Adrenal insufficiency is an important source of potentially life-threatening human disease. Defects at each level of the hypothalamic–pituitary–adrenal axis can yield impaired adrenal function that results in variable degrees of glucocorticoid or mineralocorticoid deficiency. In this chapter, we describe the physiology and regulation of adrenal steroid action, followed by presentation of mechanisms of primary, secondary, and tertiary adrenal insufficiency. The components of establishing a diagnosis of adrenal insufficiency along with its causation are summarized. Current pharmacological and psychosocial therapeutic interventions for disorders of impaired adrenal function conclude the overview.

Studies have demonstrated that same-day discharge (SDD) following thyroid resection is safe and feasible in adults but there are no similar studies in the pediatric age group. The purpose of this study is to evaluate the influence of SDD on 30-day readmission rates following thyroid surgery in pediatric patients. This retrospective cohort study used the American College of Surgeons National Surgical Quality Improvement Program–Pediatric database to evaluate 30-day readmission rates among patients < 19 years of age who underwent thyroid resection between 2012 and 2017. Patients excluded were those discharged more than 2 days after surgery. The main exposure variable was SDD and the primary outcome was 30-day readmission. Secondary outcomes included wound complications, unplanned reoperation and death. Patient characteristics were compared using chi-squared testing and odds ratios for readmission were calculated using multivariate logistic regression. Of the 1125 patients (79% female, median age 15 years), 122 (11%) were discharged on the day of surgery. Total or near-total thyroidectomy represented the majority of operations (714, 63.5%) and patients undergoing these operations were less likely to be discharged on the same day as surgery compared to those undergoing thyroid lobectomy (4.3 vs. 22.1%, P < 0.001). Twenty-nine patients were readmitted within 30 days (3 in the same day group, 26 in the later group). There was no difference in the odds of readmission between the two groups (adjusted odds ratio in SDD compared to later discharge 1.04 [95% CI 0.29–3.75, P = 0.96; readmission rate, 2.46 vs. 2.59%). Wound complications were reported in two patients, both in the later discharge group. Same-day discharge in pediatric patients undergoing thyroidectomy is not associated with an increase in 30-day readmissions or wound complications when compared to patients discharged 1 or 2 days after surgery. In selected patients, SDD may be an appropriate alternative to traditional overnight stay.

Links between autism spectrum disorder (ASD) and autoimmune diseases, including Type 1 diabetes have been proposed. This study assessed the frequency of ASD in children with Type 1 diabetes in the T1D Exchange (T1DX) registry and the impact of ASD on characteristics of children with Type 1 diabetes.

Most individuals with type 1 diabetes (T1D) do not achieve glycemic targets, particularly in youth. This analysis examined HbA1c trajectories of youth newly diagnosed with T1D. T1D Exchange registry participants <18 years with at least one HbA1c during the year of diagnosis and ≥3 duration-year aggregated HbA1c values over 10 years of follow-up were included. At diagnosis, the 4183 participants were 48% female, 81% Caucasian, age 6±4 years, and 77% privately insured. Suboptimal control was defined as HbA1c ≥9%. Group-based trajectory modelling was used to identify unique HbA1c trajectories over aggregated duration years. Five trajectories emerged (Figure). The majority of youth had stable trajectories within three distinct categories: those at (1) or above (3) glycemic target and those with suboptimal control (4). Two groups showed deterioration over time, one with suboptimal control from diagnosis (5) while the other had above target glycemia that worsened with time (2). Minority status was higher in groups with upward trend in HbA1c trajectory and suboptimal but stable control. Similar trends were seen for non-private insurance. Several distinct patterns of HbA1c progression exist in youth with T1D, partly dependent on HbA1c at diagnosis. Identifying characteristics of those with progressive deterioration in glycemic control and designing appropriate interventions for these groups is warranted. Disclosure J. Sherr: Advisory Panel; Self; Bigfoot Biomedical, Eli Lilly and Company, Insulet Corporation. Consultant; Self; Lexicon Pharmaceuticals, Inc., Medtronic, Sanofi. Research Support; Self; Dexcom, Inc., Insulet Corporation. N.C. Foster: None. K. Bethin: Research Support; Self; Novo Nordisk Inc., Xeris Pharmaceuticals, Inc. L.A. Fox: None. L.D. Mastrandrea: Advisory Panel; Self; Pediatric Diabetes Consortium. Research Support; Self; AstraZeneca, JDRF, Novo Nordisk Inc., Sanofi-Aventis, T1D Exchange. Other Relationship; Self; Novo Nordisk Inc. B.M. Nathan: None. M.J. Redondo: None. J. Silverstein: None. J. Simmons: None. M.A. Clements: Advisory Panel; Self; Glooko, Inc. Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Medtronic. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. K.M. Thrailkill: None. J.C. Wong: Advisory Panel; Self; Tidepool Project. Research Support; Self; Dexcom, Inc. J. Wood: Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc.

