Idiopathic pathological ketotic hypoglycemia: finding the needle in a haystack.

Sick children often have a decreased appetite and experience vomiting and diarrhea; however, hypoglycemia (plasma glucose concentration ≤50 mg/dL or 2.8 mmol/L) is rare. Ketotic hypoglycemia (KH) is the most common cause of hypoglycemia presenting to an Emergency Department in a previously healthy child between 6 months and 6 years of age. Ketosis and hypoglycemia are now well understood to be normal physiologic responses of young children to prolonged fasting. There is now substantial evidence that the term KH describes a variety of conditions including both the lower end of the normal distribution of fasting tolerance in young children as well as numerous rare disorders that impair fasting adaptation. Recent advances in molecular genetic testing have led to the discovery of these rare disorders. Idiopathic pathological KH is a diagnosis of exclusion that describes rare children who have abnormally limited fasting tolerance, experience recurrent episodes of KH, or develop symptoms of hypoglycemia despite elevated ketone levels, and in whom an explanation cannot be found despite extensive investigation. This review provides an approach to distinguishing between physiological KH and pathological KH and includes recommendations for management.

Ten-Year Experience of a Global and Freely Accessible e-Learning Website for Pediatric Endocrinology and Diabetes.

The European Society for Paediatric Endocrinology (ESPE) interactive website, https://www.espe-elearning.org, was first published online in 2012. We describe the various applications of the content of the e-learning website that has been greatly expanded over the last 10 years. A large module on pediatric diabetes was added with the support of the International Society for Paediatric and Adolescent Diabetes (ISPAD). A separate multilingual module was created that focuses on frontline health care providers in limited resource settings. This module has been well received, particularly in targeted parts of the world. e-Learning may also be an opportunity to expand or tailor educational activities for learners according to their differing learning needs. The e-learning website provides guidelines for those interested in general pediatrics, neonatology, clinical genetics, and pediatric gynecology. We also describe various new applications such as master classes in the format of interactive video lectures and joint and complementary e-learning/e-consultation webinars. Finally, international certification was recently realized as e-learning courses were recognized by the European Accreditation Council for Continuing Medical Education (EACCME). As a result of the social distancing measures introduced to control the COVID-19 pandemic, digital education, whether individual or in a virtual classroom setting, has become even more important since e-learning can connect and engage individuals across geographic boundaries as well as those who live in remote areas. The future of education delivery may include hybrid learning strategies, which include in-person and e-learning platforms. Combined e-learning and e-consultation webinars illustrate how international academic institutions, learned medical specialty societies and networks are uniquely placed to deliver balanced, disease-oriented, and patient-centered e-learning education and at the same time provide expert consultation. Moreover, they are well equipped to maintain professional standards and to offer appropriate accreditation.

Management of Individuals With Diabetes at High Risk for Hypoglycemia: An Endocrine Society Clinical Practice Guideline.

CONTEXT: Hypoglycemia in people with diabetes is common, especially in those taking medications such as insulin and sulfonylureas (SU) that place them at higher risk. Hypoglycemia is associated with distress in those with diabetes and their families, medication nonadherence, and disruption of life and work, and it leads to costly emergency department visits and hospitalizations, morbidity, and mortality. OBJECTIVE: To review and update the diabetes-specific parts of the 2009 Evaluation and Management of Adult Hypoglycemic Disorders: Endocrine Society Clinical Practice Guideline and to address developing issues surrounding hypoglycemia in both adults and children living with diabetes. The overriding objectives are to reduce and prevent hypoglycemia. METHODS: A multidisciplinary panel of clinician experts, together with a patient representative, and methodologists with expertise in evidence synthesis and guideline development, identified and prioritized 10 clinical questions related to hypoglycemia in people living with diabetes. Systematic reviews were conducted to address all the questions. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make recommendations. RESULTS: The panel agreed on 10 questions specific to hypoglycemia risk and prevention in people with diabetes for which 10 recommendations were made. The guideline includes conditional recommendations for use of real-time continuous glucose monitoring (CGM) and algorithm-driven insulin pumps in people with type 1 diabetes (T1D), use of CGM for outpatients with type 2 diabetes at high risk for hypoglycemia, use of long-acting and rapid-acting insulin analogs, and initiation of and continuation of CGM for select inpatient populations at high risk for hypoglycemia. Strong recommendations were made for structured diabetes education programs for those at high risk for hypoglycemia, use of glucagon preparations that do not require reconstitution vs those that do for managing severe outpatient hypoglycemia for adults and children, use of real-time CGM for individuals with T1D receiving multiple daily injections, and the use of inpatient glycemic management programs leveraging electronic health record data to reduce the risk of hypoglycemia. CONCLUSION: The recommendations are based on the consideration of critical outcomes as well as implementation factors such as feasibility and values and preferences of people with diabetes. These recommendations can be used to inform clinical practice and health care system improvement for this important complication for people living with diabetes.

