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Background: Given the limitations in access and license status of commercially developed automated insulin delivery (AID) systems, open-source AID systems are becoming increasingly popular amongst people with diabetes, including children and adolescents. This study focused on lived experiences, physical and emotional health implications of children and their caregivers following the initiation of open-source AID, their perceived challenges, and sources of support, which have not been explored by the existing literature. Methods: Qualitative data were collected through two sets of open-ended questions of a web-based multinational study survey from 60 caregivers of children with diabetes from 16 countries. The narratives were thematically analysed and a coding framework was identified through an iterative process after the alignment discussions among three coders. Results: A range of emotions, improvements of quality of life and physical health were reported as open-source AID enabled the families to shift their focus away from diabetes therapy. Caregivers were less worried about hypoglycaemia at night-time and outside of their family home, leading to increased autonomy for the child. Simultaneously, glycaemic outcomes and sleep quality of both child and caregiver improved. Nonetheless, the acquisition of suitable hardware and technical set-up could be challenging. The #WeAreNotWaiting community was the primary source of practical but also emotional support. Conclusion: Our findings show the benefits and transformative impact open-source AID and peer-support have on children with diabetes, their caregivers, and families, where commercial AID systems are not available or suitable. Further efforts are required to improve effectiveness, usability, and facilitate access for children with diabetes worldwide to benefit from this innovative treatment. Funding: European Commission (H2020-MSCA-RISE-2018), Berlin Institute of Health Digital Clinician Scientist and SPOKES Wellcome Trust Translational Partnership Program. Declaration of Interest: KB received fees for medical consulting and public speaking from Roche Diabetes Care, Dexcom, Medtronic Diabetes, Diabeloop, Novo Nordisk, Sanofi Diabetes and BCG Digital Ventures; outside the submitted work. KR received fees for medical consulting and public speaking from Dexcom, Abbott, Lilly Diabetes Care, Novo Nordisk (Germany) and Springer Healthcare UK; outside the submitted work. All other authors have nothing to disclose. Ethical Approval: Ethical approval was provided by Charite – Universitatsmedizin Berlin (EA2/140/18).

Open-source automated insulin delivery systems, commonly referred to as do-it-yourself automated insulin delivery systems, are examples of user-driven innovations that were co-created and supported by an online community who were directly affected by diabetes. Their uptake continues to increase globally, with current estimates suggesting several thousand active users worldwide. Real-world user-driven evidence is growing and provides insights into safety and effectiveness of these systems. The aim of this consensus statement is two-fold. Firstly, it provides a review of the current evidence, description of the technologies, and discusses the ethics and legal considerations for these systems from an international perspective. Secondly, it provides a much-needed international health-care consensus supporting the implementation of open-source systems in clinical settings, with detailed clinical guidance. This consensus also provides important recommendations for key stakeholders that are involved in diabetes technologies, including developers, regulators, and industry, and provides medico-legal and ethical support for patient-driven, open-source innovations.

Pancreatic β cells store insulin within secretory granules which undergo exocytosis upon elevation of blood glucose levels. Crinophagy and autophagy are instead responsible to deliver damaged or old granules to acidic lysosomes for intracellular degradation. However, excessive consumption of insulin granules can impair β cell function and cause diabetes. Atp6ap2 is an essential accessory component of the vacuolar ATPase required for lysosomal degradative functions and autophagy. Here, we show that Cre recombinase-mediated conditional deletion of Atp6ap2 in mouse β cells causes a dramatic accumulation of large, multigranular vacuoles in the cytoplasm, with reduction of insulin content and compromised glucose homeostasis. Loss of insulin stores and gigantic vacuoles were also observed in cultured insulinoma INS-1 cells upon CRISPR/Cas9-mediated removal of Atp6ap2. Remarkably, these phenotypic alterations could not be attributed to a deficiency in autophagy or acidification of lysosomes. Together, these data indicate that Atp6ap2 is critical for regulating the stored insulin pool and that a balanced regulation of granule turnover is key to maintaining β cell function and diabetes prevention.

Background Studying patients with rare Mendelian diabetes has uncovered molecular mechanisms regulating β‐cell pathophysiology. Previous studies have shown that Class IIa histone deacetylases (HDAC4, 5, 7, and 9) modulate mammalian pancreatic endocrine cell function and glucose homeostasis. Methods We performed exome sequencing in one adolescent nonautoimmune diabetic patient and detected one de novo predicted disease‐causing HDAC4 variant (p.His227Arg). We screened our pediatric diabetes cohort with unknown etiology using Sanger sequencing. In mouse pancreatic β‐cell lines (Min6 and SJ cells), we performed insulin secretion assay and quantitative RT‐PCR to measure the β‐cell function transfected with the detected HDAC4 variants and wild type. We carried out immunostaining and Western blot to investigate if the detected HDAC4 variants affect the cellular translocation and acetylation status of Forkhead box protein O1 (FoxO1) in the pancreatic β‐cells. Results We discovered three HDAC4 mutations (p.His227Arg, p.Asp234Asn, and p.Glu374Lys) in unrelated individuals who had nonautoimmune diabetes with various degrees of β‐cell loss. In mouse pancreatic β‐cell lines, we found that these three HDAC4 mutations decrease insulin secretion, down‐regulate β‐cell‐specific transcriptional factors, and cause nuclear exclusion of acetylated FoxO1. Conclusion Mutations in HDAC4 disrupt the deacetylation of FoxO1, subsequently decrease the β‐cell function including insulin secretion, resulting in diabetes.

