Continuous subcutaneous insulin infusion in newly diagnosed diabetic children

In the first century AD Aretaeus of Cappadocia described diabetes as "a wonderful but not very frequent affection among men being a melting down of the flesh and limbs into urine .... , life is short, disgusting and painful, thirst unquenchable, death inevitable". The recognition of this disease with its enormous thirst and massive production of honey sweet urine is very old. Nowadays diabetes is known as a heterogeneous disorder. Insufficient production of biologically active insulin is a common denominator in almost all forms of diabetes. Insulin deficiency results in a variety of metabolic abnormalities (hyperglycaemia, increased lipolysis, increased gluconeogenesis at the cost of amino acids). The NIH National Diabetes Data Group discerns 2 types of diabetes mellitus: insulin dependent diabetes mellitus (IDDM) and noninsulin dependent diabetes mellitus (NIDDM) (National Diabetes Data Group 1979). IDDM frequently starts in childhood. The incidence in the Netherlands is estimated to be 11.0 subjects per 100.000 inhabitants per year in the age group below 20 years (Vaandrager 1984). Since NIDDM seldom occurs in childhood it will be left out of consideration in this study. Insulin is produced by beta cells in the pancreatic islets of Langerhans. In due time after clinical onset there is hardly any beta cell activity evident. An absolute insulin deficiency ensues. As insulin plays a key role in maintaining normal metabolism, this implicates a life-long dependency on exogenous insulin administration. Since insulin is a peptide which can not be administered orally, administration of injections at least once daily is necessary. Ten to 15 years after the onset of the disease severe complications may develop (micro- and macroangiopathy) resulting in a shorter life expectancy and a reduced quality of life (Deckert 1978). It is evident that t~is chronic disease and its consequences also influence life, the psychological wellbeing and development of patients, especially those of child age. The cause of this destructive process, which is specifically directed against the pancreatic beta cells, remains to be elucidated. Current thought is that a hereditary susceptibility in combination with an environmental agent can lead to the development of IDDM (Cahill 1981). Immunological disturbances- cellular as well as humoral - have also been found at the onset of the disease (Bottazzo 1981, Buschard 1980, Lernmark 1981, Maron 1983). Their precise role has not yet been clarified.

Transition from pediatric to adult diabetes care: Smooth or slippery?

de Beaufort C, Jarosz-Chobot P, Frank M, Frank M, de Bart J, Deja G. Transition from pediatric to adult diabetes care: smooth or slippery?Objectives: The purpose of this study is to evaluate the practices of diabetes health care providers concerning the transition from pediatric to adult diabetes care. The information presented here may help increase awareness of the organization of transitional care for young people with diabetes and prevent the loss of follow-up during this vulnerable period in their lives.Methods: A questionnaire with an explanatory letter was sent to all members (n = 578) of the International Society for Pediatric and Adolescent Diabetes (ISPAD). A follow-up mailing was sent 4 months later.Results: In total, 92 questionnaires (16%) from members representing 36 countries were included in the analysis. In 76% of the centers, youth are seen until the age of 18 yr; 36% of the pediatric centers see adults > 25 yr; 30% report children under the age of 16 receive follow up from adult diabetologists or internists. About half of the programs already have a structured transition process usually targeting youth 16-25 yr of age. The majority of responders propose that preparation for transition starts at least 1 yr prior to leaving the pediatric center.Conclusion: Youth with type 1 diabetes often struggle to keep diabetes management a priority and find it challenging to maintain optimal metabolic control. When they graduate from pediatric care, some of these young people opt out of care altogether, only to resurface in the medical system when they develop complications which may have been prevented. Our survey of diabetes health care professionals in 36 countries worldwide shows that the actual transition practices in many places are far from optimal and require improvement. Transitional care should start early and strategies should promote uninterrupted, comprehensive, and accessible adult care. © 2009 John Wiley & Sons A/S

COVID-19 outbreak and pediatric diabetes: perceptions of health care professionals worldwide