Monitoring of paediatric type 1 diabetes.

PURPOSE OF REVIEW: This article reviews recent developments in methods used to monitor paediatric type 1 diabetes (T1D), including an examination of the role of glycated haemoglobin (haemoglobin A1c) and its limitations for long-term assessment of glycaemia in individual patients, self-monitoring of blood glucose, continuous glucose monitoring (CGM) systems and ketone monitoring. RECENT FINDINGS: Monitoring of glycemia and ketones, when indicated, is a cornerstone of paediatric T1D management and is essential to optimize glycaemic control. Ongoing technological advancements have led to rapid changes and considerable improvement in the methods used to monitor glucose concentrations in people with T1D. As a result of recent innovations that have enhanced accuracy and usability, CGM is now considered the optimal method for monitoring glucose concentrations and should be introduced soon after diagnosis of T1D. SUMMARY: Patients/families and healthcare providers must receive comprehensive education and proper training in the use of CGM and interpretation of the vast amounts of data. Future challenges include ensuring equal access to and optimizing clinical use of CGM to further improve T1D care and outcomes.

Carbohydrate restriction for diabetes: rediscovering centuries-old wisdom.

Carbohydrate restriction, used since the 1700s to prolong survival in people with diabetes, fell out of favor after the discovery of insulin. Despite costly pharmacological and technological developments in the last few decades, current therapies do not achieve optimal outcomes, and most people with diabetes remain at high risk for micro- and macrovascular complications. Recently, low-carbohydrate diets have regained popularity, with preliminary evidence of benefit for body weight, postprandial hyperglycemia, hyperinsulinemia, and other cardiometabolic risk factors in type 2 diabetes and, with more limited data, in type 1 diabetes. High-quality, long-term trials are needed to assess safety concerns and determine whether this old dietary approach might help people with diabetes attain clinical targets more effectively, and at a lower cost, than conventional treatment.

Plasma ß-Hydroxybutyrate for the Diagnosis of Diabetic Ketoacidosis in the Emergency Department.

OBJECTIVE: Diabetic ketoacidosis (DKA) is a common emergency department presentation of both new-onset and established diabetes mellitus (DM). ß-Hydroxybutyrate (BOHB) provides a direct measure of the pathophysiologic derangement in DKA as compared with the nonspecific measurements of blood pH and bicarbonate. Our objective was to characterize the relationship between BOHB and DKA. METHODS: This is a cross-sectional retrospective study of pediatric patients with DM presenting to an urban pediatric emergency department between January 1, 2016, and September 30, 2018. Analyses were performed on each patient's initial, simultaneous BOHB and pH. Diagnostic test characteristics of BOHB were calculated, and logistic regression was performed to investigate the effects of age and other key clinical factors. RESULTS: Among 594 patients with DM, with median age of 12.3 years (interquartile range, 8.7-15.9 years), 176 (29.6%) presented with DKA. The inclusion of age, transfer status, and new-onset in the statistical model did not improve the prediction of DKA beyond BOHB alone. ß-Hydroxybutyrate demonstrated strong discrimination for DKA, with an area under the curve of 0.95 (95% confidence interval, 0.93-0.97). A BOHB value of 5.3 mmol/L predicted DKA with optimal accuracy (90.6% of patients were correctly classified). The sensitivity, specificity, and positive and negative predictive values of this cut point were 76.7% (95% confidence interval, 69.8%-82.7%), 96.4% (94.2%-98.0%), 90.0% (84.0%-94.3%), and 90.8% (87.7%-93.3%), respectively. CONCLUSIONS: ß-Hydroxybutyrate accurately predicts DKA in children and adolescents. More importantly, because plasma BOHB is the ideal biochemical marker of DKA, BOHB may provide a more optimal definition of DKA for management decisions and treatment targets.

Efficacy of GLP-1 Agonist Therapy in Autosomal Dominant WFS1-Related Disorder: A Case Report.

