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Aims/hypothesis: Glycaemic control and clinical outcomes in diabetes are improved by continuous subcutaneous insulin infusion (CSII). Atmospheric pressure changes during flights may affect insulin delivery from pumps and cause unintended metabolic consequences, including hypoglycaemia, in people with type 1 diabetes. The present report evaluates both hypobaric flight simulation and real-world data in pilots using insulin pumps while flying., Methods: In the flight simulation part of this study, an in vitro study of insulin pumps was conducted in a hypobaric chamber, de-pressurised to 550 mmHg to mimic the atmospheric pressure changes in airliner cabins during commercial flights. Insulin delivery rates and bubble formation were recorded for standard flight protocol. Insulin infusion sets, without pumps, were tested in a simulated rapid decompression scenario. The real-world observational study was a 7.5-year retrospective cohort study in which pre- and in-flight self-monitored blood glucose (SMBG) values were monitored in pilots with insulin-treated diabetes. Commercial and private pilots granted a medical certificate to fly within the European Union Aviation Safety Agency approved protocol and receiving insulin either by pump or multiple daily injections (MDI) were included., Results: In the flight simulation study, full cartridges over-delivered 0.60 U of insulin during a 20 min ascent and under-delivered by 0.51 U during descent compared with ground-level performance. During emergency rapid decompression, 5.6 U of excess insulin was delivered. In the real-world study, seven pilots using CSII recorded 4656 SMBG values during 2345 h of flying across 1081 flights. Only 33 (0.7%) values were outside an acceptable safe range (5.0-15.0 mmol/l [90-270 mg/dl]). No clinically significant fall in the median SMBG concentration was observed after aircraft ascent and no in-flight SMBG values were within the hypoglycaemic range (<4.0 mmol/l [<72 mg/dl]). Compared with pilots receiving MDI therapy, pilots using CSII recorded more SMBG values within the acceptable range (99.3% vs 97.5%), fewer values in the low red range (0.02% vs 0.1%), fewer in-flight out-of-range values (0.2% vs 1.3%) and maintained stricter glycaemic control during flight., Conclusions/interpretation: Ambient pressure reduction during simulated flights results in bubble formation and expansion within insulin cartridges. This causes unintended delivery of small insulin doses independent of pre-determined delivery rates and represents the maximum amount of insulin that could be delivered and retracted. However, in vivo, pilots using CSII in-flight did not experience a fall in blood glucose or episodes of hypoglycaemia during these atmospheric pressure changes and the use of insulin pumps can be endorsed in view of their clinical benefits., Competing Interests: Acknowledgements: We thank B. Dick (Tams Group, Australia) for assisting with the design and construction of our equipment setup, and D. Connolly (QinetiQ, Salisbury, UK) and QinetiQ Ltd, MOD Boscombe Down for facilitating our experiments in the hypobaric chamber. We also thank the teams at Insulet, Medtronic and Tandem Diabetes Care for their product support. We are very grateful to the pilots with insulin-treated diabetes who participated in this study. We also thank J. Vening and J. Montague (aeromedical nurses, UK CAA) and D. Coghlan (aeromedical nurse, IAA) for their help with data collection and management. We also thank C. I. Panait and P. N. P. Caetano for their input on this manuscript as technical reviewers for EASA (EASA, Germany). No other individual or agency was involved in the preparation of this manuscript. The hypobaric simulation study was presented as an e-poster discussion at the 7th International Conference on Advanced Technologies & Treatments for Diabetes (ATTD) 2024 conference, 6–9 March. The abstract was titled ‘The effects of atmospheric pressure experienced during routine airline flight on infusion rates of insulin pumps’ and was published in Diabetes Technology & Therapeutics, Volume 26, Issue S2/February, as abstract no. 144 (page A-133). This study has also been accepted at the 60th EASD Annual Meeting under the title of ‘Simulated commercial flights and the effects of atmospheric pressure changes on insulin pump delivery’. The findings of the retrospective observational study were presented as an oral presentation at the 7th International Conference on Advanced Technologies & Treatments for Diabetes (ATTD) 2024 conference on 6–9 March. The abstract was titled ‘The effects of changes in atmospheric pressure on glycaemic control in pilots with insulin-treated diabetes using insulin pumps during commercial flying’ and was published in Diabetes Technology & Therapeutics, Volume 26, Issue S2/February, as abstract no. 659 (page A-58). EASA Consortium members are as follows: Chantal Mathieu (KU Leuven, Leuven, Belgium), David Russell-Jones (University of Surrey, Guildford, UK), E. Marelise W. Eekhoff (Amsterdam University Medical Center, Amsterdam, the Netherlands), Ewan Hutchison (Civil Aviation Authority, Crawley, UK), Fariba Shojaee-Moradie (University of Surrey, Guildford, UK), Felice Strollo (IRCCS San Raffaele Pisana, Rome, Italy), Gerd Köhler (Medical University of Graz, Graz, Austria), Graham Roberts (Irish Aviation Authority, Dublin, Ireland), Julia Mader (Medical University of Graz, Graz, Austria), Monika Cigler (Medical University of Graz, Graz, Austria), Renald Mecani (Medical University of Graz, Graz, Austria), Richard Helsdingen (TUI, Amsterdam, the Netherlands), Stuart Mitchell (University of Surrey, Guildford, UK) and Thomas Pieber (Medical University of Graz, Graz, Austria). Data availability: Authors agree to make data and materials supporting the results or analyses presented in their paper available upon reasonable request. Funding: The hypobaric simulation part of the study was conducted in conjunction with the Safe Use of New technologies in Diabetes in Flight (SUNDIF; NCT06408558) funded by the EASA Horizon Europe Work Programme 2021–2022. Pumps and associated expenses were covered by unrestricted grants and gifts. Insulin pump manufacturers provided product support but were not involved in the study design or carrying out of the study. No additional sources of funding was received for the retrospective observational study. Authors’ relationships and activities: BMF is a member of the UK Civil Aviation (CAA) Advisory Panel for diabetes and flying and is a member of the advisory board of Zucara Pharmaceuticals. GK is contracted as an independent advisor to Austro Control and has received research funding, speaker and advisory board honoraria from Astra Zeneca, Amgen, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Novartis, Novo Nordisk, Roche Diagnostics and Sanofi. CM is the president of EASD and serves or has served on the advisory panel for Novo Nordisk, Sanofi, Eli Lilly, Novartis, Boehringer Ingelheim, Roche, Medtronic, Imcyse, Insulet and Vertex. Financial compensation for these activities has been received by KU Leuven. KU Leuven has received research support for CM from Medtronic, Imcyse, Novo Nordisk, Sanofi and ActoBio Therapeutics. CM serves or has served on the speakers bureau for Novo Nordisk, Sanofi, Eli Lilly, Medtronic and Boehringer Ingelheim. Financial compensation for these activities has been received by KU Leuven. All external support of EASD is to be found on www.easd.org . JKM is a consultant physician for Internal Medicine, Dept of Internal Medicine Medical University of Graz, is a member on the advisory board of Abbott Diabetes Care, Becton-Dickinson, Boehringer Ingelheim, Eli Lilly, Embecta, Medtronic, Novo Nordisk A/S, Pharmasens AG, Roche Diabetes Care, Viatris and Sanofi-Aventis and received speaker honoraria from Abbott Diabetes Care, A. Menarini Diagnostics, AstraZeneca, Boehringer Ingelheim, Becton-Dickinson, Dexcom, Eli Lilly, Medtrust AG, MSD, Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis, Servier, Viatris and Ypsomed. She is a shareholder of decide Clinical Software GmbH and elyte Diagnostics and serves as CMO of elyte Diagnostics. SRH has served as a member of an expert panel of the UK CAA and provides consultancy for Novo Nordisk, Eli Lilly, and Zealand Pharma, for which his institution receives remuneration, and serves on speaker panels for Novo Nordisk and AstraZeneca, for which he receives personal remuneration. GAR is contracted as an independent advisor to the Irish Aviation Authority (IAA) and has received research funding and advisory board honoraria from Novo Nordisk, Mundipharma and Sanofi. KMS has served as a contracted medical consultant (clinical assessments) and an independent advisor to the UK Civil Aviation Authority (CAA). He has previously served on specialist advisory boards for Abbott, GSK, Merk, Novo Nordisk, Novartis, Pfizer, Sanofi and Servier. DLR-J is a Professor of Diabetes and Endocrinology at Royal Surrey County Hospital and at Nutritional Sciences, FHMS, University of Surrey, Guildford, Surrey, UK. He is also contracted as an independent advisor to the UK Civil Aviation Authority (CAA). He has received research funding and advisory board honoraria from Abbott Diabetes Care, AstraZeneca, Dexcom, Eli Lilly, Medtronic, Novartis, Novo Nordisk and Sanofi. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: The conception and design of the studies were developed by GLG, MP, FSM, BRK, DLRJ, KSF, AM, VE, VL, GK, CM, MBI, EJH, DM, SJM, BMF, KMS, SRH, GAR and JKM. Data acquisition was executed by GLG, KSF, MP, FSM, AM, VE, VL, BRK and DRJ. The subsequent analysis and interpretation of the data was performed by GLG, KSF, MBI, MP, FSM, BRK and DRJ. The drafting of the manuscript was undertaken by GLG, KSF, MP, FSM, AM, VE, VL, GK, CM, JKM, BRK, MBI, EJH, DM, SJM, BMF, KMS, SRH, GAR and DRJ. Critical revision of the manuscript was carried out by GLG, KSF, MP, FSM, AM, VE, VL, GK, CM, JKM, BRK, MBI, EJH, DM, GK, SJM, BMF, KMS, SRH, GAR and DLRJ. All authors approved the final version of the manuscript. BRK and DRJ are the guarantors of the hypobaric simulation study and DLRJ is the guarantor for the retrospective observational study. As such, BRK and DLRJ had full access to the respective data in the studies and take responsibility for the integrity of the data and the accuracy of the data analysis., (© 2024. The Author(s).)

