Type 1 diabetes (T1D) is a chronic condition caused by the immune destruction of the pancreatic beta cells. T1D has recognised asymptomatic pre-clinical stages, providing an opportunity for early diagnosis, education and treatment which may delay the onset of symptoms. The oral glucose tolerance test (OGTT) is the gold standard method to stage and monitor early-stage T1D, which can be poorly tolerated and may contribute to marked loss to follow-up. Our study aims to test the accuracy, feasibility, and acceptability of a capillary alternative (‘GTT@home’ test kit) to the gold standard OGTT. We will invite 45 children and young people (CYP) across the spectrum of glycaemia with or without diabetes, from established research platforms or clinical care, to have a standard 2-hour OGTT, with capillary samples collected alongside their venous samples, at 0 and 120 minutes. A subgroup (n=20) will also have 60-minute capillary and venous samples collected. We will also invite 45 CYP from established research platforms, who are known to have two or more islet autoantibodies and are not on insulin, to undergo a capillary OGTT at home, using the GTT@home kit. We will assess the agreement of capillary and venous glucose and measure diagnostic accuracy by calculating the sensitivity and specificity of capillary measures at established diagnostic thresholds (fasting [5.6 mmol/L, 7.0 mmol/L], 60 minutes post glucose load [11.1 mmol/L] and 120 minutes post glucose load [7.8 mmol/L and 11.1 mmol/L]), using venous glucose as the gold standard. These studies will inform our understanding of whether the GTT@home device can be used in CYP in routine clinical care.

Type 1 diabetes (T1D) is a chronic condition caused by the immune destruction of the pancreatic beta cells. T1D has recognised asymptomatic pre-clinical stages, providing an opportunity for early diagnosis, education and treatment which may delay the onset of symptoms. The oral glucose tolerance test (OGTT) is the gold standard method to stage and monitor early-stage T1D, which can be poorly tolerated and may contribute to marked loss to follow-up. Our study aims to test the accuracy, feasibility, and acceptability of a capillary alternative (‘GTT@home’ test kit) to the gold standard OGTT. We will invite 45 children and young people (CYP) across the spectrum of glycaemia with or without diabetes, from established research platforms or clinical care, to have a standard 2-hour OGTT, with capillary samples collected alongside their venous samples, at 0 and 120 minutes. A subgroup (n=20) will also have 60-minute capillary and venous samples collected. We will also invite 45 CYP from established research platforms, who are known to have two or more islet autoantibodies and are not on insulin, to undergo a capillary OGTT at home, using the GTT@home kit. We will assess the agreement of capillary and venous glucose and measure diagnostic accuracy by calculating the sensitivity and specificity of capillary measures at established diagnostic thresholds (fasting [5.6 mmol/L, 7.0 mmol/L], 60 minutes post glucose load [11.1 mmol/L] and 120 minutes post glucose load [7.8 mmol/L and 11.1 mmol/L]), using venous glucose as the gold standard. These studies will inform our understanding of whether the GTT@home device can be used in CYP in routine clinical care.