BACKGROUND: Wolfram syndrome is a rare neurodegenerative disorder, characterized by the presence of diabetes insipidus, diabetes mellitus, optic atrophy, and sensorineural deafness. The majority of cases are due to autosomal recessive biallelic variants in the WFS1 gene; however, pathogenic autosomal dominant (AD) mutations have also been described. Glucagon-like peptide (GLP-1) agonists have been studied in both animal models and humans with classic Wolfram syndrome. CASE: We present a 15-year-old female with a personal and family history of congenital strabismus, bilateral cataracts, low-frequency sensorineural hearing loss, and diabetes mellitus. Trio whole exome sequencing revealed a previously unknown maternally inherited heterozygous variant in exon 8 of the WFS1 gene c.2605_2616del12 p.Ser869_His872del, leading to the diagnosis of AD WFS1-related disorder. Treatment with a GLP-1 agonist resulted in marked improvement in glycemic control and discontinuation of insulin therapy. This patient's response to a GLP-1 agonist provides suggestive indirect evidence for a role of WFS1 on ß-cell endoplasmic reticulum stress and suggests that treatment with a GLP-1 agonist should be considered in patients with dominant forms of WS.

ISPAD Clinical Practice Consensus Guideline: Diabetic ketoacidosis in the time of COVID-19 and resource-limited settings-role of subcutaneous insulin.

The International Society for Pediatric and Adolescent Diabetes Clinical Practice Consensus Guideline 2018 for management of diabetic ketoacidosis (DKA) and the hyperglycemic hyperosmolar state provide comprehensive guidance for management of DKA in young people. Intravenous (IV) infusion of insulin remains the treatment of choice for treating DKA; however, the policy of many hospitals around the world requires admission to an intensive care unit (ICU) for IV insulin infusion. During the coronavirus 2019 (COVID-19) pandemic or other settings where intensive care resources are limited, ICU services may need to be prioritized or may not be appropriate due to risk of transmission of infection to young people with type 1 or type 2 diabetes. The aim of this guideline, which should be used in conjunction with the ISPAD 2018 guidelines, is to ensure that young individuals with DKA receive management according to best evidence in the context of limited ICU resources. Specifically, this guideline summarizes evidence for the role of subcutaneous insulin in treatment of uncomplicated mild to moderate DKA in young people and may be implemented if administration of IV insulin is not an option.

Monitoring of Pediatric Type 1 Diabetes.

Regular self-monitoring of blood glucose levels, and ketones when indicated, is an essential component of type 1 diabetes (T1D) management. Although fingerstick blood glucose monitoring has been the standard of care for decades, ongoing rapid technological developments have resulted in increasingly widespread use of continuous glucose monitoring (CGM). This article reviews recommendations for self-monitoring of glucose and ketones in pediatric T1D with particular emphasis on CGM and factors that impact the accuracy and real-world use of this technology.

Improving pediatric endocrinology trainees' knowledge about insulin pumps and continuous glucose monitors with online spaced education: Technology Knowledge Optimization in T1D (TeKnO T1D).

OBJECTIVE: We explored the impact of TeKnO T1D, an online, case-based, spaced education curriculum about insulin pump and continuous glucose monitor (CGM) use in pediatric type 1 diabetes management. METHODS: Pediatric endocrinology fellows (n = 64) were randomized to receive an educational curriculum focused on either insulin pumps or CGMs. Fellows received interactive questions twice weekly via email or mobile app. Median time to completion was 76.5 days. The primary outcome was change in knowledge as measured by performance on multiple-choice questions (MCQ) from the pre-test to the post-test. RESULTS: Forty-eight of 64 (75%) learners completed the curriculum and assessments. The pump group improved from 35.0 ± 15% on the pre-test MCQs to 61.1 ± 17% on the post-test, a 12.2 absolute percentage point greater improvement on pump-specific items than the CGM group (P = .03). The CGM group improved from 30.3 ± 15% on the pre-test MCQs to 61.4 ± 21% on the post-test, a 28.7 absolute percentage point greater improvement on CGM-specific items than the pump group (P < .001). Both groups were more likely to report an appropriate level of understanding of their respective technologies after completing the corresponding curriculum. In thematic analysis of qualitative data, fellows indicated that knowledge gains led to improved patient care. There was universal agreement about enjoyment and effectiveness of the curricula. CONCLUSIONS: TeKnO T1D proved to be an engaging, effective way to improve endocrinology fellows' knowledge and confidence about insulin pumps and CGM use in the management of pediatric type 1 diabetes.