Background:Debate exists as to whether the higher hemoglobin A1c (HbA1c) levels observed in black persons than in white persons are due to worse glycemic control or racial differences in the glycation of hemoglobin. Objective:To determine whether a racial difference exists in the relationship of mean glucose and HbA1c. Design:Prospective, 12-week observational study. Setting:10 diabetes centers in the United States. Participants:104 black persons and 104 white persons aged 8 years or older who had had type 1 diabetes for at least 2 years and had an HbA1c level of 6.0% to 12.0%. Measurements:Mean glucose concentration, measured by using continuous glucose monitoring and compared by race with HbA1c, glycated albumin, and fructosamine values. Results:The mean HbA1c level was 9.1% in black persons and 8.3% in white persons. For a given HbA1c level, the mean glucose concentration was significantly lower in black persons than in white persons (P = 0.013), which was reflected in mean HbA1c values in black persons being 0.4 percentage points (95% CI, 0.2 to 0.6 percentage points) higher than those in white persons for a given mean glucose concentration. In contrast, no significant racial differences were found in the relationship of glycated albumin and fructosamine levels with the mean glucose concentration (P > 0.20 for both comparisons). Limitation:There were too few participants with HbA1c levels less than 6.5% to generalize the results to such individuals. Conclusion:On average, HbA1c levels overestimate the mean glucose concentration in black persons compared with white persons, possibly owing to racial differences in the glycation of hemoglobin. However, because race only partially explains the observed HbA1c differences between black persons and white persons, future research should focus on identifying and modifying barriers impeding improved glycemic control in black persons with diabetes. Primary Funding Source:Helmsley Charitable Trust.

The Best Pharmaceuticals for Children Act of 2002 mandated that the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) carries out critical reviews of the gaps in knowledge and unmet needs regarding safe and effective pharmacologic treatment of infants, children, and adolescents in a broad range of disease areas. In 2012, NICHD selected diabetes mellitus as one of the pediatric disorders for review. Dr. William V. Tamborlane was named chair, and Dr. Linda DiMeglio, vice-chair, of the Diabetes Working Group. Together with Dr. George Giacoia of NICHD, they assembled a distinguished group of medical experts in childhood diabetes, including clinicians/clinical investigators from leading academic centers and from industry and representatives from the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), to carry out this review. It is very important to note that the views expressed in this article, as well as in other reports from the Diabetes Working Group, are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the FDA or EMA or any of the organizations or pharmaceutical companies represented in our working group. As shown in Supplementary Table 1, the large Diabetes Working Group was divided into five committees: Type 1 Diabetes (T1D): Therapeutics, Type 2 Diabetes (T2D): Therapeutics, T1D: Natural History and Biomarkers, T2D: Natural History and Biomarkers, and Diabetes Pharmacology. The consensus of the T2D Therapeutics Committee was that its efforts should address the crisis in care that clinicians face in treating this disorder in adolescents. Despite a plethora of new drug classes and new agents within each class that have been approved for use in adults with T2D, in …

The prevalence of cardiovascular risk factors in children with type 1 diabetes and elevated BMI in the USA is poorly defined. We aimed to test the hypothesis that children with type 1 diabetes who are overweight or obese have increased frequencies of hypertension, dyslipidemia, and micro-/macroalbuminuria compared to their healthy weight peers.