Objectives: This article compares metabolic, pancreatic, and gut-derived hormone responses to isomaltulose ingestion, before versus during submaximal sustained exercise, in adults with type 1 diabetes (T1D) using automated insulin delivery systems., Methods: In a randomized, cross-over trial, eight participants with T1D being treated with automated insulin pumps (five females, age: 47 ± 16 years, BMI: 27.5 ± 3.8 kg·m 2 , diabetes duration: 23 ± 11 years, HbA1c: 8.3 ± 0.9 [67.5 ± 9.5]% [mmol/mol]) attended the laboratory on two separate occasions and consumed an isocaloric amount of isomaltulose as either (1) a single serving (0.75g CHO·kg -1 BM) with a 25% reduction in bolus insulin 90 min before 45 min of cycling (PEC) or (2) three separate isocaloric servings (0.25g CHO·kg -1 BM each) without bolus insulin during exercise (DEC). Plasma glucose (PG), gut incretins (GLP-1 and GIP), pancreatic glucagon, exogenous insulin, and whole-body fuel oxidation rates were determined. Data were treated via a two-way repeated measures ANOVA, with p ≤ 0.05 accepted as significant., Results: PG concentrations throughout exercise were higher and less variable with DEC compared to PEC. The exercise-induced change in PG was directionally divergent between trials (PEC: ∆ - 3.2 ± 1.2 mmol/L vs. DEC: ∆ + 1.7 ± 1.5 mmol/L, p < 0.001), changing at a rate of -0.07 ± 0.03 mmol/L/min with PEC and +0.04 ± 0.03 mmol/L/min with DEC ( p < 0.001 between conditions). Throughout the exercise period, GLP-1, GIP, glucagon, and total insulin concentrations were lower with DEC (all p ≤ 0.02). The oxidation rates of carbohydrates were lower ( p = 0.009) and of lipids were greater ( p = 0.014) with DEC compared to PEC., Conclusions: The consumption of smaller servings of isomaltulose during, rather than as a single isocaloric serving before, submaximal sustained exercise provided (i) a better glycemic protective effect, (ii) a lesser push on pancreatic and gut-mediated glucoregulatory hormones, and (iii) a lower reliance on whole-body carbohydrate oxidation. Such information serves to remind us of the potential importance of nutrition for modulating the metabolic fate of an acute bout of exercise and may help inform best practice guidelines for exercise management in the T1D-sphere.

Introduction: We describe the identification and management of general population screen-detected type 1 diabetes (T1D) and share learnings for best practice., Research Design and Methods: Children diagnosed with T1D through a general population screening initiative, the EarLy Surveillance for Autoimmune diabetes (ELSA) study, were reviewed and described.Parents provided written, informed consent for inclusion in the case series., Results: 14 children with insulin requiring (stage 3) T1D are described. These cases offer unique insights into the features of screen-detected T1D. T1D is identified sooner through screening programs, characterized by absent/short symptom duration, median presenting glycated hemoglobin 6.6% (49 mmol/mol) and insulin requirements<0.5 units/kg/day. ELSA identified four children at stage 3 and another 4 progressed within 4 months of ELSA completion, including two single seropositive children. Six children developed stage 3 T1D prior to ELSA completion, including two children (14%, n=2/14) with diabetic ketoacidosis prior to confirmed antibody status., Conclusions: There are three main learnings from this case series. First, T1D identified through screening is at an earlier stage of its natural history and requires personalized insulin regimens with lower total daily insulin doses. Second, single autoantibody seropositivity can rapidly progress to stage 3. Finally, insulin requirement can manifest at any stage of the T1D screening pathway, and therefore early education around symptom recognition is essential for families participating in screening programs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immunotherapy targeting the autoimmune process in type 1 diabetes (T1D) can delay the loss of β-cells but needs to have minimal adverse effects to be an adjunct to insulin in the management of T1D. Ustekinumab binds to the shared p40 subunit of interleukin (IL)-12 and IL-23, targeting development of T helper 1 cells and T helper 17 cells (T H 1 and T H 17 cells) implicated in the pathogenesis of T1D. We conducted a double-blind, randomized controlled trial of ustekinumab in 72 adolescents aged 12-18 years with recent-onset T1D. Treatment was well tolerated with no increase in adverse events. At 12 months, β-cell function, measured by stimulated C-peptide, was 49% higher in the intervention group (P = 0.02), meeting the prespecified primary outcome. Preservation of C-peptide correlated with the reduction of T helper cells co-secreting IL-17A and interferon-γ (T H 17.1 cells, P = 0.04) and, in particular, with the reduction in a subset of T H 17.1 cells co-expressing IL-2 and granulocyte-macrophage colony-stimulating factor (IL-2 + GM-CSF + T H 17.1 cells, P = 0.04). A significant fall in β-cell-targeted (proinsulin-specific) IL-17A-secreting T cells was also seen (P = 0.0003). Although exploratory, our data suggest a role for an activated subset of T H 17.1 cells in T1D that can be targeted with minimal adverse effects to reduce C-peptide loss, which requires confirmation in a larger study. (International Standard Randomised Controlled Trial Number Registry: ISRCTN 14274380)., (© 2024. The Author(s).)

Objective: We evaluated the effect of long-term intensive metabolic control with hybrid closed-loop (CL) on residual C-peptide secretion and glucose control compared with standard insulin therapy in youth with type 1 diabetes over 48 months., Research Design and Methods: Following the 24-month primary phase of a multicenter, randomized, parallel trial of 96 newly diagnosed youth aged 10 to 16.9 years, participants were invited to an extension phase using treatment allocated at randomization. They continued with hybrid CL using the Cambridge algorithm or standard insulin therapy (control) until 48 months after diagnosis. Analysis was by intention-to-treat., Results: At 24 months after diagnosis, 81 participants (mean ± SD age 14 ± 2 years) continued in the extension phase (47 CL, 34 control). There was no difference in fasting C-peptide corrected for fasting glucose at 48 months between groups (CL: 5 ± 9 vs. control: 6 ± 14 pmol/L per mmol/L; mean adjusted difference -2 [95% CI -7, 4; P = 0.54]). Central laboratory HbA1c remained lower in the CL group by 0.9% (10 mmol/mol [95% CI 0.2, 1.5; 3, 17 mmol/mol); P = 0.009). Time in target range of 3.9 to 10.0 mmol/L was 12 percentage points (95% CI 3, 20; P = 0.008) higher in the CL group compared with control. There were 11 severe hypoglycemic events (6 CL, 5 control) and 7 diabetic ketoacidosis events (3 CL, 4 control) during the extension phase., Conclusions: Improved glycemic control was sustained over 48 months after diagnosis with CL insulin delivery compared with standard therapy in youth with type 1 diabetes. This did not appear to confer a protective effect on residual C-peptide secretion., (© 2024 by the American Diabetes Association.)

Aim: To examine the effect of interrupting prolonged sitting with short, frequent, light-intensity activity on postprandial cardiovascular markers in people with type 1 diabetes (T1D)., Materials and Methods: In a randomized crossover trial, 32 adults with T1D (mean ± SD age 28 ± 5 years, glycated haemoglobin 67.9 ± 12.6 mmol/mol, 17 women) completed two 7-h laboratory visits separated by >7 days. Participants either remained seated for 7 h (SIT) or interrupted sitting with 3-min bouts of self-paced walking at 30-min intervals commencing 1 h after each meal (SIT-LESS). Physical activity, insulin regimen, experimental start times, and meal consumption were standardized during each arm. Plasma levels of interleukin (IL)-1β, tumour necrosis factor (TNF)-α, plasminogen activator inhibitor (PAI)-1 and fibrinogen were sampled at baseline, 3.5 and 7 h, and assessed for within- and between-group effects using a repeated measures ANOVA. The estimated glucose disposal rate was used to determine the insulin resistance status., Results: Vascular-inflammatory parameters were comparable between SIT and SIT-LESS at baseline (p > .05). TNF-α, IL-1β, PAI-1 and fibrinogen increased over time under SIT, whereas these rises were attenuated under SIT-LESS (p < .001). Specifically, over the 7 h under SIT, postprandial increases were detected in TNF-α, IL-1β, PAI-1 and fibrinogen (+67%, +49%, +49% and +62%, respectively; p < .001 for all). Conversely, the SIT-LESS group showed no change in IL-1β (-9%; p > .50), whereas reductions were observed in TNF-α, PAI-1 and fibrinogen (-22%, -42% and -44%, respectively; p < .001 for all). The intervention showed enhanced effects in insulin-resistant individuals with T1D., Conclusions: Interrupting prolonged sitting with light-intensity activity ameliorates postprandial increases in vascular-inflammatory markers in T1D., Trial Registration: The trial was prospectively registered (ISRCTN13641847)., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

The physical and psychological benefits of exercise are particularly pertinent to people with type 1 diabetes (T1D). The variability in subcutaneous insulin absorption and the delay in offset and onset in glucose lowering action impose limitations, given the rapidly varying insulin requirements with exercise. Simultaneously, there are challenges to glucose monitoring. Consequently, those with T1D are less likely to exercise because of concerns regarding glucose instability. While glucose control with exercise can be enhanced using automated insulin delivery (AID), all commercially available AID systems remain limited by the pharmacokinetics of subcutaneous insulin delivery. Although glycemic responses may vary with exercises of differing intensities and durations, the principles providing the foundation for guidelines include minimization of insulin on board before exercise commencement, judicious and timely carbohydrate supplementation, and when possible, a reduction in insulin delivered in anticipation of planned exercise. There is an increasing body of evidence in support of superior glucose control with AID over manual insulin dosing in people in T1D who wish to exercise. The MiniMed™ 780G AID system varies basal insulin delivery with superimposed automated correction boluses. It incorporates a temporary (elevated glucose) target of 8.3 mmol/L (150 mg/dL) and when it is functioning, the autocorrection boluses are stopped. As the device has recently become commercially available, there are limited data assessing glucose control with the MiniMed™ 780G under exercise conditions. Importantly, when exercise was planned and implemented within consensus guidelines, %time in range and %time below range targets were met. A practical approach to exercising with the device is provided with illustrative case studies. While there are limitations to spontaneity imposed on any AID device due to the pharmacokinetics associated with the subcutaneous delivery of current insulin formulations, the MiniMed™ 780G system provides people with T1D an excellent option for exercising safely if the appropriate strategies are implemented.