Post-Transplantation Diabetes Mellitus in Pediatric Patients.

More than 80% of pediatric solid organ transplant (SOT) recipients now survive into young adulthood and many encounter transplant-related complications. Post-transplantation diabetes mellitus (PTDM), sometimes also referred to as post-transplant diabetes or new onset diabetes after transplant, occurs in 3-20% of pediatric SOT recipients depending upon the organ transplanted, age at transplantation, immunosuppressive regimen, family history, and time elapsed since transplant. To diagnose PTDM, hyperglycemia must persist beyond the initial hospitalization for transplantation when a patient is on stable doses of immunosuppressive medications. Though standard diagnostic criteria used by the American Diabetes Association (ADA) to diagnose diabetes are employed, clinicians need to be aware of the limitations of using these criteria in this unique patient population. Management of PTDM parallels strategies used for type 2 diabetes (T2D), while also carefully considering comorbidities and potential interactions with immunosuppressive medications in these patients. In caring for patients with PTDM, it is important to be familiar with these interactions and comorbidities in order to coordinate care with the transplant team and optimize outcomes for these patients.

Perioperative Management of Pediatric Patients With Type 1 Diabetes Mellitus, Updated Recommendations for Anesthesiologists.

Approximately 1 of every 300 children in the United States has type 1 diabetes mellitus (T1D), and these patients may require anesthetics for a variety of procedures. Perioperative coordination is complex, and attention to perioperative fasting, appropriate insulin administration, and management of hypo- and hyperglycemia, as well as other metabolic abnormalities, is required. Management decisions may be impacted by the patient's baseline glycemic control and home insulin regimen, the type of procedure being performed, and expected postoperative recovery. If possible, preoperative planning with input from the patient's endocrinologist is considered best practice. A multi-institutional working group was formed by the Society for Pediatric Anesthesia Quality and Safety Committee to review current guidelines in the endocrinology and anesthesia literature and provide recommendations to anesthesiologists caring for pediatric patients with T1D in the perioperative setting. Recommendations for preoperative evaluation, glucose monitoring, insulin administration, fluid management, and postoperative management are discussed, with particular attention to increasingly prevalent insulin pumps and continuous glucose monitoring (CGM).

Glycogen storage disease presenting as Cushing syndrome.

Impaired growth is common in patients with glycogen storage disease (GSD), who also may have "cherubic" facies similar to the "moon" facies of Cushing syndrome (CS). An infant presented with moon facies, growth failure, and obesity. Laboratory evaluation of the hypothalamic-pituitary-adrenal (HPA) axis was consistent with CS. He was subsequently found to have liver disease, hypoglycemia, and a pathogenic variant in PHKA2, leading to the diagnosis of GSD type IXa. The cushingoid appearance, poor linear growth and hypercortisolemia improved after treatment to prevent recurrent hypoglycemia. We suspect this child's HPA axis activation was "appropriate" and caused by chronic hypoglycemic stress, leading to increased glucocorticoid secretion that may have contributed to his poor growth and excessive weight gain. This is in contrast to typical CS, which is due to excessive adrenocorticotropic hormone (ACTH) or cortisol secretion from neoplastic pituitary or adrenal glands, ectopic secretion of ACTH or corticotropin-releasing hormone (CRH), or exogenous administration of corticosteroid or ACTH. Pseudo-CS is a third cause of excessive glucocorticoid secretion, has no HPA axis pathology, is most often associated with underlying psychiatric disorders or obesity in children and, by itself, is thought to be benign. We speculate that some diseases, including chronic hypoglycemic disorders such as the GSDs, may have biochemical features and pathologic consequences of CS. We propose that excessive glucocorticoid secretion due to chronic stress be termed "stress-induced Cushing (SIC) syndrome" to distinguish it from the other causes of CS and pseudo-CS, and that evaluation of children with chronic hypoglycemia and poor statural growth include evaluation for CS.

Hypoglycemia in the Newborn.

This article covers several aspects of the clinical management of neonatal hypoglycemia that have recently evolved, reviewing the evidence informing these recommended changes in practice. Topics covered include use of buccal dextrose gel, rationale for avoiding the traditional "mini dextrose bolus," and benefits of direct breastfeeding for the treatment of asymptomatic hypoglycemia in at-risk newborns. The reasons for increasing use of more accurate point-of-care devices for measuring neonatal glucose concentrations are discussed, as well as the implications of different published opinions regarding the determination of readiness for discharge and the most important considerations when making this determination.