Henry Anhalt

Prevalence of vitamin D insufficiency in obese children and adolescents.

OBJECTIVE Recent studies have shown a broad prevalence of vitamin D deficiency in adults. Serum 25-hydroxyvitamin D (25-OHD) levels were reported to be inversely related to body mass index (BMI) and body fat content and correlated directly with hypertension, degree of insulin resistance and progression to diabetes mellitus. We sought to determine the prevalence of vitamin D insufficiency and markers of metabolic syndrome in an obese pediatric population. METHODS Charts of 217 obese (weight >95th percentile for age and sex) children (118 females, 99 males; mean BMI 32.2 +/- 6.4 kg/m2; mean age 12.9 2 5.5; age range 7-18 years) who had received a standard physical examination at the pediatric endocrine clinic of the Infants and Childrens Hospital of Brooklyn at Maimonides, Brooklyn, NY, were retrospectively analyzed. Data obtained included age, sex, weight, BMI, height and systolic and diastolic blood pressure. The routine bloodwork panel for obesity at our pediatric endocrine facility includes fasting 25-OHD, total cholesterol, high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglycerides, ALT, AST, thyroid stimulating hormone (TSH), total T4, and insulin and glucose. Insulin sensitivity as calculated by quantitative insulin-sensitivity check index (QUICKI = 1/[log(I0) + log(G0)], where I0 is fasting insulin and G0 is fasting glucose) was computed following the visit. RESULTS Overall, 55.2% of patients were vitamin D insufficient (25-OHD <20 ng/ml). Severely low vitamin D levels (25-OHD < or =10 ng/ml) were seen in 21.6% of 217 patients, which represents almost half of the insufficient group. In the 25-OHD <20 ng/ml group age, BMI, and SBP were significantly higher than in the 25-OHD 220 ng/ml group, while QUICKI (<0.35 is consistent with insulin resistance) was borderline low in the <20 ng/ml group. HDL-C was significantly lower in the 25-OHD < or =10 ng/ml group. The 25-OHD levels correlated negatively with BMI and positively with HDL-C. No other findings were significant. CONCLUSION More than half of the obese children had vitamin D levels <20 ng/ml with equal gender distribution. Vitamin D insufficiency was associated with increased age, BMI, and SBP, and decreased HDL-C.

Turn It Off!: Diabetes Device Alarm Fatigue Considerations for the Present and the Future

Safe and widespread use of diabetes technology is constrained by alarm fatigue: When someone receives so many alarms that he or she becomes less likely to respond appropriately. Alarm fatigue and related usability issues deserve consideration at every stage of alarm system design, especially as new technologies expand the potential number and complexity of alarms. The guiding principle should be patient wellbeing, while taking into consideration the regulatory and liability issues that sometimes contribute to building excessive alarms. With examples from diabetes devices, we illustrate two complementary frameworks for alarm design: A “patient safety first” perspective and a focus on human factors. We also describe opportunities and challenges that will come with new technologies such as remote monitoring, adaptive alarms, and ever-closer integration of glucose sensing with insulin delivery.

Serum Levels of Soluble Tumor Necrosis Factor-α Receptor 2 are Linked to Insulin Resistance and Glucose Intolerance in Children

BACKGROUND Obesity and insulin resistance are increasingly common problems in children. Tumor necrosis factor-alpha (TNF-alpha) has important effects on lipid and glucose metabolism. This effect may be mediated through soluble TNF-alpha receptor 2 (sTNFR2). OBJECTIVE To investigate the relationship between insulin resistance and the TNF-alpha system in childhood obesity. CHILDREN AND METHODS Twenty-one obese and six non-obese children were studied. Body mass index (BMI) z-scores, percent body fat (PBF) and waist to hip ratio (WHR) were determined. Fasting serum levels of total cholesterol, HDL-cholesterol, LDL-cholesterol, TNF-alpha and sTNFR2 were measured. A standard 2-hour oral glucose tolerance test (dose of glucose: 1.75 g/kg, max. 75 g) was done. Insulin resistance (IR) was estimated by fasting plasma insulin, plasma insulin at 120 min, homeostasis model assessment (HOMA) and insulin area under the curve (AUC) from OGTT. Insulin sensitivity was estimated by oral glucose insulin sensitivity (OGIS120). RESULTS Among the obese participants, one child (5.2%) was found to have diabetes mellitus and four others (21.1%) impaired glucose tolerance (IGT). Obese children had significantly elevated sTNFR2 levels. Furthermore, the group of obese children with IGT and the patient with newly diagnosed diabetes mellitus together (n = 5) had significantly higher levels of serum sTNFR2 (2,865+/-320 pg/ml) than the rest of the obese (2,460+/-352 pg/ml; p = 0.016) or lean (1,969+/-362 pg/ml; p = 0.014) children. Serum sTNFR2 levels correlated positively with insulin AUC, HOMA IR, fasting plasma insulin, plasma insulin at 120 min, total cholesterol and LDL/ HDL ratio, and negatively with OGIS120. Multiple regression analysis revealed that age, WHR, sTNFR2 and LDL predicted 81% of the variability in glucose at 120 min. CONCLUSION sTNFR2 is a candidate marker of insulin resistance and glucose intolerance.