Aims: To evaluate real-world outcomes in people with Type 1 Diabetes (PwT1D) initiated on Omnipod DASH® Insulin Management System., Methods: Anonymized clinical data were submitted to a secure web-based tool within the National Health Service network. Hemoglobin A1c (HbA1c), sensor-derived glucometrics, total daily dose of insulin (TDD), and patient-reported outcome changes between baseline and follow-up were assessed. Individuals were classified to "new-to-pump" (switched from multiple daily injections) and "established-on-pump" (switched from a tethered insulin pump) groups., Results: 276 individuals from 11 centers [66.7 % female; 92 % White British; median age 41 years (IQR 20-50); diabetes duration 20 years (IQR 11-31); 49.3 % within "new-to-pump" group] were included. Baseline HbA1c was 8.0 ± 1.3 % (64 ± 14 mmol/mol). At follow-up [3 years (IQR 1.5-3.2)], HbA1c reduced by 0.3 % [(3 mmol/mol); p = 0.002] across the total population, 0.4 % [(5 mmol/mol); p = 0.001] in those "new-to-pump" and remained unchanged in those "established-on-pump". TDD decreased in the "new-to-pump" cohort (baseline:44.9 ± 21.0units vs follow-up:38.1 ± 15.4units, p = 0.002). Of those asked, 141/143 (98.6 %) stated Omnipod DASH had a positive impact on quality of life., Conclusions: Omnipod DASH was associated with improvements in HbA1c in PwT1D "new-to-pump" and maintained previous HbA1c levels in those "established-on-pump". User satisfaction in all groups and TDD reduction in those "new-to-pump" were reported., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

By reducing carbohydrate intake, people with type 1 diabetes may reduce fluctuations in blood glucose, but the evidence in this area is sparse. The aim of this study was to investigate glucose metrics during a one-week low-carbohydrate-high-fat (HF) and a low-carbohydrate-high-protein (HP) diet compared with an isocaloric high-carbohydrate (HC) diet. In a randomized, three-period cross-over study, twelve adults with insulin-pump-treated type 1 diabetes followed an HC (energy provided by carbohydrate: 48%, fat: 33%, protein: 19%), HF (19%, 62%, 19%), and an HP (19%, 57%, 24%) diet for one week. Glucose values were obtained during intervention periods using a Dexcom G6 continuous glucose monitoring system. Participant characteristics were: 33% females, median (range) age 50 (22-70) years, diabetes duration 25 (11-52) years, HbA1c 7.3 (5.5-8.3)% (57 (37-67) mmol/mol), and BMI 27.3 (21.3-35.9) kg/m 2 . Glycemic variability was lower with HF (30.5 ± 6.2%) and HP (30.0 ± 5.5%) compared with HC (34.5 ± 4.1%) (P HF-HC = 0.009, P HP-HC = 0.003). There was no difference between groups in mean glucose (HF: 8.7 ± 1.1, HP: 8.2 ± 1.0, HC: 8.7 ± 1.0 mmol/L, P Overall = 0.08). Time > 10.0 mmol/L was lower with HP (22.3 ± 11.8%) compared with HF (29.4 ± 12.1%) and HC (29.5 ± 13.4%) (P HF-HP = 0.037, P HC-HP = 0.037). In conclusion, a one-week HF and, specifically, an HP diet improved glucose metrics compared with an isocaloric HC diet.

Context: Current guidelines for exercise-related glucose management focus on reducing bolus and/or basal insulin doses and considering carbohydrate intake. Yet far less attention has been paid to the potential role of other macronutrients alongside carbohydrates on glucose dynamics around exercise., Objective: To investigate the effects of a low-carbohydrate-high-protein (LCHP) compared with a high-carbohydrate-low-protein (HCLP) pre-exercise meal on the metabolic, hormonal, and physiological responses to exercise in adults with insulin pump-treated type 1 diabetes., Methods: Fourteen adults (11 women, 3 men) with insulin pump-treated type 1 diabetes (median [range] HbA1c of 50 [43-59] mmol/mol (6.7% [6.1%-7.5%]), age of 49 [25-65] years, and body mass index of 24.0 [19.3-27.1] kg/m2) completed an unblinded, 2-arm, randomized, crossover study. Participants ingested isocaloric meals that were either LCHP (carbohydrate 21%, protein 52%, fat 27%) or HCLP (carbohydrate 52%, protein 21%, fat 27%) 90 minutes prior to undertaking 45 minutes of cycling at moderate intensity. Meal insulin bolus was dosed according to meal carbohydrate content but reduced by 25%. Basal insulin rates were reduced by 35% from meal ingestion to end of exercise., Results: Around exercise the coefficient of variability was lower during LCHP (LCHP: 14.5 ± 5.3 vs HCLP: 24.9 ± 7.7%, P = .001). Over exercise, LCHP was associated with a lesser drop (LCHP: Δ-1.49 ± 1.89 vs HCLP: Δ-3.78 ± 1.95 mmol/L, P = .001). Mean insulin concentration was 30% lower during exercise for LCHP compared with HCLP (LCHP: 25.5 ± 11.0 vs HCLP: 36.5 ± 15.9 mU/L, P < .001)., Conclusion: Ingesting a LCHP pre-exercise meal lowered plasma glucose variability around exercise and diminished the drop in plasma glucose over exercise., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: To examine the impact of interrupting prolonged sitting with frequent short bouts of light-intensity activity on glycaemic control in people with type 1 diabetes (T1D)., Materials and Methods: In total, 32 inactive adults with T1D [aged 27.9 ± 4.7 years, 15 men, diabetes duration 16.0 ± 6.9 years and glycated haemoglobin 8.4 ± 1.4% (68 ± 2.3 mmol/mol)] underwent two 7-h experimental conditions in a randomised crossover fashion with >7-day washout consisting of: uninterrupted sitting (SIT), or, interrupted sitting with 3-min bouts of self-paced walking at 30-min intervals (SIT-LESS). Standardised mixed-macronutrient meals were administered 3.5 h apart during each condition. Blinded continuous glucose monitoring captured interstitial glucose responses during the 7-h experimental period and for a further 48-h under free-living conditions., Results: SIT-LESS reduced total mean glucose (SIT 8.2 ± 2.6 vs. SIT-LESS 6.9 ± 1.7 mmol/L, p = .001) and increased time in range (3.9-10.0 mmol/L) by 13.7% (SIT 71.5 ± 9.5 vs. SIT-LESS 85.1 ± 7.1%, p = .002). Hyperglycaemia (>10.0 mmol/L) was reduced by 15.0% under SIT-LESS (SIT 24.2 ± 10.8 vs. SIT-LESS 9.2 ± 6.4%, p = .002), whereas hypoglycaemia exposure (<3.9 mmol/L) (SIT 4.6 ± 3.0 vs. SIT-LESS 6.0 ± 6.0%, p = .583) was comparable across conditions. SIT-LESS reduced glycaemic variability (coefficient of variation %) by 7.8% across the observation window (p = .021). These findings were consistent when assessing discrete time periods, with SIT-LESS improving experimental and free-living postprandial, whole-day and night-time glycaemic outcomes (p < .05)., Conclusions: Interrupting prolonged sitting with frequent short bouts of light-intensity activity improves acute postprandial and 48-h glycaemia in adults with T1D. This pragmatic strategy is an efficacious approach to reducing sedentariness and increasing physical activity levels without increasing risk of hypoglycaemia in T1D., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background and Aims: A preliminary study compared the use of continuous glucose monitoring (CGM) with the use of self-monitored blood glucose (SMBG) by aircraft pilots with insulin-treated diabetes in the United Kingdom, Ireland, and Austria, certified to fly commercial aircraft within the European Aviation Safety Agency ARA.MED.330 protocol. Methods: SMBG and simultaneous interstitial glucose measurements using CGM (Dexcom G6 ® ) were recorded during pre- and in-flight periods. Results: Eight male pilots (seven with type 1 diabetes and one with type 3c diabetes), median age of 48.5 years and median diabetes duration of 11.5 years, participated. The correlation coefficient ( R ) between 874 contemporaneously recorded SMBG and CGM values was 0.843, P  < 0.001. The mean glucose concentration was 8.78 mmol/L (standard deviation [SD] 0.67) using SMBG compared with 8.71 mmol/L (SD 0.85) recorded using CGM. The mean absolute relative difference was 9.39% (SD 3.12). Conclusions: CGM using Dexcom G6 systems is a credible alternative to SMBG for monitoring glucose levels when insulin-treated pilots fly commercial aircraft. The study was registered with Clinical Trials.gov NCT04395378.

Aims: To assess if the risk of all-cause mortality increases in people with type 1 diabetes (T1D) with increasing number of severe hypoglycaemia episodes requiring hospitalization., Materials and Methods: We conducted a national retrospective observational cohort study in people with T1D (diagnosed between 2000 and 2018). Clinical, comorbidity and demographic variables were assessed for impact on mortality for people with no, one, two and three or more episodes of severe hypoglycaemia requiring hospitalization. The time to death (all-cause mortality) from the timepoint of the last episode of severe hypoglycaemia was modelled using a parametric survival model., Results: A total of 8224 people had a T1D diagnosis in Wales during the study period. The mortality rate (95% confidence interval [CI]) was 6.9 (6.1-7.8) deaths/ 1000 person-years (crude) and 15.31 (13.3-17.63) deaths/ 1000 person-years (age-adjusted) for those with no occurrence of severe hypoglycaemia requiring hospitalization. For those with one episode of severe hypoglycaemia requiring hospitalization the mortality rate (95% CI) was 24.9 (21.0-29.6; crude) and 53.8 (44.6-64.7) deaths/ 1000 person-years (age-adjusted), for those with two episodes of severe hypoglycaemia requiring hospitalization it was 28.0 (23.1-34.0; crude) and 72.8 (59.2-89.5) deaths/ 1000 person-years (age-adjusted), and for those with three or more episodes of severe hypoglycaemia requiring hospitalization it was 33.5 (30.0-37.3; crude) and 86.3 (71.7-103.9) deaths/ 1000 person years (age-adjusted; P < 0.001). A parametric survival model showed that having two episodes of severe hypoglycaemia requiring hospitalization was the strongest predictor for time to death (accelerated failure time coefficient 0.073 [95% CI 0.009-0.565]), followed by having one episode of severe hypoglycaemia requiring hospitalization (0.126 [0.036-0.438]) and age at most recent episode of severe hypoglycaemia requiring hospitalization (0.917 [0.885-0.951])., Conclusions: The strongest predictor for time to death was having two or more episodes of severe hypoglycaemia requiring hospitalization., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To assess the effectiveness of an automated insulin delivery (AID) system around exercise in adults with type 1 diabetes (T1D). Methods: This was a three-period, randomized, crossover trial involving 10 adults with T1D (hemoglobin A1C; HbA 1c : 8.3% ± 0.6% [67 ± 6 mmol/mol]) using an AID system (MiniMed 780G; Medtronic USA). Participants performed 45 min of moderate intensity continuous exercise 90 min after consuming a carbohydrate-based meal using three strategies: (1) a 100% dose of bolus insulin with exercise announcement immediately at exercise onset "spontaneous exercise" (SE) or a 25% reduced dose of bolus insulin with exercise announcement either (2) 90 min (AE90) or (3) 45 min (AE45) before exercise. Venous-derived plasma glucose (PG) taken in 5 and 15 min intervals over a 3 h collection period was stratified into the percentage of time spent below (TBR [<3.9 mmol/L]), time in range (TIR [3.9-10 mmol/L]), and time above range (TAR [ > 10 mmol/L]). In instances of hypoglycemia, PG data were carried forward for the remainder of the visit. Results: Overall, TBR was greatest during SE (SE: 22.9 ± 22.2, AE90: 1.1 ± 1.9, AE45: 7.8% ± 10.3%, P  = 0.029). Hypoglycemia during exercise occurred in four participants in SE but one in both AE90 and AE45 ( ꭓ 2 [2] = 3.600, P  = 0.165). In the 1 h postexercise period, AE90 was associated with higher TIR (SE: 43.8 ± 49.6, AE90: 97.9 ± 5.9, AE45: 66.7% ± 34.5%, P  = 0.033), lower TBR (SE: 56.3 ± 49.6, AE90: 2.1 ± 5.9, AE45: 29.2% ± 36.5%, P  = 0.041) with the greatest source of discrepancy observed relative to SE. Conclusion: In adults using an AID system and undertaking postprandial exercise, a strategy involving both bolus insulin dose reduction and exercise announcement 90 min before commencing the activity may be most effective in minimizing dysglycemia. The study was registered as a clinical trial (Clinical Trials Register; NCT05134025).