Background Type 1 diabetes is an autoimmune disease affecting over 400,000 children and adults in the United Kingdom for which currently the only available therapy is insulin. Objective(s) To determine the efficacy and safety of the monoclonal antibody ustekinumab targeting the interleukin 12/interleukin 23 immune pathway that generates T helper 1/T helper 17 T cells to slow down the autoimmune process and preserve beta cell production in type 1 diabetes. Design Randomised, double-blind, placebo-controlled, parallel-group phase II trial. Setting Paediatric and young adult diabetes clinics across 16 sites in the United Kingdom. Participants Newly diagnosed with type 1 diabetes and aged 12–18 years. Eligibility criteria Type 1 diabetes confirmed by islet autoantibody testing, within 100 days of first insulin injection, and with residual beta cell function (stimulated C-peptide level > 0.2 nmol/l). Interventions Ustekinumab at the highest approved doses or control (saline) subcutaneously at weeks 0, 4 and 12 and subsequently every 8 weeks to week 44 (seven doses). Main outcome measures Preservation of Mixed Meal Tolerance Test stimulated 2-hour insulin C-peptide area under the curve at week 52 as compared to control (saline) treatment by analysis of covariance adjusted for baseline parameters. Randomisation 2 : 1 Remote computerised randomisation with minimisation by age and baseline C-peptide groups. Blinding Blinding of participants, investigators, laboratory and trial staff. Numbers randomised Seventy-two participants were randomised, 60% male, 18% aged 16–18 years. Recruitment Two hundred and eight potentially eligible patients were approached, and 88 patients were screened. Four participants were lost to follow-up (6%). Four participants withdrew from the treatment but attended the primary end-point assessment. Numbers analysed Six participants were missing baseline data for the primary analysis. The final analysable sample was n = 62. Outcome Ustekinumab was associated with a 49% higher endogenous stimulated insulin production than control at week 52 after adjustments for baseline factors [geometric ratio of ustekinumab to control was 1.49 (95% confidence interval 1.08 to 2.06; p = 0.02)]. Secondary analyses showed no difference in C-peptide at week 28 suggesting that the effect was ‘late’ or ‘delayed’. Ancillary analysis showed a significant reduction in activated T helper 17.1 T cells ( p < 0.001) in the treatment group which was associated with C-peptide preservation from week 28 to week 52. Harms No severe adverse events were reported and there were no differences between ustekinumab and control groups in the proportion of participants overall experiencing mild (87% vs. 88%) or moderate (32% vs. 32%) events. Limitations Sensitivity analysis showed the primary end point to be robust to exclusion of small numbers of participants with some protocol deviations and extreme values in key covariates, but not to imputation of all missing data. Conclusions Ustekinumab appears to slow down the autoimmune process providing the first clinical trial evidence that interleukin 17-secreting T cells play a pathogenic role in type 1 diabetes. Alone, it is insufficient to halt the autoimmune process. Future work Replication of this result is ongoing in a trial with a similar design in Canada. If confirmed, consideration may be given to testing other drugs targeting the interleukin 17 pathway, using ustekinumab in combination with other agents or using it earlier in the disease pathway (preclinical disease) since it is so well tolerated and simple to use. Study registration Current Controlled Trials ISRCTN14274380. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 16/36/01) and is published in full in Efficacy and Mechanism Evaluation ; Vol. 12, No. 1. See the NIHR Funding and Awards website for further award information.

Advancing age and estrogen deficiency increases susceptibility of post-menopausal women (PMW) to abdominal obesity and manifestation of cardiometabolic disease. There is limited evidence on the effect of lifestyle interventions on adiposity markers within at-risk PMW. Therefore, this study aims to evaluates an 8-weeks of home-based, equipment-free, interval training (HEFIT) with or without Mediterranean-style diet (MD) on adiposity markers in physically inactive, postmenopausal women with overweight/obesity. Thirty PMW (56.7 ± 3.9 years, BMI: 30.5 ± 5.2 kg/m2) were randomly assigned to three groups: (i) Ex; HEFIT thrice weekly/week, (ii) EX + MD, or (iii) CTL; control. Visceral Adiposity Index (VAI), body weight, BMI, waist and hip circumference (WC; HC), visceral adipose tissue (VAT), total body fat percentage, leptin, and adiponectin were determined pre- and post-8-week intervention. There was no significant between group effect on VAI. Compared to CTL, a significant between group reduction was seen in weight, BMI, and WC in both EX and EX+D (p < 0.05). Leptin and adiponectin remained unchanged in all groups (p > 0.05). Adherence rates were 85% and 96% for EX and EX+MD, respectively, and 80% of EX+D of participants had optimal adherence to diet. Concluding HEFIT with or without dietary changes could improve adiposity in overweight/obese postmenopausal women.