This is the peer reviewed version of the following article: "COVID-19 outbreak and pediatric diabetes: perceptions of health care professionals worldwide". Pediatric Diabetes (2020): 20 July, which has been published in final form at 10.1111/pedi.13084. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsCoronavirus diasease (COVID-19) is an infectious disease that startedin Wuhan, China in late 2019 and later spread around the world. Diabetes has beenrecognized as a possible risk factor for COVID-19 complications.Objective: International Society for Pediatric and Adolescent Diabetes (ISPAD) investi-gated perceptions, challenges and experience of health care professionals (HCP) takingcare of children and young people with diabetes worldwide during COVID-19 pandemic.Methods: From 21st April to 17th May 2020, during COVID-19 pandemic, a web-based survey was sent to ISPAD members and former participants of ISPAD confer-ences by email.Results: Responders from 215 diabetes centers from 75 countries completed the sur-vey. Majority were from UK (35; 16.3%), USA (20; 9.3%), and India (15; 7%). HCPwere mostly pediatric endocrinologists (64%). During COVID-19 pandemic, 16.5% ofresponders continued face-to-face consultation while most changed to telephone(32%) or video (18%) consultations. 19% reported a shortage of medical supplies.22% reported a delay in diagnosis of patients with new-onset diabetes, while 15%reported a higher incidence of DKA. 12% reported having one or more patients withCOVID-19. Most of the 86 children and adolescents with diabetes and COVID-19had only mild/moderate symptoms, while 5 required admission to an intensive careunit. No deaths were reported.Conclusions: This large global survey during COVID-19 pandemic showed that manyHCP adapted to the pandemic by resorting to telemedicine. One fourth of HCPreported delays in diagnosis and an increased rate of DKA. The emergence ofCOVID-19 pandemic had an important impact on family's behavior that might haveled to increase in diabetic ketoacidosis presentatio

Lower plasma insulin levels during overnight closed-loop in school children with type 1 diabetes: Potential advantage? A randomized cross-over trial.

BACKGROUND: Studies have shown that overnight closed-loop insulin delivery can improve glucose control and reduce the risk of hypoglycemia and hence may improve metabolic outcomes and reduce burden for children with type 1 diabetes and their families. However, research so far has not reported insulin levels while comparing closed-loop to open-loop insulin delivery in children. Therefore, in this study we obtained glucose levels as well as plasma insulin levels in children with type 1 diabetes to evaluate the efficacy of a model-based closed-loop algorithm compared to an open-loop administration. METHODS: Fifteen children with type 1 diabetes, 6-12 years, participated in this open-label single center study. We used a randomized cross over design in which we compared overnight closed-loop insulin delivery with sensor augmented pump therapy for two nights in both the hospital and at home (i.e., 1 night in-patient stay and at home per treatment condition). Only during the in-patient stay, hourly plasma insulin and blood glucose levels were assessed and are reported in this paper. RESULTS: Results of paired sample t-tests revealed that although plasma insulin levels were significantly lower during the closed-loop than in the open-loop (Mean difference 36.51 pmol/l; t(13) = 2.13, p = .03, effect size d = 0.57), blood glucose levels did not vary between conditions (mean difference 0.76 mmol/l; t(13) = 1.24, p = .12, d = 0.37). The administered dose of insulin was significantly lower during the closed-loop compared with the open-loop (mean difference 0.10 UI; t(12) = 2.45, p = .02, d = 0.68). CONCLUSIONS: Lower insulin doses were delivered in the closed-loop, resulting in lower plasma insulin levels, whereby glucose levels were not affected negatively. This suggests that the closed-loop administration is better targeted and hence could be more effective

Managing diabetes in preschool children

This article is a new chapter in the ISPAD Clinical Practice Consensus Guidelines Compendium. The complete set of guidelines can be found for free download at www.ispad.org. The evidence grading system used in the ISPAD Guidelines is the same as that used by the American Diabetes Association

A recurrent germline mutation in the 5’UTR of the androgen receptor causes complete androgen insensitivity by activating aberrant uORF translation

A subset of patients with monogenic disorders lacks disease causing mutations in the protein coding region of the corresponding gene. Here we describe a recurrent germline mutation found in two unrelated patients with complete androgen insensitivity syndrome (CAIS) generating an upstream open reading frame (uORF) in the 5' untranslated region (5'-UTR) of the androgen receptor (AR) gene. We show in patient derived primary genital skin fibroblasts as well as in cell-based reporter assays that this mutation severely impacts AR function by reducing AR protein levels without affecting AR mRNA levels. Importantly, the newly generated uORF translates into a polypeptide and the expression level of this polypeptide inversely correlates with protein translation from the primary ORF of the AR thereby providing a model for AR-5'UTR mediated translational repression. Our findings not only add a hitherto unrecognized genetic cause to complete androgen insensitivity but also underline the importance of 5'UTR mutations affecting uORFs for the pathogenesis of monogenic disorders in general