In an in-patient switch study, 10 adults with type 1 diabetes (T1D) performed 45 min of moderate-intensity exercise on 2 occasions: (1) when using their usual insulin pump (UP) and (2) after transitioning to automated insulin delivery (AID) treatment (MiniMed™ 780G). Consensus glucose management guidelines for performing exercise were applied. Plasma glucose concentrations measured over a 3-h monitoring period were stratified into time below range (TBR, <3.9 mmol/L), time in range (TIR, 3.9-10.0 mmol/L), and time above range (TAR, >10.0 mmol/L). Overall, TBR (UP: 11 ± 21 vs. AID: 3% ± 10%, P  = 0.413), TIR (UP: 53 ± 27 vs. AID: 66% ± 39%, P  = 0.320), and TAR (UP: 37 ± 34 vs. AID: 31% ± 41%, P  = 0.604) were similar between arms. A proportionately low number of people experienced exercise-induced hypoglycemia (UP: n  = 2 vs. AID: n  = 1, P  = 1.00). In conclusion, switching to AID therapy did not alter patterns of glycemia around sustained moderate-intensity exercise in adults with T1D. Clinical Trial Registration number: NCT05133765.

Introduction: Despite therapeutic advances in the field of diabetes management since the discovery of insulin 100 years ago, there are still unmet clinical needs for people with type 1 diabetes mellitus (T1DM)., Areas Covered: Genetic testing and islet autoantibodies testing allow researchers to design prevention studies. This review discusses the emerging therapy for prevention of T1DM, disease modification therapy in early course of T1DM, and therapies and technologies for established T1DM. We focus on phase 2 clinical trials with promising results, thus avoiding the exhausted list of every new therapy for T1DM., Expert Opinion: Teplizumab has demonstrated potential as a preventative agent for individuals at risk prior to the onset of overt dysglycemia. However, these agents are not without side effects, and there are uncertainties on long-term safety. Technological advances have led a substantial influence on quality of life of people suffering from T1DM. There remains variation in uptake of new technologies across the globe. Novel insulins (ultra-long acting), oral insulin, and inhaled insulin attempt to narrow the gap of unmet needs. Islet cell transplant is another exciting field, and stem cell therapy might have potential to provide unlimited supply of islet cells.

Aims: To profile acute glycaemic dynamics during graded exercise testing (GXT) and explore the influence of glycaemic indicators on the physiological responses to GXT in adults with type 1 diabetes using insulin pump therapy., Methods: This was a retrospective analysis of pooled data from four clinical trials with identical GXT protocols. Data were obtained from 45 adults with type 1 diabetes using insulin pumps [(30 females); haemoglobin A1c 59.5 ± 0.5 mmol/mol (7.6 ± 1.0%); age 49.7 ± 13.0 years; diabetes duration 31.2 ± 13.5 years; V̇O 2peak 29.5 ± 8.0 ml/min/kg]. Integrated cardiopulmonary variables were collected continuously via spiroergometry. Plasma glucose was obtained every 3 min during GXT as well as the point of volitional exhaustion. Data were assessed via general linear modelling techniques with age and gender adjustment. Significance was accepted at p ≤ .05., Results: Despite increasing duration and intensity, plasma glucose concentrations remained similar to rest values (8.8 ± 2.3 mmol/L) throughout exercise (p = .419) with an overall change of +0.3 ± 1.1 mmol/L. Starting glycaemia bore no influence on subsequent GXT responses. Per 1% increment in haemoglobin A1c there was an associated decrease in V̇O 2peak of 3.8 ml/min/kg (p < .001) and power peak of 0.33 W/kg (p < .001) concomitant with attenuations in indices of peripheral oxygen extraction [(O 2 pulse) -1.2 ml/beat, p = .023]., Conclusion: In adults with long-standing type 1 diabetes using insulin pump therapy, circulating glucose remains stable during a graded incremental cycle test to volitional exhaustion. Glycaemic indicators are inversely associated with aerobic rate, oxygen economy and mechanical output across the exercise intensity spectrum. An appreciation of these nexuses may help guide appropriate decision making for optimal exercise management strategies., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Diabetes mellitus is a long-term chronicle disorder with a high prevalence rate worldwide. Continuous blood glucose and lifestyle monitoring enabled the control of blood glucose dynamics through machine learning applications using data created by various popular sensors. This survey aims to assess various classical time series, neural networks and state-of-the-art regression models based on a wide variety of machine learning techniques to predict blood glucose and hyper/hypoglycemia in Type 1 diabetic patients. The analysis covers blood glucose prediction modeling, regression, hyper/hypoglycemia alerts, diabetes diagnosis, monitoring, and management. However, the primary focus is on evaluating models for the prediction of Type 1 diabetes. A wide variety of machine learning algorithms have been explored to implement precision medicine by clinicians and provide patients with an early warning system. The automated pancreas may benefit from predictions and alerts of hyper and hypoglycemia., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aims: To explore the association between the use of glycaemic technologies and person-reported outcomes (PROs) in adults with type 1 diabetes (T1D)., Methods: We included T1D and technology publications reporting on PROs since 2014. Only randomised controlled trials and cohort studies that used validated PRO measures (PROMs) were considered., Results: T1D studies reported on a broad range of validated PROMs, mainly as secondary outcome measures. Most studies examined continuous glucose monitoring (CGM), intermittently scanned CGM (isCGM), and the role of continuous subcutaneous insulin infusion (CSII), including sensor-augmented CSII and closed loop systems. Generally, studies demonstrated a positive impact of technology on hypoglycaemia-specific and diabetes-specific PROs, including reduced fear of hypoglycaemia and diabetes distress, and greater satisfaction with diabetes treatment. In contrast, generic PROMs (including measures of health/functional status, emotional well-being, depressive symptoms, and sleep quality) were less likely to demonstrate improvements associated with the use of glycaemic technologies. Several studies showed contradictory findings, which may relate to study design, population and length of follow-up. Differences in PRO findings were apparent between randomised controlled trials and cohort studies, which may be due to different populations studied and/or disparity between trial and real-world conditions., Conclusions: PROs are usually assessed as secondary outcomes in glycaemic technology studies. Hypoglycaemia-specific and diabetes-specific, but not generic, PROs show the benefits of glycaemic technologies, and deserve a more central role in future studies as well as routine clinical care., (© 2022 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Objective: To quantify associations of educational outcomes with type 1 diabetes status and glycemic management (HbA1c)., Research Design and Methods: This was a record linkage study of schools and higher (college) education data sets linked to national diabetes audits. The population includes all Welsh children attending school between 2009 and 2016, yielding eight academic cohorts with attainment data, including 263,426 children without diabetes and 1,212 children diagnosed with type 1 diabetes. Outcomes include standardized educational attainment for those aged 16 years, higher education participation for those aged ≥18 years, and school absences among those aged 6-16 years., Results: Comparison between children with type 1 diabetes and children without diabetes showed no strong evidence of associations for student attainment (0.001 SD, 95% CI -0.047 to 0.049, P < 0.96, n = 1,212 vs. 263,426) or higher education entry rates (odds ratio 1.067, 95% CI 0.919-1.239, P < 0.39, n = 965 vs. 217,191), despite nine more sessions of absence from school annually (P < 0.0001). However, attainment in children in the most optimal HbA1c quintile was substantially better than for children without diabetes (0.267 SD, 95% CI 0.160-0.374, P < 0.001) while being worse than for children without diabetes in the least optimal quintile (-0.395 SD, 95% CI -0.504 to -0.287, P < 0.001). Attainment did not differ by duration of "exposure" to diabetes based on age at diagnosis., Conclusions: Despite more school absences, diabetes diagnosis is not associated with educational attainment or entry into higher education, although attainment does vary by HbA1c level, which may be explained in part (or wholly) by unobserved shared personal, family, or socioeconomic characteristics associated with both success in education and effective glycemic self-management., (© 2022 by the American Diabetes Association.)

Background: Hospital-acquired diabetic ketoacidosis (HADKA) can complicate hospital admission in people with type 1 diabetes (T1D) and type 2 diabetes (T2D). We aimed to determine the characteristics of such patients and the reasons for HADKA., Methods: A retrospective analysis of patients referred to diabetes services with HADKA at Morriston Hospital between January 2016 and January 2022 was undertaken. Patients that were included were admitted without diabetic ketoacidosis (DKA), were aged 18 years and over, and who subsequently developed DKA in hospital., Results: Twenty-five patients were included with a mean age of 65.2 years; nine (32.0%) were men, 13 (52.0%) had T1D and 12 (48.0%) had T2D. Patients had a mean pre-admission glycated haemoglobin of 84.7 mmol/mol, and 17 (68.0%) were insulin-treated. Most were admitted under medicine (n=14; 56.0%) and the remainder under surgery (n=11; 44.0%). More common reasons for HADKA were erroneous insulin administration (n=9; 36.0%), infection (n=7; 28.0%) and surgery (n=5; 20.0%).Five (20.0%) patients required intensive care admission, and the mean length of hospital stay was 42.6 days (range 2-173). Three (12.0%) patients died during the hospital admission., Conclusion: HADKA was identified in a significant number of patients at our hospital and was associated with significant mortality. Earlier recognition of ketonaemia and associated medication use may prevent HADKA and improve outcomes., (© Royal College of Physicians 2022. All rights reserved.)

Background: Whether improved glucose control with hybrid closed-loop therapy can preserve C-peptide secretion as compared with standard insulin therapy in persons with new-onset type 1 diabetes is unclear., Methods: In a multicenter, open-label, parallel-group, randomized trial, we assigned youths 10.0 to 16.9 years of age within 21 days after a diagnosis of type 1 diabetes to receive hybrid closed-loop therapy or standard insulin therapy (control) for 24 months. The primary end point was the area under the curve (AUC) for the plasma C-peptide level (after a mixed-meal tolerance test) at 12 months after diagnosis. The analysis was performed on an intention-to-treat basis., Results: A total of 97 participants (mean [±SD] age, 12±2 years) underwent randomization: 51 were assigned to receive closed-loop therapy and 46 to receive control therapy. The AUC for the C-peptide level at 12 months (primary end point) did not differ significantly between the two groups (geometric mean, 0.35 pmol per milliliter [interquartile range, 0.16 to 0.49] with closed-loop therapy and 0.46 pmol per milliliter [interquartile range, 0.22 to 0.69] with control therapy; mean adjusted difference, -0.06 pmol per milliliter [95% confidence interval {CI}, -0.14 to 0.03]). There was not a substantial between-group difference in the AUC for the C-peptide level at 24 months (geometric mean, 0.18 pmol per milliliter [interquartile range, 0.06 to 0.22] with closed-loop therapy and 0.24 pmol per milliliter [interquartile range, 0.05 to 0.30] with control therapy; mean adjusted difference, -0.04 pmol per milliliter [95% CI, -0.14 to 0.06]). The arithmetic mean glycated hemoglobin level was lower in the closed-loop group than in the control group by 4 mmol per mole (0.4 percentage points; 95% CI, 0 to 8 mmol per mole [0.0 to 0.7 percentage points]) at 12 months and by 11 mmol per mole (1.0 percentage points; 95% CI, 7 to 15 mmol per mole [0.5 to 1.5 percentage points]) at 24 months. Five cases of severe hypoglycemia occurred in the closed-loop group (in 3 participants), and one occurred in the control group; one case of diabetic ketoacidosis occurred in the closed-loop group., Conclusions: In youths with new-onset type 1 diabetes, intensive glucose control for 24 months did not appear to prevent the decline in residual C-peptide secretion. (Funded by the National Institute for Health and Care Research and others; CLOuD ClinicalTrials.gov number, NCT02871089.)., (Copyright © 2022 Massachusetts Medical Society.)