Cohen syndrome (CS) is an autosomal recessive disorder with variability in the clinical manifestations, characterised by mental retardation, postnatal microcephaly, facial dysmorphism, pigmentary retinopathy, myopia, and intermittent neutropenia. Mutations in the gene COH1 have been found in an ethnically diverse series of patients. Brief clinical descriptions of 24 patients with CS are provided. The patients were from 16 families of different ethnic backgrounds and between 2.5 and 60 years of age at assessment. DNA samples from all patients were analysed for mutations in COH1 by direct sequencing. Splice site mutations were characterised using reverse transcriptase PCR analysis from total RNA samples. In this series, we detected 25 different COH1 mutations; 19 of these were novel, including 9 nonsense mutations, 8 frameshift mutations, 4 verified splice site mutations, 3 larger in frame deletions, and 1 missense mutation. We observed marked variability of developmental and growth parameters. The typical facial gestalt was seen in 23/24 patients. Early onset progressive myopia was present in all the patients older than 5 years. Widespread pigmentary retinopathy was found in 12/14 patients assessed over 5 years of age. We present evidence for extended allelic heterogeneity of CS, with the vast majority of mutations leading to premature termination codons in COH1. Our data confirm the broad clinical spectrum of CS with some patients lacking even the characteristic facial gestalt and pigmentary retinopathy at school age.

Objective To characterize the initial presentation and clinical course of patients with hepatocyte nuclear factor (HNF) 4A‒ and HNF1B‒MODY in a multinational registry. Design, Setting, and Participants Within the Diabetes Patienten Verlaufsdokumentation (DPV) registry, 44 patients with HNF4A- and 35 patients with HNF1B-MODY were characterized and compared with patients

Aims: Several commercial and open-source automated insulin dosing (AID) systems have recently been developed and are now used by an increasing number of people with diabetes (PwD). This systematic review explored the current status of real-world evidence on the latest available AID systems in helping to understand their safety and effectiveness. Methods: A systematic review of real-world studies on the effect of commercial and open-source AID system use on clinical outcomes was conducted employing a devised protocol (PROSPERO ID 257354). Results: Of 441 initially identified studies, 21 published 2018-2021 were included: 12 for Medtronic 670G; one for Tandem Control-IQ; one for Diabeloop DBLG1; two for AndroidAPS; one for OpenAPS; one for Loop; three comparing various types of AID systems. These studies found that several types of AID systems improve Time-in-Range and haemoglobin A1c (HbA1c ) with minimal concerns around severe hypoglycaemia. These improvements were observed in open-source and commercially developed AID systems alike. Conclusions: Commercially developed and open-source AID systems represent effective and safe treatment options for PwD of several age groups and genders. Alongside evidence from randomized clinical trials, real-world studies on AID systems and their effects on glycaemic outcomes are a helpful method for evaluating their safety and effectiveness.

Background: The impact of hormone dynamics throughout the menstrual cycle on insulin sensitivity represents a currently under-researched area. Despite therapeutic and technological advances, self-managing insulin therapy remains challenging for women with type 1 diabetes (T1D). Methods: To investigate perceived changes in glycemic levels and insulin requirements throughout the menstrual cycle and different phases of life, we performed semi-structured interviews with 12 women with T1D who are using personalized open-source automated insulin delivery (AID) systems. Transcripts were analyzed using thematic analysis with an inductive, hypothesis-generating approach. Results: Participants reported significant differences between the follicular phase, ovulation, and luteal phase of the menstrual cycle and also during puberty, pregnancy, and menopause. All participants reported increased comfort and safety since using AID, but were still required to manually adjust their therapy according to their cycle. A lack of information and awareness and limited guidance by health care providers were frequently mentioned. Although individual adjustment strategies exist, achieving optimum outcomes was still perceived as challenging. Conclusions: This study highlights that scientific evidence, therapeutic options, and professional guidance on female health-related aspects in T1D are insufficient to date. Further efforts are required to better inform people with T1D, as well as for health care professionals, researchers, medical device manufacturers, and regulatory bodies to better address female health needs in therapeutic advances.