin D supplements, especially as Vitamin D is being marketed as a "panacea" for a number of medical problems.Immigrant families often travel to their countries of origin, where vitamin supplements are available in formulations different from the US. Parents may not report using supplements to their child's pediatrician, as these supplements are perceived "safe" with no dangerous side effects.Case Presentation: A three year old toddler presented to the emergency room with emesis, polyuria, and lethargy. On inquiry, the family reported use of a multivitamin gel (made in Ecuador) dispensed at 1 tsp bid. Per the manufacturer's label, 5 grams (aD;one teaspoon) contains 0.096 mg (aD;100 IU) of cholecalciferol. A standard conversion of 1mug of cholecalciferol equals 40 IU1, secondary to conversion error this patient received 7,680 IU per day and 108,000 IU total vitamin D3 over 14 days, which is toxic. "Teaspoon" dosage inaccuracies and potentially excessive administration by caretakers compounded vitamin D toxicity.Initial lab values revealed Ca 16 mg/dl, iPTH 2.25 pg/mL (15-65), 25 OH vit D3: >512ng/mL(30-100), and UCa/UCreatinine 1.14mg/mg(<0.2). Hydration, lasix, calcitonin (6 days), and prednisolone (7 days) were used to manage the hypercalcemia. After 15 days of treatment, the 25 OH vitamin D3 was 324 ng/ml and the calcium decreased to 11.2 mg/dL. Conclusion s: In our case, dispensing and labeling errors led the parents to administer high doses of vitamin D to their toddler, leading to hypercalcemia. This highlights several issues regarding vitamin supplement usage.First, physicians should be aware of the dosage conversion of vitamin D in terms of IU, mg and mcg to calculate if the prescribed dose is appropriate for their patients. In addition, as there are no established manufacturing standards for certain vitamin supplement formulations-such as gels-caution should be exercised as more reports are emerging of toxic ingestion from overzealous supplementation. Verification of supplement source and composition is essential. Lastly, educating parents about the safe use of vitamin D supplements-emphasizing the need to report imported supplements to the patient's pediatrician-is important to avoiding erroneous toxic ingestion
EMBASE:70833827
ISSN: 0163-769x
CID: 175829
Sleep architecture and glucose and insulin homeostasis in obese adolescents
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
PMCID:3198280
PMID: 21933909
ISSN: 1935-5548
CID: 146228
Early presentation of bilateral gonadoblastoma in Denys-Drash syndrome: A cautionary tale for prophylactic gonadectomy [Meeting Abstract]
Background: Contiguous gene deletion of the Wilms tumor gene (WT1) is associated with two well described syndromes; Denys-Drash (DDS) and Frasier (FS). Both are associated with nephropathy and ambiguous genitalia and have overlapping clinical and molecular features (1). The known risk of Wilms tumors in DDS and gonadoblastomas in FS patients requires tumor surveillance.Case report: We evaluated a newborn with ambiguous genitalia, intact Mullerian structures (uterus) and small bilateral perivesicular gonads with a 46,XY (SRY+) karyotype. The physical exam revealed labia with clitoromegaly (1.2 cm in length). There were separate uretheral and vaginal openings with no urogenital sinus. Labs in the early neonatal period (Quest Diagnostics: all male references) revealed 17-OH-Progesterone 96 (<420 ng/dL), testosterone 133 (2-23 ng/dL; tanner 1), DHEAS 441 (73-367 ug/dL), inhibin A <1 (<21 pg/mL; prepubertal), inhibin B 35 (<161 pg/mL; 3-9 years old), and AMH 3.7 (87.3-243 ng/mL; 1-6 years old). After a joint discussion with the family, geneticist, endocrinologist, and psychologist the infant was assigned a female gender. Based on the phenotype (ambiguous genitalia, pre and postnatal hydronephrosis, and genitourinary abnormalities), the exon and exon-intron boundaries were sequenced. A missense mutation leading to the substitution of lysine for glutamine at position 369 of the WT1 protein (Q369K) in exon 8 was found to be consistent with Denys-Drash syndrome. At seven months of age the patient underwent a clitoroplasty and gonadectomy. Bilateral gonadoblastomas were found in an indeterminate left gonad and a right testis. In addition, the patient had bilateral grade 2-3 vesicoureteral reflux and progressed to end stage renal failure at 11 months of age (creatinine 1.4mg/dl). Consequently, the patient has secondary hyperparathyroidism with PTH 691 (12-65 pg/mL), calcium 7.2 (8-10.4 mg/dL), and phosphorus 7 (2.7-4.5 mg/dL). The patient's most recent renal ultrasound does not show evidence of a Wilms tumor (2).Conclusion: This is one of the earliest cases of bilateral gonadoblastoma reported in DDS. This case highlights the importance of early gonadectomy at the time of diagnosis of the WT1 gene mutation as these tumors have potential for malignant transformation
EMBASE:70675891
ISSN: 0163-769x
CID: 159286
Continuous glucose monitoring (CGM): An invaluable monitoring tool for management of hypoglycemia during chemotherapy for acute lymphoblastic leukemia (ALL) [Meeting Abstract]
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 67th percentile, BMI 90th 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
EMBASE:70675646
ISSN: 0163-769x
CID: 159287
Relationships between IGF axis parameters, inflammatory markers, and adipocytokines in obese adolescents [Meeting Abstract]
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
EMBASE:70677022
ISSN: 0163-769x
CID: 159280
