Consensus guidance for monitoring individuals with islet autoantibody-positive pre-stage 3 type 1 diabetes.

Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programmes are being increasingly emphasised. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb+) children and adults who are at risk of (confirmed single IAb+) or living with (multiple IAb+) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in non-specialised settings. To inform this monitoring, JDRF in conjunction with international experts and societies developed consensus guidance. Broad advice from this guidance includes the following: (1) partnerships should be fostered between endocrinologists and primary-care providers to care for people who are IAb+; (2) when people who are IAb+ are initially identified there is a need for confirmation using a second sample; (3) single IAb+ individuals are at lower risk of progression than multiple IAb+ individuals; (4) individuals with early-stage type 1 diabetes should have periodic medical monitoring, including regular assessments of glucose levels, regular education about symptoms of diabetes and DKA, and psychosocial support; (5) interested people with stage 2 type 1 diabetes should be offered trial participation or approved therapies; and (6) all health professionals involved in monitoring and care of individuals with type 1 diabetes have a responsibility to provide education. The guidance also emphasises significant unmet needs for further research on early-stage type 1 diabetes to increase the rigour of future recommendations and inform clinical care.

Consensus Guidance for Monitoring Individuals With Islet Autoantibody-Positive Pre-Stage 3 Type 1 Diabetes.

Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programs are being increasingly emphasized. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb+) children and adults who are at risk for (confirmed single IAb+) or living with (multiple IAb+) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in nonspecialized settings. To inform this monitoring, JDRF, in conjunction with international experts and societies, developed consensus guidance. Broad advice from this guidance includes the following: 1) partnerships should be fostered between endocrinologists and primary care providers to care for people who are IAb+; 2) when people who are IAb+ are initially identified, there is a need for confirmation using a second sample; 3) single IAb+ individuals are at lower risk of progression than multiple IAb+ individuals; 4) individuals with early-stage type 1 diabetes should have periodic medical monitoring, including regular assessments of glucose levels, regular education about symptoms of diabetes and DKA, and psychosocial support; 5) interested people with stage 2 type 1 diabetes should be offered trial participation or approved therapies; and 6) all health professionals involved in monitoring and care of individuals with type 1 diabetes have a responsibility to provide education. The guidance also emphasizes significant unmet needs for further research on early-stage type 1 diabetes to increase the rigor of future recommendations and inform clinical care.

Perspectives on the role of exercise in the treatment of pediatric type 1 diabetes.

BACKGROUND: Studies demonstrate that children with type 1 diabetes may not be meeting exercise recommendations. This, coupled with the lack of data on the determinants of exercise promotion in youth, may indicate a need for additional focus on exercise guidelines and promotion in youth with type 1 diabetes. OBJECTIVE: The objective of this study is to understand provider perspectives regarding exercise promotion in children with type 1 diabetes. SUBJECTS AND METHODS: An online survey regarding perspectives on exercise was emailed to Pediatric Endocrine Society members. RESULTS: Of the 84 respondents, 85.5% believe counseling regarding exercise recommendations is a priority. However, 87.8% did not identify Office of Disease Prevention and Health Promotion (ODPHP) guidelines correctly and 79.3% did not identify American Diabetes Association (ADA) guidelines correctly. Providers who exercised regularly (P = .009) and providers who identified ODPHP guidelines correctly (P = .004) were more likely to identify ADA guidelines correctly. Providers who identified ADA guidelines correctly were 4.21 times (OR 4.21; 95% CI 1.30-13.7) more likely to make good recommendations and those who discussed recommendations at diagnosis were 6.10 times (OR 6.10; 95% CI 1.76-21.2) more likely to make good recommendations. CONCLUSION: To our knowledge, this study is the first to investigate provider perspectives of exercise promotion in children with type 1 diabetes. We found provider recommendations were not consistent with ADA exercise guidelines and most providers were not fully aware of the recommendations. Future research should address increasing provider education regarding exercise guidelines and developing exercise promotion tools.

Cortisol Levels in Children With Diabetic Ketoacidosis Associated With New-Onset Type 1 Diabetes Mellitus.