INTRODUCTION:Gestational diabetes mellitus (GDM) is common in pregnancy and is increasing in prevalence. It is associated with an increased risk of maternal and perinatal complications if not diagnosed and managed early. Most guidelines suggest making a diagnosis of GDM using an oral glucose tolerance test (OGTT) between 24 and 28 weeks of pregnancy at which stage there still is an increased risk of complications. Increased beta-cell secretory product concentrations have been observed prior to changes in glycaemia and can potentially be used as an early marker to diagnose and assess risk of developing GDM. METHODS:The study was a prospective, longitudinal cohort study. OGTTs were carried out at visit one: 16-18 weeks and visit two: 24-28 weeks gestation in pregnant women with at least one risk factor for GDM [Body Mass Index >30 kg/m2, previous macrosomic baby (>4.5 kg), previous GDM, first degree relative with type 2 diabetes mellitus (T2DM)]. Blood sampling was performed at fasting, 30 min, 1 and 2 hours following a 75-g oral glucose load. Samples were analysed for glucose, total and intact proinsulin, insulin and C-peptide. Hormonal concentrations at visit 1 were compared between those that remained normal glucose tolerant (NGT) and those that progressed to GDM at visit 2 using receiver operator characteristic (ROC) area under the curve (AUC) to assess for discrimination between the two groups. RESULTS:Unfortunately, a smaller than planned sample size was recruited due to the start of COVID-19 pandemic midway through the study. 83 pregnant women had OGTT at visit 1. Of these, 12 reached the threshold for GDM at visit 1 and were excluded. In total, data from 66 patients were included for analysis (5 Did Not Attend). Visit 1 hormone comparisons were carried out between 51 who remained NGT and 15 who progressed to GDM at visit 2. There were no significant differences at each time point in ROC AUC between the two groups for total and intact proinsulin and insulin. However, there were significant differences observed in C-peptide ROC AUC at 30 (p=0.041) and 60 min (p=0.003) between the two groups. CONCLUSIONS:This study did not demonstrate significant increase in early proinsulin concentrations in patients that developed GDM. However, there were differences in C-peptide concentrations. The COVID-19 pandemic restricted the recruitment of patient numbers and further studies in a larger cohort will be needed to validate these findings. TRIAL REGISTRATION NUMBER:ISRCTN16416602.

Objective We evaluated the effect of long-term intensive metabolic control with hybrid closed‑loop on residual C-peptide secretion and glucose control compared to 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 either hybrid closed-loop using Cambridge algorithm (CL) or standard insulin therapy (control) until 48 months post-diagnosis. Analysis was by intention-to-treat. Results At 24-months post-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±14pmol/L per mmol/L; mean adjusted difference -2 [95% CI -7, 4; p=0.54]). Central lab HbA1c remained lower in the CL group by 0.9% [10mmol/mol] (95% CI 0.2, 1.5 [3, 17mmol/mol]; p=0.009). Time in target range 3.9 to 10.0mmol/L was 12 percentage points (95% CI 3, 20; p=0.008) higher in the CL group compared to control. Eleven severe hypoglycemic events (6 CL, 5 control) and seven DKA events (3 CL, 4 control) occurred during the extension phase. Conclusions Improved glycemic control was sustained over 48 months after diagnosis with closed‑loop insulin delivery compared to standard therapy in youth with type 1 diabetes. This did not appear to confer a protective effect on residual C-peptide secretion.

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 (TH1 and TH17 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 (TH17.1 cells, P = 0.04) and, in particular, with the reduction in a subset of TH17.1 cells co-expressing IL-2 and granulocyte-macrophage colony-stimulating factor (IL-2+ GM-CSF+ TH17.1 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 TH17.1 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).