Small RNA profiling of low biomass samples: identification and removal of contaminants

Background Sequencing-based analyses of low-biomass samples are known to be prone to misinterpretation due to the potential presence of contaminating molecules derived from laboratory reagents and environments. DNA contamination has been previously reported, yet contamination with RNA is usually considered to be very unlikely due to its inherent instability. Small RNAs (sRNAs) identified in tissues and bodily fluids, such as blood plasma, have implications for physiology and pathology, and therefore the potential to act as disease biomarkers. Thus, the possibility for RNA contaminants demands careful evaluation. Results Herein, we report on the presence of small RNA (sRNA) contaminants in widely used microRNA extraction kits and propose an approach for their depletion. We sequenced sRNAs extracted from human plasma samples and detected important levels of non-human (exogenous) sequences whose source could be traced to the microRNA extraction columns through a careful qPCR-based analysis of several laboratory reagents. Furthermore, we also detected the presence of artefactual sequences related to these contaminants in a range of published datasets, thereby arguing in particular for a re-evaluation of reports suggesting the presence of exogenous RNAs of microbial and dietary origin in blood plasma. To avoid artefacts in future experiments, we also devise several protocols for the removal of contaminant RNAs, define minimal amounts of starting material for artefact-free analyses, and confirm the reduction of contaminant levels for identification of bona fide sequences using ‘ultra-clean’ extraction kits. Conclusion This is the first report on the presence of RNA molecules as contaminants in RNA extraction kits. The described protocols should be applied in the future to avoid confounding sRNA studies. Keywords: RNA sequencing; Artefact removal; Exogenous RNA in human blood plasma; Contaminant RNA; Spin column

Persistence of birth mode-dependent effects on gut microbiome composition, immune system stimulation and antimicrobial resistance during the first year of life

Caesarean section delivery (CSD) disrupts mother-to-neonate transmission of specific microbial strains and functional repertoires as well as linked immune system priming. Here we investigate whether differences in microbiome composition and impacts on host physiology persist at 1 year of age. We perform high-resolution, quantitative metagenomic analyses of the gut microbiomes of infants born by vaginal delivery (VD) or by CSD, from immediately after birth through to 1 year of life. Several microbial populations show distinct enrichments in CSD-born infants at 1 year of age including strains of Bacteroides caccae, Bifidobacterium bifidum and Ruminococcus gnavus, whereas others are present at higher levels in the VD group including Faecalibacterium prausnitizii, Bifidobacterium breve and Bifidobacterium kashiwanohense. The stimulation of healthy donor-derived primary human immune cells with LPS isolated from neonatal stool samples results in higher levels of tumour necrosis factor alpha (TNF-α) in the case of CSD extracts over time, compared to extracts from VD infants for which no such changes were observed during the first year of life. Functional analyses of the VD metagenomes at 1 year of age demonstrate a significant increase in the biosynthesis of the natural antibiotics, carbapenem and phenazine. Concurrently, we find antimicrobial resistance (AMR) genes against several classes of antibiotics in both VD and CSD. The abundance of AMR genes against synthetic (including semi-synthetic) agents such as phenicol, pleuromutilin and diaminopyrimidine are increased in CSD children at day 5 after birth. In addition, we find that mobile genetic elements, including phages, encode AMR genes such as glycopeptide, diaminopyrimidine and multidrug resistance genes. Our results demonstrate persistent effects at 1 year of life resulting from birth mode-dependent differences in earliest gut microbiome colonisation

Integrated multi-omics of the human gut microbiome in a case study of familial type 1 diabetes.

The gastrointestinal microbiome is a complex ecosystem with functions that shape human health. Studying the relationship between taxonomic alterations and functional repercussions linked to disease remains challenging. Here, we present an integrative approach to resolve the taxonomic and functional attributes of gastrointestinal microbiota at the metagenomic, metatranscriptomic and metaproteomic levels. We apply our methods to samples from four families with multiple cases of type 1 diabetes mellitus (T1DM). Analysis of intra- and inter-individual variation demonstrates that family membership has a pronounced effect on the structural and functional composition of the gastrointestinal microbiome. In the context of T1DM, consistent taxonomic differences were absent across families, but certain human exocrine pancreatic proteins were found at lower levels. The associated microbial functional signatures were linked to metabolic traits in distinct taxa. The methodologies and results provide a foundation for future large-scale integrated multi-omic analyses of the gastrointestinal microbiome in the context of host-microbe interactions in human health and disease