There is little data documenting cortisol levels in children with diabetic ketoacidosis (DKA), despite the fact that untreated adrenal insufficiency (AI) could worsen the outcome of DKA. In this cross-sectional study, we assessed serum cortisol levels in 28 children with DKA and new onset type 1 diabetes mellitus evaluated at our center over a 5-year period. Average duration of diabetes-related symptoms was positively associated with age ( P = .002), and significantly lower hemoglobin A1c levels were observed in the youngest children. The mean cortisol level was 40.9 µg/dL, with a range of 7.8 to 119 µg/dL. Cortisol levels were found to be inversely associated with serum pH ( P = .007). There was no difference in the clinical outcome of the 4 patients who had cortisol levels less than 18 µg/dL. Overall, we did not find clinical or laboratory evidence of diminished cortisol reserve; however, the possibility of AI must be kept in mind when treating children with DKA.

Mechanisms and Disease Associations of Haplotype-Dependent Allele-Specific DNA Methylation.

Haplotype-dependent allele-specific methylation (hap-ASM) can impact disease susceptibility, but maps of this phenomenon using stringent criteria in disease-relevant tissues remain sparse. Here we apply array-based and Methyl-Seq approaches to multiple human tissues and cell types, including brain, purified neurons and glia, T lymphocytes, and placenta, and identify 795 hap-ASM differentially methylated regions (DMRs) and 3,082 strong methylation quantitative trait loci (mQTLs), most not previously reported. More than half of these DMRs have cell type-restricted ASM, and among them are 188 hap-ASM DMRs and 933 mQTLs located near GWAS signals for immune and neurological disorders. Targeted bis-seq confirmed hap-ASM in 12/13 loci tested, including CCDC155, CD69, FRMD1, IRF1, KBTBD11, and S100A(∗)-ILF2, associated with immune phenotypes, MYT1L, PTPRN2, CMTM8 and CELF2, associated with neurological disorders, NGFR and HLA-DRB6, associated with both immunological and brain disorders, and ZFP57, a trans-acting regulator of genomic imprinting. Polymorphic CTCF and transcription factor (TF) binding sites were over-represented among hap-ASM DMRs and mQTLs, and analysis of the human data, supplemented by cross-species comparisons to macaques, indicated that CTCF and TF binding likelihood predicts the strength and direction of the allelic methylation asymmetry. These results show that hap-ASM is highly tissue specific; an important trans-acting regulator of genomic imprinting is regulated by this phenomenon; and variation in CTCF and TF binding sites is an underlying mechanism, and maps of hap-ASM and mQTLs reveal regulatory sequences underlying supra- and sub-threshold GWAS peaks in immunological and neurological disorders.

HLA-E-restricted regulatory CD8(+) T cells are involved in development and control of human autoimmune type 1 diabetes.

A key feature of the immune system is its ability to discriminate self from nonself. Breakdown in any of the mechanisms that maintain unresponsiveness to self (a state known as self-tolerance) contributes to the development of autoimmune conditions. Recent studies in mice show that CD8(+) T cells specific for the unconventional MHC class I molecule Qa-1 bound to peptides derived from the signal sequence of Hsp60 (Hsp60sp) contribute to self/nonself discrimination. However, it is unclear whether they exist in humans and play a role in human autoimmune diseases. Here we have shown that CD8(+) T cells specific for Hsp60sp bound to HLA-E (the human homolog of Qa-1) exist and play an important role in maintaining peripheral self-tolerance by discriminating self from nonself in humans. Furthermore, in the majority of type 1 diabetes (T1D) patients tested, there was a specific defect in CD8(+) T cell recognition of HLA-E/Hsp60sp, which was associated with failure of self/nonself discrimination. However, the defect in the CD8(+) T cells from most of the T1D patients tested could be corrected in vitro by exposure to autologous immature DCs loaded with the Hsp60sp peptide. These data suggest that HLA-E-restricted CD8(+) T cells may play an important role in keeping self-reactive T cells in check. Thus, correction of this defect could be a potentially effective and safe approach in the therapy of T1D.

Generalized acanthosis nigricans in an otherwise healthy young child.

Acanthosis nigricans in children is usually a benign condition most commonly associated with obesity. Generalized acanthosis nigricans is a very rare condition, especially in childhood. We report a 6-year-old boy with a 4-year history of generalized hyperpigmentation and velvety thickening of the skin. Despite an extensive examination, no evidence for an underlying neoplastic or endocrinologic disease was found.