Background: We compared the performance of three currently available laboratory benchtop glucose analyzers with the outgoing YSI 2300 Stat Plus. Methods: Plasma samples (100), across a wide glucose concentration range were analysed on the YSI 2500, Randox daytona+ (glucose oxidase) and EKF Biosen in a single laboratory and compared to the YSI 2300 Stat Plus. Results: All three analyzers showed good agreement with the YSI 2300 Stat Plus, and only a small bias (≤1% YSI 2500 and Randox daytona+, 4.6% EKF Biosen) was observed for each analyzer. None of the three comparator analyzers were affected by either proportional or constant bias, thus no significant differences between the YSI 2300 Stat Plus and the comparator methods were identified. Conclusions: The results from this study suggest all could be considered as suitable reference laboratory glucose analyzers and replacements for the recently withdrawn YSI 2300 Stat Plus.

Background: We evaluated the effect of long-term intensive metabolic control with hybrid closed loop on residual C-peptide secretion and glucose control compared to standard insulin therapy in youth with type 1 diabetes over 48 months. Methods: Following the 24 month primary phase of a multicentre, randomised, parallel trial of 96 newly diagnosed youth aged 10-16.9 years, participants entered an extension phase using either hybrid closed-loop with Cambridge algorithm (CL) or standard insulin therapy (control) until 48 months post diagnosis. Analysis was intention-to-treat. Results: At 24 months after diagnosis, 81 participants (mean±SD age 12±2 years) continued in the extension (47 CL). There was no difference in fasting C-peptide corrected for fasting glucose at 48 months between groups (CL: 0.3±0.5 vs control: 0.3±0.8pmol/L per mg/dL; mean adjusted difference ‑0.1 [95% CI ‑0.4, 0.2; p=0.54]). Central lab HbA1c remained lower in CL group by 10mmol/mol [0.9%] (95% CI 3, 17 [0.2, 1.5%]; p=0.01) at 48 months. Eleven severe hypoglycaemic events (6 CL, 5 control) and seven DKA occurred (3 CL, 4 control). Conclusions: Improved glycaemic control was sustained over 48 months after diagnosis with closed loop insulin delivery compared to standard therapy in youth with type 1 diabetes. This did not appear to confer a protective effect on residual C-peptide secretion. Disclosure J. Ware: Other Relationship; Novo Nordisk, Ypsomed AG. C.K. Boughton: Consultant; CamDiab. Speaker's Bureau; Ypsomed AG. J.M. Allen: None. M.E. Wilinska: Consultant; CamDiab. S. Hartnell: Speaker's Bureau; Ypsomed AG. Employee; CamDiab. A. Thankamony: None. T. Randell: Consultant; Abbott. Speaker's Bureau; Novo Nordisk. R. Besser: Advisory Panel; Provention Bio, Inc. Speaker's Bureau; Medscape, Health Partners Institute. A. Ghatak: None. D. Elleri: None. N. Trevelyan: None. F. Campbell: None. J. Sibayan: None. R. Bailey: None. P. Calhoun: None. G.J. Dunseath: None. R. Hovorka: Other Relationship; CamDiab. Research Support; Abbott, Dexcom, Inc., Ypsomed AG. Speaker's Bureau; Ypsomed AG, Abbott, Novo Nordisk, Novartis Pharmaceuticals Corporation. Funding NIHR EME (14/23/09); Helmsley Trust (2016PG-T1D045 and 2016PG-T1D046); JDRF (22-2013-266 and 2-RSC-2019-828-M-N); National Institute for Health Research Cambridge Biomedical Research Centre

