Faculty Bibliography

Background: Treatment options for adolescents with Type 2 diabetes (T2DM) are limited to metformin and/or insulin (in adults there are >100 Rx options). Most adolescents with T2DM are in poor glycemic control 1. If this worrisome trend continues these adolescents, mostly of minority racial/ethnic groups, will have retinopathy, neuropathy and nephropathy in their twenties when compared to adults who are diagnosed with T2DM in their forties 2. Objectives: Pilot study to investigate whether insulin pump therapy is a feasible treatment modality, improves quality of life (QOL) in adolescents with T2DM over a 3-month period. Pumps are considered appropriate, safe and efficacious by the American Diabetes Association in children with T1 DM 3, though studies demonstrating their efficacy in adolescents with T2DM are lacking. Method: In an open-label pilot (clinicaltrials.gov#02748122) adolescents with T2DM in poor control (HbA1c > 8%) on insulin (0.5-1.5 U/kg/day or more) and/or oral hypoglycemic agents were recruited. Adolescents were placed on a continuous glucose monitoring system (CGMS) before the pump start. At 1, 2 and 3 months pumps were downloaded and settings were titrated accordingly. Validated QOL questionnaires: the Pediatric Quality of Life Inventory (PedsQL: generic and diabetes modules), diabetes empowerment and treatment satisfaction scales were administered at the start and end of the pilot. Insulin pump MMT 723 and i-Pro2 professional, both made by Medtronic Inc., were used. Results: Five female adolescents (mean +/- SD: age: 16.3+/- 1.9 years; duration of diabetes: 5.4+/- 3 years; BMI: 30+/- 3) have completed the pilot. The total daily dose (TDD) of Lantus at the start of the study was 53+/-3 units. At the end of the pilot pump settings were as follows: basal rate: 1.4+/-0.4 U/hr; insulin carbohydrate ratio: 7+/-1 and insulin sensitivity factor: 23+/-7. The average blood sugars at the start and end of the pilot were: 205+/-91 and 161+/-70 mg/dl, respectively. The Hba1c at the start and end of the pilot were 11.7+/-1.4% and 10.3+/-1.8%, respectively. The acceptance was 40% with two adolescents opting to continue with insulin pumps for their ongoing diabetes management. Insulin requirements went down by 30% and the QOL parameters showed a trend to improvement. Conclusions: At the end of the pilot HbA1 c decreased by 1.3% which was significant. This result validates that insulin pumps when used by motivated adolescents improve glycemic control even over a short-term period. Teaching pump therapy to these technologically savvy adolescents was easy and adherence was fair (two subjects wore the pump 50% of the time of the study duration). Until more Rx options get approval insulin pumps may be an option to consider as more adolescents fail metformin and insulin injections and face enormous physical and psychological challenges of their poorly controlled T2DM

BACKGROUND: Insulin resistance and endothelial dysfunction share a reciprocal relationship that links the metabolic and cardiovascular sequelae of obesity. We characterized the brachial artery reactivity testing (BART) and carotid artery-intima media thickness (CIMT) in adolescents categorized as obese insulin resistant (OIR) and obese not insulin resistant (ONIR). Lipoprotein particle (p) analysis and inflammatory cytokines in OIR and ONIR groups were also analyzed. METHODS: Obese adolescents (n=40; mean body mass index [BMI] 35.6) were categorized as ONIR and OIR based on their homeostatic model assessment of insulin resistance (HOMA-IR) calculation ( than 3.4). Ultrasound measured conduit arterial function BART, microvascular function (post-ischemic hyperemia) and conduit artery structure CIMT. RESULTS: BART did not differ according to IR status (mean+/-SD: 7.0+/-4.3% vs. 5.9+/-3.4% in ONIR and OIR, respectively, p=0.3, but post-ischemic hyperemia was significantly greater in the ONIR group (4.5+/-2.2 vs. 3.5+/-3, p=0.04). Atherogenic lipoprotein particles; large VLDL particles and small LDL particles were higher in the OIR compared to ONIR group. CONCLUSIONS: OIR adolescents demonstrate an inflamed atherogenic milieu compared to the ONIR adolescents. Microvascular function, but not conduit vessel structure or function, was impaired in association with IR.

We present the clinical phenotype of a toddler who presented with vitamin D-resistant rickets, with one of the highest initial levels of alkaline phosphatase and parathyroid hormone (PTH) levels reported in the literature. The toddler had novel compound heterozygous mutations in the ligand-binding site of the vitamin D receptor and had an excellent response to calcitriol (1,25(OH)2D).

