Preneet Cheema Brar

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 A1c (HbA1c) 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 HbA1c 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.

Suspected Nonalcoholic Fatty Liver Disease Is Not Associated with Vitamin D Status in Adolescents after Adjustment for Obesity

This study investigated a potential independent association between hypovitaminosis D and suspected nonalcoholic fatty liver disease (NAFLD) in a nationally representative sample of the US adolescents. Data from 1630 subjects 12–19 years of age were examined using the National Health and Nutrition Examination Survey, 2001–2004. The vitamin D status of subjects was categorized into quartiles of serum 25-hydroxyvitamin D. Subjects with serum ALT > 30 U/L were classified as having suspected NAFLD. Data regarding age, sex, race, BMI, and poverty level were also analyzed in bivariate and multivariate analyses using SAS and SUDAAN software. Suspected NAFLD was identified in 12.1% of adolescents in the lowest quartile compared to 6.9% of adolescents in the second quartile, 8.0% in the third quartile, and 13.17% in the highest quartile of serum 25(OH)D concentrations (P = .05). In analyses utilizing vitamin D as a continuous variable, no independent association was found between Vitamin D levels and rates of elevated ALT levels. In multivariate analyses, higher risks for suspected NAFLD were observed in males and overweight adolescents; however, vitamin D status was not found to be independently associated with suspected NAFLD after adjusting for obesity.

Screening Obese Children and Adolescents for Prediabetes and/or Type 2 Diabetes in Pediatric Practices A Validation Study

Background. Increased prevalence of type 2 diabetes mellitus (T2DM) makes it important for pediatricians to use effective screening tools for risk assessment of prediabetes/T2DM in children. Methods. Children (n = 149) who had an oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) were studied. American Diabetes Association recommended screening criteria—HbA1c ≥5.7% and fasting plasma glucose (FPG) ≥100 mg/dL—were compared against OGTT. The homeostatic model assessment of insulin resistance (HOMA-IR), a mathematical index derived from fasting insulin and glucose, was compared with OGTT. We studied whether combining screening tests (HbA1c and fasting glucose or HbA1c and HOMA-IR) improved accuracy of prediction of the OGTT. Results. HbA1c of ≥5.7% had a sensitivity of 75% and specificity of 57% when compared with the OGTT. Combining screening tests (HbA1c ≥5.7% and FPG ≥100 mg/dL; HbA1c ≥5.7% and HOMA-IR ≥3.4) resulted in improved sensitivity (95.5% for each), with the HbA1c-FPG doing better than the HbA1c-HOMA-IR combination in terms of ability to rule out prediabetes (likelihood ratio [LR]) negative. 0.07 vs 0.14). Conclusions. HbA1c of ≥5.7% provided fair discrimination of glucose tolerance compared with the OGTT. The combination of HbA1c and FPG is a useful method for identifying children who require an OGTT.

Early presentation of bilateral gonadoblastomas in a Denys-Drash syndrome patient: A cautionary tale for prophylactic gonadectomy

Abstract Mutation of the Wilms tumor gene (WT1) is associated with two well-described syndromes called Denys-Drash (DDS) and Frasier (FS). Both are associated with nephropathy and ambiguous genitalia and have overlapping clinical and molecular features. The known risk of Wilms tumor in DDS and gonadoblastoma (GB) in FS patients requires tumor surveillance. The literature reports the occurrence of GB in DDS as lower than FS. This case highlights a very early presentation of bilateral GB in DDS and the consideration of early prophylactic gonadectomy at the time of diagnosis with DDS.

Insulin-like growth factor-I and insulin-like growth factor binding protein-1 are related to cardiovascular disease biomarkers in obese adolescents

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.

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 ≤ .0005) predicted Si. The OGTT-derived index WBISI correlated with the FSIGT-derived Si (r = .608, P < .0005). IGI correlated with AIRg from FSIGT (r = .704, P < .0005). Conclusions. OGTT-based measures correlated with FSIGT-derived measures of insulin sensitivity and secretion. In particular, we demonstrated that WBISI can be a reliable alternative to FSIGT-derived Si in clinical settings where OGTT is a more feasible option.

Birth weight, early life weight gain and age at menarche: a systematic review of longitudinal studies

Adiposity in pre‐ and postnatal life may influence menarcheal age. Existing evidence is primarily cross‐sectional, failing to address temporality, for which the role of adiposity in early life remains unclear. The current study sought to systematically review longitudinal studies evaluating the associations between birth weight and infant/childhood weight status/weight gain in relation to menarcheal age.

The relationship between insulin resistance and endothelial dysfunction in obese adolescents

Abstract 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 (≤or> 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.

Salivary Testosterone during the Minipuberty of Infancy

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.


Continuous Glucose Monitoring: A Valuable Monitoring Tool for Management of Hypoglycemia During Chemotherapy for Acute Lymphoblastic Leukemia

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.