Background We assessed whether a sustained period of intensive glucose control with hybrid closed-loop for 12 months following diagnosis of type 1 diabetes in children and adolescents can preserve C-peptide secretion compared to standard insulin therapy. Methods In an open-label, multicentre, randomised, parallel trial, youth aged 10–16.9 years were randomised within 21 days of type 1 diabetes diagnosis to hybrid closed-loop or standard insulin therapy (control). Primary end point was the difference in mixed-meal C-peptide area under the curve 12 months post diagnosis. Key secondary end points included time spent in target glucose range, glycated haemoglobin and time spent below target glucose range at 12 months. Analysis was by intention to treat. The Closed Loop from Onset in Type 1 Diabetes consortium secured external funding for participants to continue on beyond 12 months, but the funding by National Institute for Health and Care Research and the results reported here refer only to the 12 months follow-up. Results We randomised 97 participants (mean ± standard deviation age 12 ± 2 years), 51 to closed-loop and 46 to control therapy. There was no difference in C-peptide area under the curve at 12 months between groups [geometric mean (interquartile range) closed-loop (n = 46): 0.35 pmol/ml (0.16, 0.49) vs. control (n = 37): 0.46 pmol/ml (0.22, 0.69); mean adjusted difference –0.06 (95% confidence interval –0.14 to 0.03); p = 0.19]. The proportion of time in target range 3.9–10.0 mmol/l based on 14-day masked LibrePro (Abbott Diabetes Care, Maidenhead, UK) sensor glucose data at 12 months was 10 percentage points (95% confidence interval 2 to 17) higher in the closed-loop group (64 ± 14%) compared to control group (54 ± 23%). Arithmetic mean glycated haemoglobin A1c was lower in the closed-loop group by 4 mmol/mol (0.4%) [95% confidence interval 0 to 8 mmol/mol (0.0% to 0.7%)] at 12 months. The mean difference in time spent < 3.9 mmol/l between groups was 0.9 percentage points (95% confidence interval –1.0 to 2.8). Three severe hypoglycaemic events occurred in the closed-loop group (two participants), and one in the control group; one diabetic ketoacidosis occurred in the closed-loop group. Conclusions A sustained period of hybrid closed-loop glucose control following diagnosis of type 1 diabetes in children and adolescents does not slow down the decline in residual C-peptide secretion compared with standard insulin therapy. Despite the lack of effect on C-peptide, glycaemic control was sustained in the closed-loop group, whereas glycaemic control deteriorated in the control group 6 to 9 months after diagnosis and closed-loop safely accommodated the variability in exogenous insulin requirements which occur with beta-cell recovery post diagnosis. Limitations of the study included no central measurement of auto-antibodies at diagnosis. There was imbalance in the rate of diabetic ketoacidosis at diagnosis which is associated with a more rapid decline in C-peptide secretion, but this was adjusted for in the analyses. This highlights the need for improved therapies to allow youth to achieve recommended glycaemic targets from onset of type 1 diabetes irrespective of the lack of effect on residual C-peptide secretion. Future work includes ongoing follow-up of the study population for up to 4 years after diagnosis to observe how any differences in glycaemic control between treatment groups develop over time. Trial registration This trial is registered as Clinicaltrials.gov NCT02871089. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 14/23/09), the Helmsley Trust (2016PG-T1D045 and 2016PG-T1D046), and JDRF (22-2013-266 and 2-RSC-2019-828-M-N), and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 8. See the NIHR Funding and Awards website for further award information. Additional support for the artificial pancreas work was from the NIHR Cambridge Biomedical Research Centre and NIHR Oxford Biomedical Research Centre. Abbott Diabetes Care supplied free glucose monitoring devices, and Dexcom supplied discounted continuous glucose monitoring devices. Medtronic supplied discounted insulin pumps, phone enclosures, continuous glucose monitoring devices, and pump consumables.