OBJECTIVE Treatment of severe hypoglycemia with loss of consciousness or seizure outside of the hospital setting is presently limited to intramuscular glucagon requiring reconstitution immediately prior to injection, a process prone to error or omission. A needle-free intranasal glucagon preparation was compared with intramuscular glucagon for treatment of insulin-induced hypoglycemia. RESEARCH DESIGN AND METHODS At eight clinical centers, a randomized crossover noninferiority trial was conducted involving 75 adults with type 1 diabetes (mean age, 33 ± 12 years; median diabetes duration, 18 years) to compare intranasal (3 mg) versus intramuscular (1 mg) glucagon for treatment of hypoglycemia induced by intravenous insulin. Success was defined as an increase in plasma glucose to ≥70 mg/dL or ≥20 mg/dL from the glucose nadir within 30 min after receiving glucagon. RESULTS Mean plasma glucose at time of glucagon administration was 48 ± 8 and 49 ± 8 mg/dL at the intranasal and intramuscular visits, respectively. Success criteria were met at all but one intranasal visit and at all intramuscular visits (98.7% vs. 100%; difference 1.3%, upper end of 1-sided 97.5% CI 4.0%). Mean time to success was 16 min for intranasal and 13 min for intramuscular (P < 0.001). Head/facial discomfort was reported during 25% of intranasal and 9% of intramuscular dosing visits; nausea (with or without vomiting) occurred with 35% and 38% of visits, respectively. CONCLUSIONS Intranasal glucagon was highly effective in treating insulin-induced hypoglycemia in adults with type 1 diabetes. Although the trial was conducted in a controlled setting, the results are applicable to real-world management of severe hypoglycemia, which occurs owing to excessive therapeutic insulin relative to the impaired or absent endogenous glucagon response.

BACKGROUND:The rapid emergence of type 2 diabetes (T2D) in the pediatric population has left pediatric endocrinologists with limited artillery in terms of management. While multiple medications are available for adults, Food and Drug Administration (FDA)-approved medications in children are limited to only metformin and insulin. Additional treatment options require randomized controlled trials, yet heretofore several barriers at the participant and institutional level have impeded these studies from proceeding in children and adolescents. Identification of the most challenging obstacles that pediatric endocrinologists experience in participating in industry-sponsored T2D trials may facilitate development of feasible platforms for future studies.MATERIALS AND METHODS:We conducted an anonymous online survey consisting of 31 questions that assessed potential barriers to industry-sponsored clinical trials in pediatric patients with T2D. The survey was sent to members of the Pediatric Endocrine Society (PES), and members conducted the survey between October and November of 2014. As part of the survey, respondents rated the significance of several possible barriers to participation in industry-sponsored T2D studies.RESULTS:We received a total of 207 responses from members of PES. Baseline demographics showed that 50% of represented institutions care for 50 or fewer T2D patients age 18 years and younger; 70% of institutions diagnose 20 or fewer new T2D cases per year; and 3 racial groups predominated: African American, Hispanic, and Caucasian. A total of 70% of responders have a research infrastructure to participate in clinical trials, but only half have dedicated research nurses. Protocol restrictions on participant recruitment due to current glycemic control or medication use as well as frequent visit schedules were reported to be major obstacles. In addition, the financial support provided to centers to carry out the studies is insufficient.CONCLUSIONS:Efforts must be made to ease the burden of research participation on both pediatric T2D patients as well as pediatric endocrinologists.

Rickels et al. (1) report the results of a randomized crossover noninferiority study, making the firm assertion that intranasal glucagon was highly effective in treating insulin-induced hypoglycemia in type 1 diabetes. Unfortunately, the methods described in their article fail to support such a strong claim. We have several concerns about their ambitious conclusion. First, because of the controlled and artificial environment, this was not an effectiveness but an efficacy trial. Testing effectiveness requires carrying out the comparison in a “real-world setting” of severe hypoglycemia. Second, the design of the study does not seem appropriate considering that the intention was to prove intranasal glucagon was clinically equivalent to …

OBJECTIVE Treatment of severe hypoglycemia outside of the hospital setting is limited to intramuscular glucagon requiring reconstitution prior to injection. The current study examined the safety and dose-response relationships of a needle-free intranasal glucagon preparation in youth aged 4 to <17 years. RESEARCH DESIGN AND METHODS A total of 48 youth with type 1 diabetes completed the study at seven clinical centers. Participants in the two youngest cohorts (4 to <8 and 8 to <12 years old) were randomly assigned to receive either 2 or 3 mg intranasal glucagon in two separate sessions or to receive a single, weight-based dose of intramuscular glucagon. Participants aged 12 to <17 years received 1 mg intramuscular glucagon in one session and 3 mg intranasal glucagon in the other session. Glucagon was given after glucose was lowered to <80 mg/dL (mean nadir ranged between 67 and 75 mg/dL). RESULTS All 24 intramuscular and 58 of the 59 intranasal doses produced a ≥25 mg/dL rise in glucose from nadir within 20 min of dosing. Times to peak plasma glucose and glucagon levels were similar under both intramuscular and intranasal conditions. Transient nausea occurred in 67% of intramuscular sessions versus 42% of intranasal sessions (P = 0.05); the efficacy and safety of the 2- and 3-mg intranasal doses were similar in the youngest cohorts. CONCLUSIONS Results of this phase 1, pharmacokinetic, and pharmacodynamic study support the potential efficacy of a needle-free glucagon nasal powder delivery system for treatment of hypoglycemia in youth with type 1 diabetes. Given the similar frequency and transient nature of adverse effects of the 2- and 3-mg intranasal doses in the two youngest cohorts, a single 3-mg intranasal dose appears to be appropriate for use across the entire 4- to <17-year age range.