BACKGROUND: The hypothalamic-pituitary-gonadal axis is transiently activated during the postnatal months in boys, a phenomenon termed "minipuberty" of infancy, when serum testosterone (T) increases to pubertal levels. Despite high circulating T there are no signs of virilization. We hypothesize that free T as measured in saliva is low, which would explain the absence of virilization. METHODS: We measured serum total T and free T in saliva using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 30 infant boys, aged 1-6 months, and in 12 adolescents, aged 11-17 years. RESULTS: Total serum T in all infants was, as expected, high (172 +/- 78 ng/dL) while salivary T was low (7.7 +/- 4 pg/mL or 0.45 +/- 0.20%). In contrast, salivary T in the adolescents was much higher (41 +/- 18 pg/mL or 1.3 +/- 0.36%) in relation to their total serum T (323 +/- 117 ng/dL). We provide for the first time reference data for salivary T in infants. CONCLUSION: Measurement of salivary T by LC-MS/MS is a promising noninvasive technique to reflect free T in infants. The low free T explains the absence of virilization. The minipuberty of infancy is more likely of intragonadal than peripheral significance..

This review highlights the presentations of myopathy in children in both hypothyroid and hyperthyroid states with an emphasis on the pathophysiology, diagnosis and treatment. Based on our review of the literature data, myopathy should be considered in all children presenting with muscular weakness or altered muscle enzymes in the context of thyroid disease.

CONTEXT: Insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-1 have been linked to cardiovascular disease (CVD) risk and pathophysiology in adults, but there are limited data in youth. OBJECTIVE: The aim of the study was to examine the relationship between IGF and IGFBP-1 with traditional and non-traditional CVD risk factors including inflammatory markers and body composition in an obese pediatric cohort. DESIGN: A cross-sectional study. SETTING: The study was carried out at a university children's hospital. SUBJECTS: Sixty-one obese non-diabetic adolescents. OUTCOMES: Fasting IGF-I, IGFBP-1, lipoprotein profiles, high-sensitivity C-reactive protein (hsCRP), and total adiponectin as well as insulin sensitivity measures, blood pressure (BP), and anthropometrics. RESULTS: IGFBP-1 was negatively associated with insulin sensitivity measures, body mass index (BMI), and diastolic BP in males. IGF-I was negatively associated with hsCRP (r = -0.479, p < 0.0005), and IGFBP-1 was positively associated with adiponectin (r = 0.545, p < 0.0005). The IGF-I/CRP and IGFBP-1/adiponectin associations remained significant when controlling for both BMI and insulin sensitivity index (SI ). Both IGF-I and IGFBP-1 were negatively associated with waist circumference (r = -0.327 and r = -0.275, respectively) and sagittal abdominal diameter (r = -0.333 and r = -0.371, respectively), while IGFBP-1 was negatively associated with fat mass (r = -0.347, p = 0.01) as well as neck circumference and fat-free mass in males. Controlling for BMI z-score and SI , IGFBP-1 remained negatively associated with diastolic blood pressure (r = 0.706, p = 0.001 and neck circumference (r = -0.548, p = 0.15) in males. CONCLUSIONS: IGF-I and IGFBP-1 associate with CVD risk markers and may add to clinical assessments of cardiometabolic dysfunction in youth.