Background: Self-monitoring of glucose is important to the successful management of diabetes; however, existing monitoring methods require a degree of invasive measurement which can be unpleasant for users. This study investigates the accuracy of a noninvasive glucose monitoring system that analyses spectral variations in microwave signals. Methods: An open-label, pilot design study was conducted with four cohorts (N = 5/cohort). In each session, a dial-resonating sensor (DRS) attached to the wrist automatically collected data every 60 seconds, with a novel artificial intelligence (AI) model converting signal resonance output to a glucose prediction. Plasma glucose was measured in venous blood samples every 5 minutes for Cohorts 1 to 3 and every 10 minutes for Cohort 4. Accuracy was evaluated by calculating the mean absolute relative difference (MARD) between the DRS and plasma glucose values. Results: Accurate plasma glucose predictions were obtained across all four cohorts using a random sampling procedure applied to the full four-cohort data set, with an average MARD of 10.3%. A statistical analysis demonstrates the quality of these predictions, with a surveillance error grid (SEG) plot indicating no data pairs falling into the high-risk zones. Conclusions: These findings show that MARD values approaching accuracies comparable to current commercial alternatives can be obtained from a multiparticipant pilot study with the application of AI. Microwave biosensors and AI models show promise for improving the accuracy and convenience of glucose monitoring systems for people with diabetes.

IntroductionResistant starch (RS) has beneficial effects on postprandial glucose metabolism in both animals and adults. Hitherto, there have been no studies in children of the acute metabolic and hormonal effects of RS-containing meals.ObjectivesWe aimed to compare serial plasma glucose, insulin, gut hormone, leptin profiles and satiety scores in obese children after meals containing variable amounts of RS.MethodsThis was a single blind, non-randomised, crossover study of 20 obese children aged 10–14 years old without comorbidities. Three test meals containing rice (M1), rice cooked with coconut oil (M2), rice cooked in coconut oil with lentils (M3) were given in sequence after a 12-hour fast . Blood samples were analysed for glucose (PG), insulin, leptin, glucagon-like polypeptide (GLP) 1, ghrelin and peptide YY (PYY) at appropriate times between 0 and 180 min.ResultsMeal M2 resulted in significantly lower postprandial glucose values compared with meal M1 (maximal incremental glucose, ∆Cmax, p<0.05; area under the curve, ∆AUC0–3, p<0.01) and meal M3 (maximal concentration, Cmax, p<0.01; ∆Cmax, p<0.001, and ∆AUC0–3p<0.01). M2 also produced lower insulin values compared with M1 (p<0.05). Postprandial ghrelin was significantly higher after M1 compared with M3 (p<0.05). PYY, GLP1 and median satiety scores were not significantly different between the three meals.ConclusionThis study shows that M2, the meal containing RS alone, induced beneficial effects on acute postprandial glucose, insulin and ghrelin concentrations in obese children without diabetes. Acute postprandial satiety scores were not significantly affected by the three meals.Trial registration numberSLCTR/2020/007.

Objectives: Cardiovascular disease (CVD) and associated risk factors within the prison population often present at a younger age in this cohort. Given CVD is largely preventable, it warrants investigation to fully quantify this risk. This study explored the relative predicted 10-year CVD risk and examined the calculated heart age in a representative sample of male individuals aged 25-84 years within the prison environment. Study design: This was a cross-sectional study. Methods: Data were collected on 299 men who underwent a cardiometabolic risk assessment in HMP Parc, Bridgend. The QRISK2 algorithm was used to calculate 10-year CVD risk, relative risk (to general population) and the predicted heart age of an individual. Between-group differences (prison population vs general community) in cardiovascular risk predictions (10-year CVD risk and heart age) were assessed. Results: We observed that at all age groups, the relative risk of predicted 10-year CVD scores in the prison population was double that of the community risk (2.1 +/- 0.6), and this was most apparent in the oldest age group (>= 50 years: 17.0% compared to 8.8%; P < 0.001). Overall, the heart age of the sample was 7.5 (6.7-8.2) years higher than their own chronological age, and this difference increased to above 9 years in those aged >= 40 years. Conclusions: This study provides quantifiable evidence to the elevated CVD risk in prison. Heart age predictions were almost a decade higher in those aged >= 40 years. Lowering the screening age for CVD by around 5 years in the prison population should be considered. (c) 2023 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.