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OBJECTIVE:It is generally accepted that complete β-cell destruction eventually occurs in individuals with type 1 diabetes, which has implications for treatment approaches and insurance coverage. The frequency of residual insulin secretion in a large cohort of individuals at varying ages of diagnosis and type 1 diabetes duration is unknown.RESEARCH DESIGN AND METHODS:The frequency of residual insulin secretion was determined by measurement of nonfasting serum C-peptide concentration in 919 individuals with type 1 diabetes according to prespecified groups based on age at diagnosis and duration of disease (from 3 to 81 years' duration). Stimulated C-peptide was measured in those with detectable nonfasting values and a group of those with undetectable values as control.RESULTS:The overall frequency of detectable nonfasting C-peptide was 29%, decreasing with time from diagnosis regardless of age at diagnosis. In all duration groups, the frequency of C-peptide was higher with diagnosis age >18 years compared with ≤18 years. Nineteen percent of those with undetectable nonfasting C-peptide were C-peptide positive upon stimulation testing.CONCLUSIONS:The American Diabetes Association's definition of type 1 diabetes as "usually leading to absolute insulin deficiency" results in clinicians often considering the presence of residual insulin secretion as unexpected in this population. However, our data suggest that residual secretion is present in almost one out of three individuals 3 or more years from type 1 diabetes diagnosis. The frequency of residual C-peptide decreases with time from diagnosis regardless of age at diagnosis, yet at all durations of disease, diagnosis during adulthood is associated with greater frequency and higher values of C-peptide.

IMPORTANCE Previous studies assessing the effect of metformin on glycemic control in adolescents with type 1 diabetes have produced inconclusive results.OBJECTIVE To assess the efficacy and safety of metformin as an adjunct to insulin in treating overweight adolescents with type 1 diabetes.DESIGN, SETTING, AND PARTICIPANTS Multicenter (26 pediatric endocrinology clinics), double-blind, placebo-controlled randomized clinical trial involving 140 adolescents aged 12.1 to 19.6 years (mean [SD] 15.3 [1.7] years) with mean type 1 diabetes duration 7.0 (3.3) years, mean body mass index (BMI) 94th (4) percentile, mean total daily insulin 1.1 (0.2) U/kg, and mean HbA(1c) 8.8% (0.7%).INTERVENTIONS Randomization to receive metformin (n = 71) (<= 2000mg/d) or placebo (n = 69).MAIN OUTCOMES AND MEASURES Primary outcome was change in HbA(1c) from baseline to 26 weeks adjusted for baseline HbA(1c). Secondary outcomes included change in blinded continuous glucose monitor indices, total daily insulin, BMI, waist circumference, body composition, blood pressure, and lipids.RESULTS Between October 2013 and February 2014, 140 participants were enrolled. Baseline HbA(1c) was 8.8% in each group. At 13-week follow-up, reduction in HbA(1c) was greater with metformin (-0.2%) than placebo (0.1%; mean difference, -0.3%[95% CI, -0.6% to 0.0%]; P = .02). However, this differential effect was not sustained at 26-week follow up when mean change in HbA(1c) from baseline was 0.2% in each group (mean difference, 0%[95% CI, -0.3% to 0.3%]; P = .92). At 26-week follow-up, total daily insulin per kg of body weight was reduced by at least 25% from baseline among 23%(16) of participants in the metformin group vs 1% (1) of participants in the placebo group (mean difference, 21% [95% CI, 11% to 32%]; P = .003), and 24%(17) of participants in the metformin group and 7%(5) of participants in the placebo group had a reduction in BMI z score of 10% or greater from baseline to 26 weeks (mean difference, 17%[95% CI, 5% to 29%]; P = .01). Gastrointestinal adverse events were reported by more participants in the metformin group than in the placebo group (mean difference, 36%[95% CI, 19% to 51%]; P < .001).CONCLUSIONS AND RELEVANCE Among overweight adolescents with type 1 diabetes, the addition of metformin to insulin did not improve glycemic control after 6 months. Of multiple secondary end points, findings favored metformin only for insulin dose and measures of adiposity; conversely, use of metformin resulted in an increased risk for gastrointestinal adverse events. These results do not support prescribing metformin to overweight adolescents with type 1 diabetes to improve glycemic control.

