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Insulin gene (INS) mutations cause a rare form of maturity-onset diabetes of the young (MODY), a heterogeneous group of autosomal dominant diabetes with at least 14 confirmed causative genes. Here, we describe a family with MODY due to a novel INS mutation, detected using massively parallel sequencing (MPS). The proband presented aged 11 years with mild diabetic ketoacidosis. She was negative for IA2 and GAD antibodies. She had a strong family history of diabetes affecting both her two siblings and her mother, none of whom had ketosis but who were considered to have type 1 diabetes and managed on insulin, and her maternal grandfather, who was managed for decades on sulfonylureas. Of note, her younger sister had insulin deficiency but an elevated fasting proinsulin:insulin ratio of 76% (ref 5%-30%). Sanger sequencing of HNF4A, HNF1A, and HNF1B in the proband was negative. Targeted MPS using a custom-designed amplicon panel sequenced on an Illumina MiSeq detected a heterozygous INS mutation c.277G>A (p.Glu93Lys). Sanger sequencing confirmed the variant segregated with diabetes within the family. Structural analysis of this variant suggested disruption of a critical hydrogen bond between insulin and the insulin receptor; however, the clinical picture in some individuals also suggested abnormal insulin processing and insulin deficiency. This family has a novel INS mutation and demonstrated variable insulin deficiency. MPS represents an efficient method of MODY diagnosis in families with rarer gene mutations., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: There is no consensus on the optimal insulin treatment for children newly diagnosed with type 1 diabetes mellitus (T1DM). The aims of this study were (i) to describe the insulin regimens used at diagnosis by patient age and geographical region and (ii) to explore differences between and within Australia (AU) and New Zealand (NZ) with regards to other aspects of patient management and education., Methods: An online survey of medical professionals caring for children with T1DM in AU and NZ was undertaken. Questions included clinic demographics, insulin regimen/dosing choices and patient education., Results: Of 110 clinicians identified, 100 responded (91%). The majority of those in AU (69%, P < 0.0001) favour multiple daily injections (MDI) for all ages. In NZ, for patients < 10 years old, (twice daily (BD)) BD therapy was favoured (75%, P < 0.0001), with MDI dominant for ages ≥ 10 years (82%, P < 0.0001). Insulin pump therapy was never considered at diagnosis in NZ, but 38% of clinicians in AU considered using pumps at diagnosis in patients <2 years, but rarely in patients aged 2 and over (16%). Differences in clinician choices were also seen in relation to starting insulin dose., Conclusion: This is the first study to examine current clinical practice with regards to children newly diagnosed with T1DM. Practice varies across Australasia by clinician and region. This lack of consensus is likely driven by ongoing debates in the current paediatric diabetes evidence base as well as by differences in clinician/centre preference, variations in resourcing and their interpretations of the influence of various patient factors., (© 2017 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Objectives: To describe the dermatological changes associated with continuous subcutaneous insulin infusion (CSII) therapy in youth with type 1 diabetes mellitus (T1D). To assess their association with duration of CSII, age, adiposity, HbA1(c), insulin dose, insulin brand, infusion set or site., Study Design: We conducted a cross-sectional study of 50 consecutive patients with T1D who were using CSII for >6 months (26 female; age, 13.3 +/- 3.5 years [mean +/- SD]; CSII duration, 2.8 +/- 1.7 years; HbA1(c), 7.7% +/- 1.1%). A grading scale was devised. Ultrasound scanning was performed in 8 subjects., Results: The mean (+/-SD) severity score was 6.3 +/- 3.5 (range, 0-14; maximum possible, 69). Most common were scars <3 mm diameter (94%), erythema not associated with nodules (66%), subcutaneous nodules (62%), and lipohypertrophy (42%). There was a significant negative correlation between severity score and body mass index z-score (r = -0.3, P = .039), but no correlation with HbA1(c), insulin brand or site. Infusion sets inserted at 90 degrees were associated with lower scores (P = .03). Less than 5% of patients and parents considered stopping CSII because of skin concerns. Ultrasound scanning results of CSII sites revealed mild increased echogenicity of the dermis and hypodermis., Conclusions: Dermatological changes were frequent, with increased severity associated with lower adiposity. These complications were not associated with glycemic control, nor did they prompt most to consider stopping CSII.