Although important for digestion and metabolism in repose, the healthy endocrine pancreas also plays a key role in facilitating energy transduction around physical exercise. During exercise, decrements in pancreatic β-cell mediated insulin release opposed by increments in α-cell glucagon secretion stand chief among the hierarchy of glucose-counterregulatory responses to decreasing plasma glucose levels. As a control hub for several major glucose regulatory hormones, the endogenous pancreas is therefore essential in ensuring glucose homeostasis. Type 1 diabetes (T1D) is pathophysiological condition characterised by a destruction of pancreatic β-cells resulting in pronounced aberrations in glucose control. Yet beyond the beta-cell perhaps less considered is the impact of T1D on all other pancreatic endocrine cell responses during exercise and whether they differ to those observed in healthy man. For physicians, understanding how the endocrine pancreas responds to exercise in people with and without T1D may serve as a useful model from which to identify whether there are clinically relevant adaptations that need consideration for glycaemic management. From a physiological perspective, delineating differences or indeed similarities in such responses may help inform appropriate exercise test interpretation and subsequent program prescription. With more complex advances in automated insulin delivery (AID) systems and emerging data on exercise algorithms, a timely update is warranted in our understanding of the endogenous endocrine pancreatic responses to physical exercise in people with and without T1D. By placing our focus here, we may be able to offer a nexus of better understanding between the clinical and engineering importance of AIDs requirements during physical exercise., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 McCarthy, Schmidt, Christensen, Bain, Nørgaard and Bracken.)

This study sought to detail and compare the in-ride nutritional practices of a group of professional cyclists with type 1 diabetes (T1D) under training and racing conditions. We observed seven male professional road cyclists with T1D (Age: 28 ± 4 years, HbA 1c : 6.4 ± 0.4% [46 ± 4 mmol.mol -1 ], VO 2max : 73.9 ± 4.3 ml.kg -1 .min -1 ) during pre-season training and during a Union Cycliste Internationale multi-stage road cycling race (Tour of Slovenia). In-ride nutritional, interstitial glucose, and performance variables were quantified and compared between the two events.    The in-ride energy intake was similar between training and racing conditions     ( p = 0.909), with carbohydrates being the major source of fuel in both events during exercise at a rate of 41.9 ± 6.8 g.h -1 and 45.4 ± 15.5 g.h -1 ( p = 0.548), respectively. Protein consumption was higher during training (2.6 ± 0.6 g.h -1 ) than race rides (1.9 ± 0.9 g.h -1 ; p = 0.051).   A similar amount of time was spent within the euglycaemic range (≥70-≤180 mg.dL -1 ): training 77.1 ± 32.8% vs racing 73.4 ± 3.9%; p = 0.818. These data provide new information on the in-ride nutritional intake in professional cyclists with T1D during different stages of the competitive season.

Objectives: The aim of this study was to assess the relationship between specific erythrocyte fatty acid levels and vascular health in type 1 diabetes (T1D) with and without insulin resistance (IR)., Methods: We analyzed baseline pretreatment data in a subset of 23 patients with T1D from a previously published randomized controlled trial consisting of comprehensive erythrocyte-derived fatty acid profiles and a panel of inflammation-associated endothelial markers. Estimated glucose disposal rate was used to identify and categorize patients with IR. We utilized principal component analysis (PCA) to cluster vascular biomarkers to compute a single "vascular signal" and utilized univariate linear regression models to investigate the association with IR and fatty acid profiles., Results: Subjects with IR displayed significantly higher levels of linoleic acid (p=0.001), lower levels of eicosapentaenoic acid (EPA) (p<0.001), lower levels of omega-3 polyunsaturated fatty acid (n-3PUFA) (p<0.006) and an increased omega-6 (n-6)PUFA:n-3PUFA ratio (p=0.001). IR was associated with significantly higher linoleic acid levels, total n-6PUFA and an increased ratio of n-6PUFA:n-3PUFA, and negatively associated with arachidonic acid and EPA levels, total saturated fatty acid and total n-3PUFA. The PCA-derived vascular biomarker cluster was positively associated with linoleic acid and n-6PUFA:n-3PUFA ratio, and inversely associated with EPA., Conclusions: Specific erythrocyte membrane fatty acid compositions are associated with impaired vascular health and IR in adults with T1D. These findings suggest that IR and risk of associated complications may be influenced by specific fatty acid profiles, and thus potentially modified by the selective targeting of dietary fatty acids., (Copyright © 2021 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to use a compositional analysis approach to account for the inherent co-dependencies between behaviors and to explore how daily movement behaviors influence cardiovascular health in children with and without T1D., Research Design and Methods: Augmentation index, pulse wave velocity (PWV) and heart rate variability were measured in 20 children with (11.9 ± 1.6 years) and 17 children without T1D (11.6 ± 2.2 years). Subsequently, physical activity and sleep were assessed at 20 Hz for 28 consecutive days using a wrist-worn accelerometer. Compositional analyses were utilized to explore the relative effects of each movement behavior and the overall movement complex on cardiovascular parameters, with predictive modeling used to explore the effects of reallocating 20 min between behaviors., Results: Arterial stiffness markers were most influenced by the total movement composition, whereas autonomic function was most influenced by sedentary time and sleep relative to all other behaviors. Reallocation of time from moderate-to-vigorous physical activity (MVPA) to any other behavior was predicted to negatively affect all cardiovascular measures, independent of disease status, whereas reallocating time to MVPA was consistently predicted to improve all outcome measures. Additionally, the same intensity of physical activity appeared to be more potent for cardiovascular health in T1D children compared to nondiabetic peers., Conclusions: Intensity, rather than volume, of physical activity may be key in reducing risk of premature adverse changes in cardiovascular health, whereas increasing time in MVPA could potentially the slow progression of cardiovascular aging in children with diabetes., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

After years of intensive investigation, the definition of glycaemic variability remains unclear and the term variability in glucose homoeostasis might be more appropriate covering both short and long-term glycaemic variability. For the latter, we remain in the search of an accurate definition and related targets. Recent work leads us to consider that the within-subject variability of HbA1c calculated from consecutive determinations of HbA1c at regular time-intervals could be the most relevant index for assessing the long-term variability with a threshold value of 5% (%CV = SD of HbA1c/mean HbA1c) to separate stability from lability of HbA1c. Presently, no one can deny that short- and long-term glucose variability should be maintained within their lower ranges to limit the incidence of hypoglycaemia. Usually, therapeutic strategies aimed at reducing post-meal glucose excursions, i.e. the major contributor to daily glucose fluctuations, exert a beneficial effect on the short-term glucose variability. This explains the effectiveness of adjunct therapies with either GLP- receptor agonists or SGLT inhibitors in type 2 diabetes. In type 1 diabetes, the application of a CGM device alone reduces the short-term glycaemic variability. In contrast, sophisticated insulin delivery does not necessarily lead to such reductions despite marked downward shifts of 24-hour glycaemic profiles. Such contrasting observations raise the question as to whether the prolonged wear of CGM devices is or not the major causative factor for improvement in glucose variability among intensively insulin-treated persons with type 1 diabetes., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Introduction: Most individuals newly diagnosed with type 1 diabetes (T1D) have 10%-20% of beta-cell function remaining at the time of diagnosis. Preservation of residual beta-cell function at diagnosis may improve glycaemic control and reduce longer-term complications.Immunotherapy has the potential to preserve endogenous beta-cell function and thereby improve metabolic control even in poorly compliant individuals. We propose to test ustekinumab (STELARA), a targeted and well-tolerated therapy that may halt T-cell and cytokine-mediated destruction of beta-cells in the pancreas at the time of diagnosis., Methods and Analysis: This is a double-blind phase II study to assess the safety and efficacy of ustekinumab in 72 children and adolescents aged 12-18 with new-onset T1D.Participants should have evidence of residual functioning beta-cells (serum C-peptide level >0.2nmol/L in the mixed-meal tolerance test (MMTT) and be positive for at least one islet autoantibody (GAD, IA-2, ZnT8) to be eligible.Participants will be given ustekinumab/placebo subcutaneously at weeks 0, 4 and 12, 20, 28, 36 and 44 in a dose depending on the body weight and will be followed for 12 months after dose 1.MMTTs will be used to measure the efficacy of ustekinumab for preserving C-peptide area under the curve at week 52 compared with placebo. Secondary objectives include further investigations into the efficacy and safety of ustekinumab, patient and parent questionnaires, alternative methods for measuring insulin production and exploratory mechanistic work., Ethics and Dissemination: This trial received research ethics approval from the Wales Research Ethics Committee 3 in September 2018 and began recruiting in December 2018.The results will be disseminated using highly accessed, peer-reviewed medical journals and presented at conferences., Trial Registration Number: ISRCTN14274380., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Objective: To determine the risk factors for having diabetic retinopathy (DR) in children and young people (CYP) with type 1 diabetes (T1DM) at first screening., Methods: Records from the Diabetes Eye Screening Wales (DESW) service for people in Wales, UK, with T1DM diagnosed under age 18 years were combined with other electronic health record (EHR) data in the Secure Anonymised Information Linkage (SAIL) Databank. Data close to the screening date were collected, and risk factors derived from multivariate, multinomial logistic regression modelling., Results: Data from 4172 persons, with median (lower quartile, upper quartile) age 16.3 (13.0, 22.3) years and duration of diabetes 6.6 (2.3, 12.3) years were analysed. 62.6% (n = 2613) had no DR, 26.7% (n = 1112) background DR, and 10.7% (n = 447) had referable DR (RDR). No RDR was observed under 19 years of age. Factors associated with an increased risk of DR were diabetes duration, elevated HbA 1c , and diastolic blood pressure. People diagnosed with T1DM at 12 years or older had an additional risk for each year they had diabetes compared to those diagnosed before age 12 controlling for the diabetes duration (odds ratios 1.23 and 1.34, respectively)., Conclusions: This study found that 37.4% of the study cohort had DR at first screening, the risk being greater the longer the duration of diabetes or higher the HbA 1c and diastolic blood pressure. In addition, people diagnosed at 12 years of age or over were more likely to have DR with each additional year with diabetes., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.)