The prevalence of non-alcoholic fatty liver disease and metabolic syndrome in obese children.

Abstract Background and aim: In the context of present epidemic of childhood obesity, we aimed to fi nd the prevalence of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome (MS) in a cohort of obese children. Methodology: Retrospective chart analysis of 700 obese children was done for their anthropometric and biochemical investigations. Results: Some 15.4% (9.8% girls, 22% boys) subjects had NAFLD (ALT> 40 IU/L) after excluding other identifi able causes of liver dysfunction. Age, weight, TG, fasting serum insulin and HOMA-IR levels were higher in children with NAFLD. Twenty-eight percent children had MS. Children with NAFLD had an odds ratio of 2.65 for having MS (boys 4.6, girls 1.7). The prevalence of MS increased with age 5–9 years (21%), 10–16 years (30%), 17–20 years (35%). Conclusion: Given high prevalence of NAFLD and MS in obese children, childhood obesity should be seriously considered as a disease and not just a cosmetic issue.

Effect of metformin and rosiglitazone in a prepubertal boy with Alstrom syndrome.

UNLABELLED Alström syndrome (AS) is an autosomal recessive disorder characterized by progressive pigmentary retinopathy, sensorineural hearing loss, fatty liver infiltration, obesity, insulin resistance and early-onset type 2 diabetes mellitus (DM2). Early onset of insulin resistance and DM2 are key components of this syndrome. AIM To study the effect of early initiation of the insulin sensitizer metformin combined with rosiglitazone in a patient with AS with impaired glucose tolerance. PATIENT An 8 year-old boy with AS presented with acanthosis nigricans and insulin resistance at the age of 6 years. He had progressive excessive weight gain from 9 months of age. By the age of 1 year he developed photosensitivity, blindness and nystagmus. At the age of 5.5 years, his body mass index (BMI) was above the 95th percentile. He developed impaired glucose tolerance at 6 years of age and treatment with metformin was initiated. After 8 months of treatment with metformin he developed DM2. The dose of metformin was increased, and rosiglitazone added. METHODS A 2-hour oral glucose tolerance test (OGTT) and a rapid intravenous glucose tolerance test (IVGTT) were performed before treatment was initiated, after treatment with metformin and at the end of 1 year of combination therapy with metformin and rosiglitazone to calculate quantitative insulin sensitivity check index (QUICKI) and acute insulin response (AIR). For mutation analysis, all exons and splice site sequences of the ALMS1 gene were amplified and sequenced. RESULTS Metformin treatment alone at the stage of impaired glucose tolerance did not prevent progression to DM2. However, metformin at a higher dose and in combination with rosiglitazone resulted in improvement of pancreatic beta-cell function, shown by markedly improved first-phase insulin response to glucose measured by AIR. The patient was found to have two heterozygous nonsense mutations in ALMS1, 8008 C-->T Ter, R2670X, and 11449 C-->T Ter, Q3817X. These alterations cause premature stops and result in a truncated ALMS1 protein. CONCLUSION We suggest that early initiation of combined therapy comprising a high dose of metformin plus rosiglitazone may be valuable in managing insulin resistance and DM2 in children with AS.

Closed-Loop Control Performance of the Hypoglycemia-Hyperglycemia Minimizer (HHM) System in a Feasibility Study

Background: This feasibility study investigated the insulin-delivery characteristics of the Hypoglycemia-Hyperglycemia Minimizer (HHM) System—an automated insulin delivery device—in participants with type 1 diabetes. Methods: Thirteen adults with type 1 diabetes were enrolled in this nonrandomized, uncontrolled, clinical-research-center-based feasibility study. The HHM System comprised a continuous subcutaneous insulin infusion pump, a continuous glucose monitor (CGM), and a model predictive control algorithm with a safety module, run on a laptop platform. Closed-loop control lasted approximately 20 hours, including an overnight period and two meals. Results: When attempting to minimize glucose excursions outside of a prespecified target zone, the predictive HHM System decreased insulin infusion rates below the participants’ preset basal rates in advance of below-zone excursions (CGM < 90 mg/dl), and delivered 80.4% less insulin than basal during those excursions. Similarly, the HHM System increased infusion rates above basal during above-zone excursions (CGM > 140 mg/dl), delivering 39.9% more insulin than basal during those excursions. Based on YSI, participants spent a mean ± standard deviation (SD) of 0.2 ± 0.5% of the closed-loop control time at glucose levels < 70 mg/dl, including 0.3 ± 0.9% for the overnight period. The mean ± SD glucose based on YSI for all participants was 164.5 ± 23.5 mg/dl. There were nine instances of algorithm-recommended supplemental carbohydrate administrations, and there was no severe hypoglycemia or diabetic ketoacidosis. Conclusions: Results of this study indicate that the current HHM System is a feasible foundation for development of a closed-loop insulin delivery device.