Objective: To assess the concurrent validity of fasting indexes of insulin sensitivity and secretion in obese prepubertal (Tanner stage 1) children and pubertal (Tanner stages 2-5) adolescents using estimates from the modified minimal model frequently sampled intravenous glucose tolerance test (FSIVGTT) as a criterion measure., Research Design and Methods: Eighteen obese children and adolescents (11 girls and 7 boys, mean age 12.2 +/- 2.4 years, mean BMI 35.4 +/- 6.2 kg/m(2), mean BMI-SDS 3.5 +/- 0.5, 7 prepubertal and 11 pubertal) participated in the study. All participants underwent an insulin-modified FSIVGTT on two occasions, and 15 repeated this test a third time (mean 12.9 and 12.0 weeks apart). S(i) measured by the FSIVGTT was compared with homeostasis model assessment (HOMA) of insulin resistance (HOMA-IR), quantitative insulin-sensitivity check index (QUICKI), fasting glucose-to-insulin ratio (FGIR), and fasting insulin (estimates of insulin sensitivity derived from fasting samples). The acute insulin response (AIR) measured by the FSIVGTT was compared with HOMA of percent beta-cell function (HOMA-beta%), FGIR, and fasting insulin (estimates of insulin secretion derived from fasting samples)., Results: There was a significant negative correlation between HOMA-IR and S(i) (r = -0.89, r = -0.90, and r = -0.81, P < 0.01) and a significant positive correlation between QUICKI and S(i) (r = 0.89, r = 0.90, and r = 0.81, P < 0.01) at each time point. There was a significant positive correlation between FGIR and S(i) (r = 0.91, r = 0.91, and r = 0.82, P < 0.01) and a significant negative correlation between fasting insulin and S(i) (r = -90, r = -0.90, and r = -0.88, P < 0.01). HOMA-beta% was not as strongly correlated with AIR (r = 0.60, r = 0.54, and r = 0.61, P < 0.05)., Conclusions: HOMA-IR, QUICKI, FGIR, and fasting insulin correlate strongly with S(i) assessed by the FSIVGTT in obese children and adolescents. Correlations between HOMA-beta%, FGIR and fasting insulin, and AIR were not as strong. Indexes derived from fasting samples are a valid tool for assessing insulin sensitivity in prepubertal and pubertal obese children.

Background: Hyperinsulinism (HI) due to dysregulation of pancreatic beta-cell insulin secretion is the most common and most severe cause of persistent hypoglycemia in infants and children. In the 65 years since HI in children was first described, there has been a dramatic advancement in the diagnostic tools available, including new genetic techniques and novel radiologic imaging for focal HI; however, there have been almost no new therapeutic modalities since the development of diazoxide. Summary: Recent advances in neonatal research and genetics have improved our understanding of the pathophysiology of both transient and persistent forms of neonatal hyperinsulinism. Rapid turnaround of genetic test results combined with advanced radiologic imaging can permit identification and localization of surgically-curable focal lesions in a large proportion of children with congenital forms of HI, but are only available in certain centers in "developed" countries. Diazoxide, the only drug currently approved for treating HI, was recently designated as an "essential medicine" by the World Health Organization but has been approved in only 16% of Latin American countries and remains unavailable in many under-developed areas of the world. Novel treatments for HI are emerging, but they await completion of safety and efficacy trials before being considered for clinical use. Key Messages: This international consensus statement on diagnosis and management of HI was developed in order to assist specialists, general pediatricians, and neonatologists in early recognition and treatment of HI with the ultimate aim of reducing the prevalence of brain injury caused by hypoglycemia. A previous statement on diagnosis and management of HI in Japan was published in 2017. The current document provides an updated guideline for management of infants and children with HI and includes potential accommodations for less-developed regions of the world where resources may be limited. [ABSTRACT FROM AUTHOR]