Aims: To understand factors associated with repeat non-attendance at screening for diabetes-related retinopathy., Methods: Retrospective observational study using anonymised data from Diabetic Eye Screening Wales for people with a full history of screening invitations and attendances was linked with primary and secondary care records held in the Secure Anonymised Information Linkage Databank. Repeat non-attendance was defined as no record of attendance during any 36-month period despite three cycles of annual screening invitations. The associations between repeat non-attendance and potential risk factors were examined using multivariable logistic regression analysis, stratified according to type 1 and type 2 diabetes., Results: A total of 18% with type 1 diabetes (1146/6513) and 8% with type 2 diabetes (12,475/156,525) were repeat non-attenders. Participants attending their very first appointment were least likely to become repeat non-attenders [odds ratio (95% confidence interval)]: type 1 diabetes: 0.12 (0.09, 0.17) and type 2 diabetes: 0.08 (0.07, 0.09). For both types of diabetes, those of a younger age, living in areas of higher deprivation and subject to multiple house moves were at greater risk of becoming repeat non-attenders., Conclusion/interpretation: A more tailored approach is needed for the younger population, those living in areas of higher deprivation and/or undergoing multiple residential relocation and to ensure attendance at their initial appointment to minimise future repeat non-attendance., (© 2021 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Objectives: To evaluate the usefulness and effectiveness of a new structured education module for children with type 1 diabetes: S tructured E ducation R eassuring E mpowering N urturing (SEREN) 'Diabetes at Diagnosis'., Design: Retrospective questionnaire-based service evaluation., Setting: 12/14 paediatric diabetes centres across Wales took part., Participants: Children diagnosed with type 1 diabetes 1 year before (pre-SEREN group) and 1 year after the introduction of SEREN (post-SEREN group) were selected using a national diabetes register., Resource: 'Diabetes at Diagnosis' delivers structured education to empower children and families with self-management of type 1 diabetes., Evaluation: Primary outcomes were patient-reported effectiveness and user-friendliness of the educational resources and quality of life (PedsQL). Age-appropriate child and parent questionnaires were provided. Clinical outcomes included glycated haemoglobin (HbA1c) at 6 and 12 months, service engagement and diabetes-related hospital admissions in the first year., Results: 89/106 responded pre-SEREN and 108/115 post-SEREN, with no demographic differences at diagnosis. Parent scores for educational package evaluation significantly improved post-SEREN, with a non-significant trend towards improved results in children. PedsQL scores were similar. There was no change in HbA1c overall. Subgroup analyses at 12 months showed a trend towards a lower HbA1c in key stage 1-2 (62 vs 58 mmol/mol, p=0.06) and increased HbA1c in key stage 3-4 (56 vs 66 mmol/mol, p=0.009). There were no differences in hospital admissions or missed clinic appointments., Conclusions: This is an evaluation of the only standardised type 1 diabetes structured education programme in use for children throughout Wales. This module improved parent-reported outcomes and showed a non-significant trend towards improved usefulness in children, without a difference in a PedsQL scores overall. Ongoing evaluation of the cohort who received subsequent SEREN modules may show the long-term benefit of the programme., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: This study aimed to investigate the influence of residual β-cell function on counterregulatory hormonal responses to hypoglycemia during acute physical exercise in people with type 1 diabetes (T1D). A secondary aim was to explore relationships between biomarkers of pancreatic β-cell function and indices of glycemia following acute exercise including the nocturnal period., Methods: This study involved an exploratory, secondary analysis of data from individuals with T1D who partook in a four-peroid, randomized, cross-over trial involving a bout of evening exercise followed by an overnight stay in a clinical laboratory facility. Participants were split into two groups: (i) a stimulated C-peptide level of ≥30 pmol⋅L-1 (low-level secretors [LLS], n = 6) or (ii) <30 pmol⋅L-1 (microsecretors [MS], n = 10). Pancreatic hormones (C-peptide, proinsulin, and glucagon), catecholamines (epinephrine [EPI] and norepinephrine [NE]), and metabolic biomarkers (blood glucose, blood lactate, and β-hydroxybutyrate) were measured at rest, during exercise with and without a hypoglycemic (blood glucose ≤3.9 mmol⋅L-1) episode, and throughout a 13-h postexercise period. Interstitial glucose monitoring was used to assess indices of glycemic variability., Results: During in-exercise hypoglycemia, LLS presented with greater sympathoadrenal (EPI and NE P ≤ 0.05) and ketone (P < 0.01) concentrations. Glucagon remained similar (P = 0.09). Over exercise, LLS experienced larger drops in C-peptide and proinsulin (both P < 0.01) as well as greater increases in EPI (P < 0.01) and β-hydroxybutyrate (P = 0.03). LLS spent less time in the interstitial-derived hypoglycemic range acutely postexercise and had lower glucose variability throughout the nocturnal period., Conclusion: Higher residual β-cell function was associated with greater sympathoadrenal and ketonic responses to exercise-induced hypoglycemia as well as improved glycemia leading into and throughout the nocturnal hours. Even a minimal amount of residual β-cell function confers a beneficial effect on glycemic outcomes during and after exercise in people with T1D., (Copyright © 2021 by the American College of Sports Medicine.)

Purpose: This study aimed to determine the glycemic responses to cardiopulmonary exercise testing (CPET) in individuals with type 1 diabetes (T1D) and to explore the influence of starting blood glucose (BG) concentrations on subsequent CPET outcomes., Methods: This study was a retrospective, secondary analysis of pooled data from three randomized crossover trials using identical CPET protocols. During cycling, cardiopulmonary variables were measured continuously, with BG and lactate values obtained minutely via capillary earlobe sampling. Anaerobic threshold was determined using ventilatory parameters. Participants were split into (i) euglycemic ([Eu] >3.9 to ≤10.0 mmol·L-1, n = 26) and (ii) hyperglycemic ([Hyper] >10.0 mmol·L-1, n = 10) groups based on preexercise BG concentrations. Data were assessed via general linear modeling techniques and regression analyses. P values of ≤0.05 were accepted as significant., Results: Data from 36 individuals with T1D (HbA1c, 7.3% ± 1.1% [56.0 ± 11.5 mmol·mol-1]) were included. BG remained equivalent to preexercise concentrations throughout CPET, with an overall change in BG of -0.32 ± 1.43 mmol·L-1. Hyper had higher HR at peak (+10 ± 2 bpm, P = 0.04) and during recovery (+9 ± 2 bpm, P = 0.038) as well as lower O2 pulse during the cool down period (-1.6 ± 0.04 mL per beat, P = 0.021). BG responses were comparable between glycemic groups. Higher preexercise BG led to greater lactate formation during exercise. HbA1c was inversely related to time to exhaustion (r = -0.388, P = 0.04) as well as peak power output (r = -0.355, P = 0.006) and O2 pulse (r = -0.308, P = 0.015)., Conclusions: This study demonstrated 1) stable BG responses to CPET in patients with T1D; 2) although preexercise hyperglycemia did not influence subsequent glycemic dynamics, it did potentiate alterations in various cardiac and metabolic responses to CPET; and 3) HbA1c was a significant factor in the determination of peak performance outcomes during CPET., (Copyright © 2020 by the American College of Sports Medicine.)

Introduction: Studies of prevalence and the demographic profile of type 1 diabetes are challenging because of the relative rarity of the condition, however, these outcomes can be determined using routine healthcare data repositories. Understanding the epidemiology of type 1 diabetes allows for targeted interventions and care of this life-affecting condition., Objectives: To describe the prevalence, incidence and demographics of persons with type 1 diabetes diagnosed in Wales, UK, using the Secure Anonymised Information Linkage (SAIL) Databank., Methods: Data derived from primary and secondary care throughout Wales available in the SAIL Databank were used to identify people with type 1 diabetes to determine the prevalence and incidence of type 1 diabetes over a 10 year period (2008-18) and describe the demographic and clinical characteristics of this population by age, socioeconomic deprivation and settlement type. The seasonal variation in incidence rates was also examined., Results: The prevalence of type 1 diabetes in 2018 was 0.32% in the whole population, being greater in men compared to women (0.35% vs 0.28% respectively); highest in those aged 15-29 years (0.52%) and living in the most socioeconomically deprived areas (0.38%). The incidence of type 1 diabetes over 10 years was 14.0 cases/100,000 people/year for the whole population of Wales. It was highest in children aged 0-14 years (33.6 cases/100,000 people/year) and areas of high socioeconomic deprivation (16.8 cases/100,000 people/year) and least in those aged 45-60 years (6.5 cases/100,000 people/year) and in areas of low socioeconomic deprivation (11.63 cases/100,000 people/year). A seasonal trend in the diagnoses of type 1 diabetes was observed with higher incidence in winter months., Conclusion: This nation-wide retrospective epidemiological study using routine data revealed that the incidence of type 1 diabetes in Wales was greatest in those aged 0-14 years with a higher incidence and prevalence in the most deprived areas. These findings illustrate the need for health-related policies targeted at high deprivation areas to include type 1 diabetes in their remit., Competing Interests: Statement on conflicts of interest: None of the authors expressed any conflict of interest.

Background: Type 1 diabetes is characterised by progressive loss of functional β-cell mass, necessitating insulin treatment. We aimed to investigate the hypothesis that combining anti-interleukin (IL)-21 antibody (for low-grade and transient immunomodulation) with liraglutide (to improve β-cell function) could enable β-cell survival with a reduced risk of complications compared with traditional immunomodulation., Methods: This randomised, parallel-group, placebo-controlled, double-dummy, double-blind, phase 2 trial was done at 94 sites (university hospitals and medical centres) in 17 countries. Eligible participants were adults aged 18-45 years with recently diagnosed type 1 diabetes and residual β-cell function. Individuals with unstable type 1 diabetes (defined by an episode of severe diabetic ketoacidosis within 2 weeks of enrolment) or active or latent chronic infections were excluded. Participants were randomly assigned (1:1:1:1), with stratification by baseline stimulated peak C-peptide concentration (mixed-meal tolerance test [MMTT]), to the combination of anti-IL-21 and liraglutide, anti-IL-21 alone, liraglutide alone, or placebo, all as an adjunct to insulin. Investigators, participants, and funder personnel were masked throughout the treatment period. The primary outcome was the change in MMTT-stimulated C-peptide concentration at week 54 (end of treatment) relative to baseline, measured via the area under the concentration-time curve (AUC) over a 4 h period for the full analysis set (intention-to-treat population consisting of all participants who were randomly assigned). After treatment cessation, participants were followed up for an additional 26-week off-treatment observation period. This trial is registered with ClinicalTrials.gov, NCT02443155., Findings: Between Nov 10, 2015, and Feb 27, 2019, 553 adults were assessed for eligibility, of whom 308 were randomly assigned to receive either anti-IL-21 plus liraglutide, anti-IL-21, liraglutide, or placebo (77 assigned to each group). Compared with placebo (ratio to baseline 0·61, 39% decrease), the decrease in MMTT-stimulated C-peptide concentration from baseline to week 54 was significantly smaller with combination treatment (0·90, 10% decrease; estimated treatment ratio 1·48, 95% CI 1·16-1·89; p=0·0017), but not with anti-IL-21 alone (1·23, 0·97-1·57; p=0·093) or liraglutide alone (1·12, 0·87-1·42; p=0·38). Despite greater insulin use in the placebo group, the decrease in HbA 1c (a key secondary outcome) at week 54 was greater with all active treatments (-0·50 percentage points) than with placebo (-0·10 percentage points), although the differences versus placebo were not significant. The effects diminished upon treatment cessation. Changes in immune cell subsets across groups were transient and mild (<10% change over time). The most frequently reported adverse events included gastrointestinal disorders, in keeping with the known side-effect profile of liraglutide. The rate of hypoglycaemic events did not differ significantly between active treatment groups and placebo, with an exception of a lower rate in the liraglutide group than in the placebo group during the treatment period. No events of diabetic ketoacidosis were observed. One participant died while on liraglutide (considered unlikely to be related to trial treatment) in connection with three reported adverse events (hypoglycaemic coma, pneumonia, and brain oedema)., Interpretation: The combination of anti-IL-21 and liraglutide could preserve β-cell function in recently diagnosed type 1 diabetes. The efficacy of this combination appears to be similar to that seen in trials of other disease-modifying interventions in type 1 diabetes, but with a seemingly better safety profile. Efficacy and safety should be further evaluated in a phase 3 trial programme., Funding: Novo Nordisk., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