Objective:The aims of this study were to determine metabolic characteristics of normal weight and overweight 2-5 year old children and to collect data pertinent to energy intake. Design and methods:Study participants (2-5years) (n=103) were recruited when they arrived for full mouth rehabilitation under general anesthesia.Height and weight were measured.After induction of anesthesia, waist circumference was measured and fasting bloods drawn (lipids, glucose, insulin and CRP).BMI, WCHtR and HOMA-IR were calculated.Metabolic and anthropometric characteristics were compared between normal and overweight children.Statistical comparisons were performed using two-sided t-tests or chi-square test.Block food frequency questionnaires were completed by the caretakers.Results: 34.4% (n =33) of participants were overweight.WCHtR was 0.05 units higher and both LDL and total cholesterol were high in the overweight group.WCHtR positively correlated with BMI z-score, WC, insulin, glucose, and CRP (r=0.75, 0.67, 0.31, 0.29, 0.25, 0.32, 0.33, respectively) and negatively correlated with HDL (r=-0.30).Conclusions: Among 2-5 year old with poor dental health, the prevalence of BMI ≥ 85 th percentile is very high and abnormalities in cardiovascular risk factors are already present.To our knowledge, this is the first study demonstrating an association between waist circumference to height ratio and CRP and insulin resistance in children less than 5 years.Overweight preschoolers should be screened for associated cardiovascular markers such as abnormal lipid profile.

Background: The quantification of obesity has been limited by the unreliability of the Body Mass Index (BMI= Kg/M2) and the expense and X-ray exposures CT and DEXA scans. White light scanning, a technology that constructs a three dimensional avatar of the human body, permits, for the first time, the calculation of body surface area, volume and shape to relate these measures to the manifestations of the metabolic syndrome. The scans are safe and can be carried out with a patient, dressed in underclothes, in less than a minute. Methodology: Patients were scanned before and after bariatric surgery 1) to determine the accuracy of the methodology vs. body measurements by RN’s, 2) to follow weight loss and body shape, 3) to assess the three dimensional shape of the lost fat, 4) to determine whether the surgery changed the shape of patients from ‘‘apple’’to ‘‘pear’’and 5) to identify whether the shapes of the …

Youth with type 1 diabetes (T1DM) gain weight after insulin therapy initiation. We aimed to study the effects of Enhanced Dietary Counseling (EDC) compared to Standard of Care Dietary Counseling (SDC) on BMI trajectory in youth with new-onset T1DM. Youth with new-onset T1DM ( n = 47; 8.9 + 4.2 years) were randomized 6 weeks post-diagnosis to either SDC per American Diabetes Association guidelines ( n = 25) or EDC ( n = 22: SDC plus monthly nutritional education and 3-day food records (FRs) at 6 and 24 weeks). Weights and heights were measured at diagnosis, 6 weeks, 3, 6, and 12 months post-diagnosis; pre-diagnosis BMI was obtained from pediatricians’ records. BMI Z score was used to track BMI change. Knowledge of recommended daily energy intake (DEI) and daily carbohydrate intake was assessed at follow-up visits. Changes in BMI Z scores were similar in SDC versus EDC subjects from pre-diagnosis to 12 months post-diagnosis. BMI Z score at 12 months exceeded pre-diagnosis level in 58.5 % subjects (54.5 % EDC vs. 63.1 % SDC, p = 0.75). From 6 weeks to 6 months, percentage of subjects correctly recalling recommended DEI increased in EDC along with percentage of subjects meeting recommended daily fruit servings intake from 25 % (6 weeks) to 64 % (6 months), p = 0.047). EDC did not prevent BMI Z score increases in youth with new-onset T1DM, and BMI Z score exceeded pre-diagnosis levels in >50 % 12 months post-diagnosis. A family-based approach and/or additional intervention may be needed to prevent excessive weight gain.