Objective: Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of diabetes, with multiple causative genes. Some MODY subtypes can be treated with sulfonylureas instead of insulin, improving glycemic control, complication rates, quality of life (QoL), and costs. Using massively parallel sequencing (MPS), we recently determined the prevalence of pathogenic/likely pathogenic MODY variants in an Australian pediatric diabetes cohort. Here, these data are used to estimate cost-effectiveness of using MPS for MODY in all pediatric diabetes cases compared with standard practice (sequencing limited to individuals with specific clinical features).Research Design and Methods: A Markov decision model was developed to estimate incremental costs and quality-adjusted life-years (QALYs) of MPS screening, modeled over 30 years. We used our observed prevalence of 2.14% compared with 0.7% for standard practice, based on published data. The probabilities and utility weightings of long-term diabetes complications were based on HbA1c and estimated from published data. A series of one-way sensitivity analyses were performed using the net monetary benefit framework.Results: Routine MPS screening for MODY was more effective and less costly than standard care screening, with 26 QALYs gained and 1,016,000 AUD (782,000 USD) saved per 1,000 patients. Cost of screening was fully offset within 10 years. Routine MPS screening remained dominant until MODY prevalence fell to <1.1%.Conclusions: Routine MPS screening for MODY in the pediatric population with diabetes could reduce health system costs and improve patient QoL. Our results make a compelling argument for routine genetic screening in all children with presumed type 1 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Vitamin D is synthesised in the skin through the action of UVB radiation (sunlight), and 25-hydroxy vitamin D ( 25OHD) measured in serum as a marker of vitamin D status. Several studies, mostly conducted in high latitudes, have shown an association between type 1 diabetes mellitus ( T1DM) and low serum 25OHD. We conducted a case-control study to determine whether, in a sub-tropical environment with abundant sunlight (latitude 27.5°S), children with T1DM have lower serum vitamin D than children without diabetes. Fifty-six children with T1DM (14 newly diagnosed) and 46 unrelated control children participated in the study. Serum 25OHD, 1,25-dihydroxy vitamin D (1,25( OH)2 D) and selected biochemical indices were measured. Vitamin D receptor (VDR) polymorphisms Taq1, Fok1, and Apa1 were genotyped. Fitzpatrick skin classification, self-reported daily hours of outdoor exposure, and mean UV index over the 35 d prior to blood collection were recorded. Serum 25OHD was lower in children with T1DM (n = 56) than in controls (n = 46) [mean (95% CI) = 78.7 (71.8-85.6) nmol/L vs. 91.4 (83.5-98.7) nmol/L, p = 0.02]. T1DM children had lower self-reported outdoor exposure and mean UV exposure, but no significant difference in distribution of VDR polymorphisms. 25OHD remained lower in children with T1DM after covariate adjustment. Children newly diagnosed with T1DM had lower 1,25( OH)2 D [median ( IQR) = 89 (68-122) pmol/L] than controls [121 (108-159) pmol/L, p = 0.03], or children with established diabetes [137 (113-153) pmol/L, p = 0.01]. Children with T1DM have lower 25OHD than controls, even in an environment of abundant sunlight. Whether low vitamin D is a risk factor or consequence of T1DM is unknown. [ABSTRACT FROM AUTHOR]

Objectives To explore the feasibility of conducting a 10-week home-based physical activity (PA) programme and evaluate the changes in insulin sensitivity (SI) commensurate with the programme in obese young people. Design Open-labelled intervention. Setting Home-based intervention with clinical assessments at a tertiary paediatric hospital. Subjects 18 obese (body mass index (BMI)>International Obesity Task Force age and sex-specifi c cut-offs) children and adolescents (8-18 years, 11 girls/7 boys) were recruited. 15 participants (nine girls/six boys, mean±SE age 11.8±0.6 years, BMI-SD scores (BMI-SDS) 3.5±0.1, six prepubertal/nine pubertal) completed the intervention. Intervention The programme comprised biweekly home visits over 10 weeks with personalised plans implemented aiming to increase moderate-intensity PA. Pedometers and PA diaries were used as self-monitoring tools. The goals were to (1) teach participants behavioural skills related to adopting and maintaining an active lifestyle and (2) increase daily participation in PA.Outcome measures Mean steps/day were assessed. SI assessed by the frequently sampled intravenous glucose tolerance test and other components of the insulin resistance syndrome were measured.Results Mean steps/day increased signifi cantly from 10 363±927 (baseline) to 13 013±1131 (week 10) (p<0.05). SI was also signifi cantly increased, despite no change in BMI-SDS, and remained so after an additional 10-week follow-up. Conclusions The results suggest that such a homebased PA programme is feasible. SI improved without changes in BMI-SDS. More rigorous evaluations of such programmes are warranted. [ABSTRACT FROM AUTHOR]