This review aims to address the issue of whether or not the newer metrics, developed for continuous glucose monitoring [real-time CGM (rtCGM), intermittently scanned CGM (isCGM)], enhance assessment of the "glucose tetrad": Ambient hyperglycaemia, short-term glycaemic variability, postprandial glucose excursions and hypoglycaemia. The ever-increasing number of metrics offered with rtCGM and isCGM includes intermediate-term indicators referred to as "time in range" (TIR), the time spent in the range of 70-180mg/dL (TIR 70-180); time spent above the range of 180mg/dL (TAR>180); and time spent below the range of 70mg/dL or 54mg/dL (TBR<70 or TBR<54). The former two values are strongly correlated with HbA1c levels and can therefore serve as short- or medium-term markers of ambient hyperglycaemia, depending on whether glucose sensors are worn over periods of several days or weeks, respectively, whereas the latter indices (TBR<70 or<54) are more relevant for capturing hypoglycaemic events and quantifying their magnitude and duration, in contrast to random spot testing with self-monitoring of blood glucose. Nevertheless, although analyses of 24h glucose profiles by CGM provide a highly valuable method for quantifying postprandial glucose excursions and short-term glycaemic variability, neither of these factors can be fully represented by such TIR metrics. Thus, other metrics are clearly needed for more comprehensive assessment of glucose homoeostasis., (Copyright © 2020. Published by Elsevier Masson SAS.)

Objective: Little is known about the role of physical activity accumulation in cardiovascular disease risk for children with type 1 diabetes. Improved insight to identify factors of influence in key health outcomes could be provided by considering the entire physical activity profile., Methods: Pulse wave velocity (PWV), augmentation index and heart rate variability (HRV) were assessed cross-sectionally in children with (n = 29, 12.1 ± 2.1 years) and without (n = 19, 12.1 ± 2.1 years) type 1 diabetes. Time spent sedentary and in each physical activity intensity, intensity gradient and average acceleration were derived from seven consecutive days of monitoring with wrist-worn accelerometry. Comparison between groups and influence of physical activity accumulation on cardiovascular metrics were explored with linear mixed models., Results: Diabetic children demonstrated a higher PWV and a greater volume of light physical activity (p < 0.01), a more negative intensity gradient (p < 0.01), a lower average acceleration and less time in bouted moderate-to-vigorous physical activity (MVPA; p < 0.05). Overall, intensity gradient was strongly correlated with average acceleration, MVPA and bouted MVPA (r 2 = 0.89, r 2 = 0.80, r 2 = 0.79, respectively; all p < 0.05), while average acceleration was correlated with MVPA and bouted MVPA (r 2 = 0.85, r 2 = 0.83, respectively; p < 0.05). Accounting for disease status, intensity gradient and average acceleration were significant predictors of HRV indices (p < 0.05) and PWV (p < 0.01, p < 0.05, respectively)., Conclusion: Overall, MVPA was most associated with central stiffness, highlighting the importance of meeting activity guidelines. Diabetic children demonstrated poorer cardiovascular health than their counterparts, likely attributable to a lower intensity and physical activity volume, identifying physical activity intensity as a key target for future interventions., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Diabetes in pregnancy is associated with preterm delivery, birthweight extremes, and increased rates of congenital anomaly, stillbirth, and neonatal death. We aimed to identify and compare modifiable risk factors associated with adverse pregnancy outcomes in women with type 1 diabetes and those with type 2 diabetes and to identify effective maternity clinics., Methods: In this national population-based cohort study, we used data for pregnancies among women with type 1 or type 2 diabetes collected in the first 5 years of the National Pregnancy in Diabetes audit across 172 maternity clinics in England, Wales, and the Isle of Man, UK. Data for obstetric complications (eg, preterm delivery [<37 weeks' gestation], large for gestational age [LGA] birthweight [>90th percentile]) and adverse pregnancy outcomes (congenital anomaly, stillbirth, neonatal death) were obtained for pregnancies completed between Jan 1, 2014, and Dec 31, 2018. We assessed associations between modifiable (eg, HbA 1c , BMI, pre-pregnancy care, maternity clinic) and non-modifiable risk factors (eg, age, ethnicity, deprivation, duration of type 1 diabetes) with pregnancy outcomes in women with type 1 diabetes compared with those with type 2 diabetes. We calculated associations between maternal factors and perinatal deaths using a regression model, including diabetes type and duration, maternal age, BMI, deprivation quintile, first trimester HbA 1c , preconception folic acid, potentially harmful medications, and third trimester HbA 1c ., Findings: Our dataset included 17 375 pregnancy outcomes in 15 290 pregnant women. 8690 (50·0%) of 17 375 pregnancies were in women with type 1 diabetes (median age at delivery 30 years [10-90th percentile 22-37], median duration of diabetes 13 years [3-25]) and 8685 (50·0%) were in women with type 2 diabetes (median age at delivery 34 years [27-41], median duration of diabetes 3 years [0-10]). The rates of preterm delivery (3325 [42·5%] of 7825 pregnancies among women with type 1 diabetes, 1825 [23·4%] of 7815 with type 2 diabetes; p<0·0001), and LGA birthweight (4095 [52·2%] of 7845 with type 1 diabetes, 2065 [26·2%] of 7885 with type 2 diabetes; p<0·0001) were higher in type 1 diabetes. The prevalence of congenital anomaly (among women with type 1 diabetes: 44·8 per 1000 livebirths, terminations, and fetal losses; among women with type 2 diabetes: 40·5 per 1000 livebirths, terminations, and fetal losses; p=0·17) and stillbirth (type 1 diabetes: 10·4 per 1000 livebirths and stillbirths; type 2 diabetes: 13·5 per 1000 livebirths and stillbirths; p=0·072) did not significantly differ between diabetes types, but rates of neonatal death were higher in mothers with type 2 diabetes than in those with type 1 diabetes (type 1 diabetes: 7·4 per 1000 livebirths; type 2 diabetes 11·2 per 1000 livebirths; p=0·013). Across the whole study population, independent risk factors for perinatal death (ie, stillbirth or neonatal death) were third trimester HbA 1c of 6·5% (48 mmol/mol) or higher (odds ratio 3·06 [95% CI 2·16-4·33] vs HbA 1c <6·5%), being in the highest deprivation quintile (2·29 [1·16-4·52] vs the lowest quintile), and having type 2 diabetes (1·65 [1·18-2·31] vs type 1 diabetes). Variations in HbA 1c and LGA birthweight were associated with maternal characteristics (age, diabetes duration, deprivation, BMI) without substantial differences between maternity clinics., Interpretation: Our data highlight persistent adverse pregnancy outcomes in women with type 1 or type 2 diabetes. Maternal glycaemia and BMI are the key modifiable risk factors. No maternity clinics were had appreciably better outcomes than any others, suggesting that health-care system changes are needed across all clinics., Funding: None., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aim: To explore the influence of clinical exercise trial participation on glycaemia and insulin therapy use in adults with type 1 diabetes (T1D). Research Design and Methods: This study involved a secondary analysis of data collected from 16 individuals with T1D who completed a randomized clinical trial consisting of 23-h in-patient phases with a 45-min evening bout of moderate intensity continuous exercise. Participants were switched from their usual basal-bolus therapy to ultra-long acting insulin degludec and rapid-acting insulin aspart as well as provided with unblinded interstitial flash-glucose monitoring systems. To assess the impact of clinical trial participation, weekly data obtained at the screening visit (pre-study involvement) were compared against those collated on the last experimental visit (post-study involvement). Interstitial glucose [iG] data were split into distinct glycaemic ranges and stratified into day (06:00-23:59) and night (00:00-05:59) time periods. A p -value of ≤ 0.05 was accepted for significance. Results: Following study completion, there were significant decreases in both the mean nocturnal iG concentration (Δ-0.9 ± 4.5 mmol.L -1 , p < 0.001) and the time spent in severe hyperglycaemia (Δ-7.2 ± 9.8%, p = 0.028) during the night-time period. The total daily (Δ-7.3 ± 8.4 IU, p = 0.003) and basal only (Δ-2.3 ± 3.8 IU, p = 0.033) insulin dose requirements were reduced over the course of study involvement. Conclusions: Participation in clinical research may foster improved nocturnal glycaemia and reduced insulin therapy use in people with T1D. Recognition of these outcomes may help encourage volunteers to partake in clinical research opportunities for improved diabetes-related health outcomes. Clinical Trial Registration: DRKS.de; DRKS00013509., Competing Interests: The authors declare that this study was funded by Novo Nordisk A/S as part of an investigator sponsored study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. OMc* has received a Zienkiewcz scholarship and travel grants from Novo Nordisk. OMo has received lecture fees from Medtronic, travel grants from Novo Nordisk A/S, Novo Nordisk AT, Novo Nordisk UK and Medtronic AT, research grants from Sêr Cymru II COFUND fellowship/European Union, Sanofi-Aventis, Novo Nordisk A/S, Novo Nordisk AT, Dexcom Inc., as well as material funding from Abbott Diabetes Care. ME has received a KESS2/European Social Fund scholarship and travel grants from Novo Nordisk A/S and Sanofi-Aventis. SB has received research grants (includes principal investigator, collaborator or consultant and pending grants as well as grants already received) from Health care and Research Wales (Welsh Government) and Novo Nordisk. He has received other research support from Healthcare and Research Wales (Welsh Government), honoraria from Novo Nordisk, Sanofi, Lilly, Boehringer Ingelheim and Merck, and has an ownership interest in Glycosmedia (diabetes on-line news service). RB reports having received honoraria, travel, and educational grant support from Boehringer-Ingelheim, Eli Lilly and Company, Novo Nordisk, and Sanofi-Aventis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 McCarthy, Deere, Eckstein, Pitt, Wellman, Bain, Moser and Bracken.)