Introduction: Acute myopathy occurs in both hyperthyroid and hypothyroid states, the mechanism of which is not clearly understood (1). Some cases of myopathy are attributed to a relative hypothyroid state at the cellular level (2). Elevated levels of creatine kinase (CK) are observed in hypothyroid myopathy but not in hyperthyroid myopathy. However, CK elevations have been associated with antithyroid drug treatment (3). We report an adolescent with Graves' disease who had CK elevation on methimazole (MMI) treatment and after radioactive iodine ablation. Case report: 13 year old female diagnosed with Graves' disease who on diagnosis had the following labs: Free T4: 5.6 ng/dl (Normal range: 0.9-1.9 ng/dl), Free T 3: 19 pg/ml (2.3-4.2pg/ml), TSH: <0.008 uIU/ml (0.35-4.8 uIU/ml), TSI: 338% (<140 %) and she was started on methimazole (MMI: 30mg/day) and propranolol. The teenager reported muscle aches 4 months after starting MMI and on testing CK levels were elevated at 516 U/L (35-155 U/L) (3X normal) and MMI was discontinued. The patient tested negative for rheumatologic conditions like polymyositis where testing included ANA, anti Smith ab, dsDNA ab, anti RNP ab, Jo-1 ab, Scl- 70 ab and centromere B ab. The teenager experienced rapid and marked improvement in her muscle symptoms and CK levels decreased to 153 U/L (35-155 U/L) in a week. As thyroid hormones rebounded rapidly on discontinuation of MMI: Free T4: 2.03 (0.9-1.9ng/dl), Free T3: 8.4 (2.3-4.2pg/ml)), the treatment options were restarting MMI at a lower dose or radioablation and the family opted for the latter. The patient underwent radioactive iodine ablation (131I) with 12.5millicuries. Two months status post radio ablation, the patient became hypothyroid: Free T4:0.33 (0.9-1.9 ng/dl), TSH: 102 uIU/ml (0.35-4.8 uIU/ml)) and she developed acute myopathic symptoms which were again associated with CK elevation (higher than preablation) of 1093 U/L (35-155 U/L). On initiation of levothyroxine at 50mcg daily, CK levels decreased to 266 U/L (35-155U/L) in 10 weeks and symptoms improved. Conclusion: True incidence of acute myopathy associated with pediatric Graves' disease is higher than described in literature. Learning points from our case are: a) Pediatric Graves' disease families should be counseled about muscle symptoms and CK levels be measured when warranted by clinical history; b) Trending CK levels during the course of treatment may be prudent as our case demonstrates reemergence of myopathy in the hypothyroid state status post radio ablation; c) Addition of levothyroxine along with antithyroid medication may offset the local hypothyroid state within the muscle tissue resulting in CK augmentation

BACKGROUND: Circulating levels of 25 (OH) vitamin D (VD) mediate deterioration of beta cell function in vitamin D deficiency (VDD) states. Higher parathyroid hormone (PTH) levels have a negative impact on the beta cell function and insulin sensitivity (1, 2). Understanding the independent effect of VD and PTH on different aspects of glucose homeostasis may be paramount, especially when treating obese adolescents with VDD. OBJECTIVE: To study the independent effects of VD and PTH on surrogates (sensitivity and secretory indices derived from oral glucose tolerance test: OGTT) before and after Rx for VDD. METHODS: In a single blinded randomized placebo controlled study (cross over design with sample size= 7) obese adolescents with VDD (25 (OH) < 20 ng/dl) were recruited. Adolescents received 50,000 IU of ergocalciferol (group A) once weekly or placebo (group B) for 6 weeks. At week 7, subjects were reassigned to receive VD 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. OGTT indices: Insulin sensitivity was assessed by homeostatic model assessment index of insulin resistance (HOMA-IR) (3) and Whole body insulin sensitivity index (WBISI) (4), while B cell function was evaluated by insulinogenic index (IGI) (5) derived from an OGTT. RESULTS: Six of the seven patients were female(mean +/- SD): age 15.4+/-1.9 years, BMI 34 +/- 3.7, preRx VD 17.8+/- 2, postRx VD 22 +/- 5.7(> 19ng/ml); preRx PTH 58 +/- 20.8, postRx PTH 51 +/- 12.6 (15-75 pg/mL). When stratified by changes in VD postRx (group1= increase of 30% or more in VD level; group 2= <30 % change) indices derived from OGTT were: WBISI4.3 +/- 0.5 vs. 3.4 +/- 1.9, HOMA-IR: 2.7 +/- 0.4 vs. 4.1 +/- 3, IGI: 1.9+/- 0.6 vs. 1.6+/- 1. IGI to be statistically significant between groups (independent sample t test: p= 0.031). When stratified by change in PTH levels postRx (group 1= decrease in PTH level n=4 vs. group 2 increase in PTH level n=3) indices derived from OGTT were: WBSI 4.1 +/- 0.7 vs. 3 +/- 2.2 HOMA-IR: 3+/- 0.3 vs. 4.1+/- 3.7, IGI: 1.6+/- 1 vs. 1.8+/- 0.6. HOMA-IR and WBISI were found to be different between groups (p= 0.010 and p=0.07 respectively) CONCLUSIONS: VD and PTH work synergistically in bone health though they likely influence glucose metabolism through independent mechanism. a) Optimization of vitamin D may require using 2-3 fold higher doses (as suggested by the Endocrine society for adults) to achieve levels of 25(OH) D levels >30 ng/ml thereby maximizing the beneficial effects of vitamin D on glucose homeostasis. b) Preliminary results show that VD levels postRx correlate with secretory index IGI and PTH levels postRx with sensitivity indices: HOMA-IR and WBISI. The relative contributions of VD and PTH on aspects of glucose metabolism may have unique therapeutic implications for glucose dysregulation