Unusual Phenotypical Variations in a Boy with McCune-Albright Syndrome

Background: McCune-Albright syndrome (MAS) typically comprises the constellation of polyostotic fibrous dysplasia, café-au-lait spots, and associated endocrinopathies including gonadotropin-independent precocious puberty, excessive growth hormone production and gigantism, hyperthyroidism, and hyperparathyroidism. Objective: We report the unique case of a boy with the diagnostic criteria of MAS accompanied by atypical short stature and macroorchidism without precocious puberty. Patient: An 8.4-year-old prepubertal boy presented with a history of recurrent bone fractures, multiple café-au-lait spots, bilateral macroorchidism, and short stature. X-ray of the extremities was consistent with polyostotic fibrous dysplasia. Serum inhibin B (IB) and anti-müllerian hormone (AMH) were elevated; testosterone, LH, and FSH were normal for age. Results: PCR-based DNA analysis of bone tissue revealed a substitution of arginine for cysteine at position 201 in the Gsα protein resulting in activation of the Gsα subunit. Conclusions: We report a second case of MAS associated with macroorchidism. In this case, isolated Sertoli cell hyperfunction was also associated with microlithiasis and was not associated with peripheral precocious puberty. Short stature not associated with GH-IGF-1 axis abnormality was a second anomalous finding in this case. Our experience suggests that the phenotypic variation in MAS is wider than previously described.

Limitations of Continuous Glucose Monitor Usage

Much progress has been made in diabetes treatments since the first dose of insulin was administered in 1921. However, a truly transformational moment in diabetes care occurred when urine testing gave way to capillary blood home glucose monitoring. As improvements were made to these devices, continuous glucose monitoring (CGM) was introduced. The advantages of experiential learnings gleaned from seeing continuous real-time data have been borne out in numerous peer-reviewed journals. Limitations to use of CGM include patients level of numeracy and literacy, development of alarm fatigue, interfering substances leading to erroneous readings, high rates of discontinuation, and poor reimbursement.

Effect of Algorithm Aggressiveness on the Performance of the Hypoglycemia-Hyperglycemia Minimizer (HHM) System

Background: The Hypoglycemia-Hyperglycemia Minimizer (HHM) System aims to mitigate glucose excursions by preemptively modulating insulin delivery based on continuous glucose monitor (CGM) measurements. The “aggressiveness factor” is a key parameter in the HHM System algorithm, affecting how readily the system adjusts insulin infusion in response to changing CGM levels. Methods: Twenty adults with type 1 diabetes were studied in closed-loop in a clinical research center for approximately 26 hours. This analysis focused on the effect of the aggressiveness factor on the insulin dosing characteristics of the algorithm and, to a lesser extent, on the glucose control results observed. Results: As the aggressiveness factor increased from conservative to medium to aggressive: the maximum observed insulin dose delivered by the algorithm—which is designed to give doses that are corrective in nature every 5 minutes—increased (1.00 vs 1.15 vs 2.20 U, respectively); tendency to adhere to the subject’s nominal basal dose decreased (61.9% vs 56.6% vs 53.4%); and readiness to decrease insulin below basal also increased (18.4% vs 19.4% vs 25.2%). Glucose analyses by both CGM and Yellow Springs Instruments (YSI) indicated that the aggressive setting of the algorithm resulted in the least time spent at levels >180 mg/dL, and the most time spent between 70-180 mg/dL. There was no severe hyperglycemia, diabetic ketoacidosis, or severe hypoglycemia for any of the aggressiveness values investigated. Conclusions: These analyses underscore the importance of investigating the sensitivity of the HHM System to its key parameters, such as the aggressiveness factor, to guide future development decisions.

Basal Insulin Requirements on Continuous Subcutaneous Insulin Infusion during the First 12 Months after Diagnosis of Type 1 Diabetes Mellitus

Introduction: While the endogenous first-phase insulin response has disappeared by the time of diagnosis of type 1 diabetes mellitus (T1DM), anecdotal evidence suggests that these patients can continue to have a second-phase insulin response during the first 12 months after diagnosis. We hypothesized that patients who are started on continuous subcutaneous insulin infusion (CSII) at the time of diagnosis of T1DM would have a lower basal insulin requirement than the 40–60% usually expected. Methods: We analyzed 38 patients with T1DM, age 9.9 ± 6.4 years, 71% male, who were started on CSII within the first month of diagnosis. Results: Average basal insulin requirements were 47–49% of total daily dose during the first 12 months after diagnosis and decreased from 0.30 U/kg/day at diagnosis to 0.20 U/kg/day by 12 months. Baseline percentage of basal insulin was significantly correlated with hemoglobin A1c at baseline and at six months. The percentage of basal insulin requirement at 12 months after diagnosis was significantly correlated with baseline body mass index (BMI) and current BMI. No other correlations between percentage of basal insulin requirements and any other factors were seen. Conclusion: Our data suggest that, even though some endogenous insulin production remains during the first year after diagnosis of T1DM, the distribution of basal versus total daily insulin requirements remains the same as in the general population of people with diabetes. There may be benefits to starting patients on a higher basal rate at time of diagnosis for overall glycemic control during the first six months. Further research is needed to optimize starting insulin doses to maximize their potential in preserving beta-cell function.