Aim: To detail the extent and prevalence of post-exercise and nocturnal hypoglycemia following peri-exercise bolus insulin dose adjustments in individuals with type 1 diabetes (T1D) using multiple daily injections of insulins aspart (IAsp) and degludec (IDeg)., Methods and Results: Sixteen individuals with T1D, completed a single-centred, randomised, four-period crossover trial consisting of 23-h inpatient phases. Participants administered either a regular (100%) or reduced (50%) dose (100%; 5.1 ± 2.4, 50%; 2.6 ± 1.2 IU, p < 0.001) of individualised IAsp 1 h before and after 45-min of evening exercise at 60 ± 6% V̇O 2max . An unaltered dose of IDeg was administered in the morning. Metabolic, physiological and hormonal responses during exercise, recovery and nocturnal periods were characterised. The primary outcome was the number of trial day occurrences of hypoglycemia (venous blood glucose ≤ 3.9 mmol L - 1 ). Inclusion of a 50% IAsp dose reduction strategy prior to evening exercise reduced the occurrence of in-exercise hypoglycemia (p = 0.023). Mimicking this reductive strategy in the post-exercise period decreased risk of nocturnal hypoglycemia (p = 0.045). Combining this strategy to reflect reductions either side of exercise resulted in higher glucose concentrations in the acute post-exercise (p = 0.034), nocturnal (p = 0.001), and overall (p < 0.001) periods. Depth of hypoglycemia (p = 0.302), as well as ketonic and counter-regulatory hormonal profiles were similar., Conclusions: These findings demonstrate the glycemic safety of peri-exercise bolus dose reduction strategies in minimising the prevalence of acute and nocturnal hypoglycemia following evening exercise in people with T1D on MDI. Use of newer background insulins with current bolus insulins demonstrates efficacy and advances current recommendations for safe performance of exercise., Clinical Trials Register: DRKS00013509., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate physiological responses to cardiopulmonary exercise (CPX) testing in adults with type 1 diabetes compared with age-, sex-, and BMI-matched control participants without type 1 diabetes., Research Design and Methods: We compared results from CPX tests on a cycle ergometer in individuals with type 1 diabetes and control participants without type 1 diabetes. Parameters were peak and threshold variables of VO 2 , heart rate, and power output. Differences between groups were investigated through restricted maximum likelihood modeling and post hoc tests. Differences between groups were explained by stepwise linear regressions ( P < 0.05)., Results: Among 303 individuals with type 1 diabetes (age 33 [interquartile range 22; 43] years, 93 females, BMI 23.6 [22; 26] kg/m 2 , HbA 1c 6.9% [6.2; 7.7%] [52 (44; 61) mmol/mol]), VO 2peak (32.55 [26.49; 38.72] vs. 42.67 ± 10.44 mL/kg/min), peak heart rate (179 [170; 187] vs. 184 [175; 191] beats/min), and peak power (216 [171; 253] vs. 245 [200; 300] W) were lower compared with 308 control participants without type 1 diabetes (all P < 0.001). Individuals with type 1 diabetes displayed an impaired degree and direction of the heart rate-to-performance curve compared with control participants without type 1 diabetes (0.07 [-0.75; 1.09] vs. 0.66 [-0.28; 1.45]; P < 0.001). None of the exercise physiological responses were associated with HbA 1c in individuals with type 1 diabetes., Conclusions: Individuals with type 1 diabetes show altered responses to CPX testing, which cannot be explained by HbA 1c . Intriguingly, the participants in our cohort were people with recent-onset type 1 diabetes; heart rate dynamics were altered during CPX testing., (© 2020 by the American Diabetes Association.)

Objectives: Individuals with type 1 diabetes try to manage the risk of exercise-induced hypoglycemia by either pre-exercise/pre-meal bolus insulin dose reductions and/or consuming additional carbohydrates during exercise. Both strategies have proven to be effective in offsetting hypoglycemia, but it remains unclear which one is more beneficial. The aim of this study was to assess the efficacy of carbohydrate supplementation vs bolus insulin dose reduction in prevention of hypoglycemia during moderate-intensity exercise in those with type 1 diabetes., Methods: This investigation was a retrospective, controlled analysis of 2 independent clinical trials. All participants performed continuous, moderate-intensity cycle ergometer exercise for ∼45 minutes. Two therapy management groups and a control group were compared. Group A was supplemented with 15 to 30 g carbohydrates at a glycemic threshold of 7.0 mmol/L during exercise, group B reduced their individual bolus insulin dose by 50% with their last meal before exercise and group C served as a control., Results: No hypoglycemic events occurred in group A, whereas 4 events were recorded in groups B (p=0.02) and C (p=0.02)., Conclusions: Carbohydrate supplementation was superior to bolus insulin reduction for prevention of hypoglycemia during exercise in people with type 1 diabetes., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Physical exercise is an important component in the management of type 1 diabetes across the lifespan. Yet, acute exercise increases the risk of dysglycaemia, and the direction of glycaemic excursions depends, to some extent, on the intensity and duration of the type of exercise. Understandably, fear of hypoglycaemia is one of the strongest barriers to incorporating exercise into daily life. Risk of hypoglycaemia during and after exercise can be lowered when insulin-dose adjustments are made and/or additional carbohydrates are consumed. Glycaemic management during exercise has been made easier with continuous glucose monitoring (CGM) and intermittently scanned continuous glucose monitoring (isCGM) systems; however, because of the complexity of CGM and isCGM systems, both individuals with type 1 diabetes and their healthcare professionals may struggle with the interpretation of given information to maximise the technological potential for effective use around exercise (ie, before, during and after). This position statement highlights the recent advancements in CGM and isCGM technology, with a focus on the evidence base for their efficacy to sense glucose around exercise and adaptations in the use of these emerging tools, and updates the guidance for exercise in adults, children and adolescents with type 1 diabetes., (© 2020 The Authors. Pediatric Diabetes published by John Wiley & Sons Ltd.)

International charities and health care organizations advocate regular physical activity for health benefit in people with type 1 diabetes. Clinical expert and international diabetes organizations' position statements support the management of good glycemia during acute physical exercise by adjusting exogenous insulin and/or carbohydrate intake. Yet research has detailed, and patients frequently report, variable blood glucose responses following both the same physical exercise session and insulin to carbohydrate alteration. One important source of this variability is insulin delivery to the circulation. With modern insulin analogs, it is important to understand how different insulins, their delivery methods, and inherent physiological factors, influence the reproducibility of insulin absorption from the injection site into circulation. Furthermore, contrary to the adaptive pancreatic response to exercise in the person without diabetes, the physiological and metabolic shifts with exercise may increase circulating insulin concentrations that may contribute to exercise-related hyperinsulinemia and consequent hypoglycemia. Thus, a furthered understanding of factors underpinning insulin delivery may offer more confidence for healthcare professionals and patients when looking to improve management of glycemia around exercise., (Copyright © 2020 Pitt, McCarthy, Hoeg-Jensen, Wellman and Bracken.)

Aims: To assess insulin therapy, macronutrient intake and glycaemia in professional cyclists with type 1 diabetes (T1D) over a 5-day Union Cycliste Internationale road-cycle race., Material and Methods: In this prospective observational study, seven professional cyclists with T1D (age 28 ± 4 years, body mass index 20.9 ± 0.9 kg/m 2 , glycated haemoglobin concentration 56 ± 7 mmol/mol [7.3% ± 0.6%]) were monitored during a five-stage professional road cycling race. Real-time continuous glucose monitoring (rtCGM) data, smart insulin pen dose data and macronutrient intake were assessed by means of repeated-measure one-way ANOVA and post hoc testing. Associations between exercise physiological markers and rtCGM data, insulin doses and macronutrient intake were assessed via linear regression modelling (P ≤ 0.05)., Results: Bolus insulin dose was significantly reduced over the 5-day period (P = 0.03), while carbohydrate intake (P = 0.24) and basal insulin doses remained unchanged (P = 0.64). A higher mean previous-day race intensity was associated with a lower mean sensor glucose level (P = 0.03), less time above range level 2 (>13.9 mmol/L [250 mg/dL]; P = 0.05) and lower doses of bolus insulin (P = 0.04) on the subsequent day. No significant associations were found for any other glycaemic range and glycaemic variability (P > 0.05)., Conclusions: This is the first study to demonstrate the influence of previous-day race intensity on subsequent bolus insulin dose requirements in professional cyclists with T1D. These data may help inform therapeutic strategies to ensure safe exercise performance., (© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Introduction: This study sought to compare the metabolomic, hormonal and physiological responses to hypoglycemia versus euglycemia during exercise in adults with type 1 diabetes (T1D)., Research Design and Methods: Thirteen individuals with T1D (hemoglobin; 7.0%±1.3% (52.6±13.9 mmol/mol), age; 36±15 years, duration diabetes; 15±12 years) performed a maximum of 45 min submaximal exercise (60%±6% V̇O 2max ). Retrospectively identified exercise sessions that ended in hypoglycemia ((HypoEx) blood glucose (BG)≤3.9 mmol/L) were compared against a participant-matched euglycemic condition ((EuEx) BG≥4.0, BG≤10.0 mmol/L). Samples were compared for detailed physiological and hormonal parameters as well as metabolically profiled via large scale targeted ultra-high-performance liquid chromatography coupled to tandem mass spectrometry. Data were assessed using univariate and multivariate analysis techniques with false discovery rate adjustment. Significant results were considered at p≤0.05., Results: Cardiorespiratory and counterregulatory hormone responses, whole-body fuel use and perception of fatigue during exercise were similar under conditions of hypoglycemia and euglycemia (BG 3.5±0.3 vs 5.8±1.1 mmol/L, respectively p<0.001). HypoEx was associated with greater adenosine salvage pathway activity (5'-methylthioadenosine, p=0.023 and higher cysteine and methionine metabolism), increased utilization of glucogenic amino acids (glutamine, p=0.021, alanine, aspartate and glutamate metabolism and homoserine/threonine, p=0.045) and evidence of enhanced β-oxidation (lower carnitine p<0.001, higher long-chain acylcarnitines)., Conclusions: Exposure to acute hypoglycemia during exercise potentiates alterations in subclinical indices of metabolic stress at the level of the metabolome. However, the physiological responses induced by dynamic physical exercise may mask the symptomatic recognition of mild hypoglycemia during exercise in people with T1D, a potential clinical safety concern that reinforces the need for diligent glucose management., Trial Registration Number: DRKS00013509., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)