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Introduction: While integrated care programs are proliferating around the world, rigorous measurement and evaluation of the intended and unintended effects of these programs are rare outside of the context of specific research programs. There are a number of reasons for the lack of evaluation including implementation without regard to measurement and evaluation, a lack of funding for evaluation activity, and challenges associated with measurement and evaluation in complex interventions. As a result, most research on integrated care is descriptive including case studies that most often summarize what was implemented, in some cases how it was implemented, but far less often what outcomes were achieved. Approach: We describe an evaluation framework for integrated care. It includes multiple components of evaluation (implementation, reporting and feedback, methods and measures) and a host of supplementary tools for measuring successful implementation of integrated care. The broad approach is to use rapid-cycle realist-informed evaluation methodology inclusive of implementation science, person-centred evaluation and comparative-effectiveness methodology. The approach to evaluation adds value and must be adaptable to local variations in models and organizational approaches to integrating care. Evaluation is framed into four components: Implementation: The evaluation of integrated care must first assess the implementation of new models of delivery, including description of the policy and organizational context of providers. Drawing from approaches taken including the Consolidated Framework for Implementation Research, evaluation is best begun parallel with the implementation of new models of integrated care allowing for early successes and challenges or barriers to be identified. Program operational monitoring: Second, programs themselves need to set out key measure of performance. A logic model for program implementation may be a particularly useful way to ensure that the program design will enable desired outcomes and ensure the essential component of the logic model are measured. Patient-centred assessment: The third major component of evaluation is patient-centred measurement including patient reported outcome and patient reported experience measures. Ultimately, patients themselves are the best target for measurement of integrated care. We will address essential domains for measurement of patient and caregiver outcomes and patient and caregiver experience. Outcome evaluation: Finally outcome evaluation is an essential activity. While the most rigorous form of outcome evaluation might involve experimental designs, the focus here is primarily on quasi-experimental approaches. Conclusion: This presentation describes a comprehensive framework for realist-informed rapid-cycle evaluations for integrated care programs. The framework is used to evaluate integrated care. Requirements for Implementation of Evaluation will also be discussed

Abstract Background Severe hypoglycaemia (SH) is one of the most feared complications of type 1 diabetes (T1DM) with a reported prevalence of nearly 40%. In randomized trials of Multiple Daily Injections (MDI) and Continuous Subcutaneous Insulin Infusion (CSII) therapy there is a possible benefit of CSII in reducing SH. However few trials have used basal insulin analogues as the basal insulin in the MDI group and individuals with established SH have often been excluded from prospective studies. In published studies investigating the effect of Real Time Continuous Glucose Monitoring (RT-CGM) benefit in terms of reduced SH has not yet been demonstrated. The primary objective of this study is to elucidate whether in people with T1DM complicated by impaired awareness of hypoglycaemia (IAH), rigorous prevention of biochemical hypoglycaemia using optimized existing self-management technology and educational support will restore awareness and reduce risk of recurrent SH. Methods/design This is a multicentre prospective RCT comparing hypoglycaemia avoidance with optimized MDI and CSII with or without RT-CGM in a 2×2 factorial design in people with type 1 diabetes who have IAH. The primary outcome measure for this study is the difference in IAH (Gold score) at 24 weeks. Secondary outcomes include biomedical measures such as HbA1c, SH incidence, blinded CGM analysis, self monitored blood glucose (SMBG) and response to hypoglycaemia in gold standard clamp studies. Psychosocial measures including well-being and quality of life will also be assessed using several validated and novel measures. Analysis will be on an intention-to-treat basis. Discussion Most existing RCTs using this study’s interventions have been powered for change in HbA1c rather than IAH or SH. This trial will demonstrate whether IAH can be reversed and SH prevented in people with T1DM in even those at highest risk by using optimized conventional management and existing technology. Trial Registration ISRCTN52164803 Eudract No: 2009-015396-27

Aims/hypothesis: We aimed to: (1) externally validate the five-item Hypoglycaemia Awareness Questionnaire (HypoA-Q) impaired awareness subscale (HypoA-Q IA); (2) examine how impaired awareness of hypoglycaemia (IAH) relates to the risk of severe hypoglycaemia and level 2 hypoglycaemia; and (3) identify factors associated with IAH., Methods: Nationwide survey of T1D Exchange registrants was conducted to collect data on demographics, 6 month severe-hypoglycaemia history, hypoglycaemia awareness status (via HypoA-Q IA, the Gold instrument and the Clarke instrument) and continuous glucose monitor (CGM) measures. The Clarke hypoglycaemia awareness factor (Clarke-HAF) was calculated to exclude severe-hypoglycaemia history items. Analyses included Cronbach's α, Spearman correlations and logistic regression., Results: Valid survey responses were collected from N=1580 adults with type 1 diabetes (median age, 44 years; 52% female participants; median HbA 1c , 48 mmol/mol [6.5%]). Of these, 94% of participants were using CGMs and 69% were using hybrid closed-loop (HCL) systems; 30% had at least one severe-hypoglycaemia episode in the past 6 months. The HypoA-Q IA had satisfactory internal reliability (α=0.79) and construct validity. Higher HypoA-Q IA scores were independently associated with greater risk of severe hypoglycaemia (p<0.001), performing comparably to the Gold instrument and the Clarke-HAF instrument. HypoA-Q IA-determined IAH was independently associated with 88% higher odds of developing severe hypoglycaemia (p<0.001) and twofold higher odds for spending ≥1% of time in level 2 hypoglycaemia (p=0.011). Higher age and longer diabetes duration were associated with higher IAH risk (p<0.001). CGM and HCL use was associated with lower IAH risk (p<0.001)., Conclusions/interpretation: The HypoA-Q IA is a brief, valid and reliable tool for assessing IAH in today's technology-oriented era. IAH was independently associated with severe hypoglycaemia and level 2 hypoglycaemia in a cohort with high prevalence of advanced diabetes technology use and HbA 1c within the recommended range. CGM and HCL use was related to lower IAH risk., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Management of type 1 diabetes (T1D) requires the use of insulin, which can cause hypoglycaemia (low blood glucose levels). While most hypoglycaemic episodes can be self-treated, all episodes can be sudden, inconvenient, challenging to prevent or manage, unpleasant and/or cause unwanted attention or embarrassment. Severe hypoglycaemic episodes, requiring assistance from others for recovery, are rare but potentially dangerous. Repeated exposure to hypoglycaemia can reduce classic warning symptoms ('awareness'), thereby increasing risk of severe episodes. Thus, fear of hypoglycaemia is common among adults with T1D and can have a negative impact on how they manage their diabetes, as well as on daily functioning, well-being and quality of life. While advances in glycaemic technologies and group-based psycho-educational programmes can reduce fear, frequency and impact of hypoglycaemia, they are not universally or freely available, nor do they fully resolve problematic hypoglycaemia or associated worries. This study aims to determine the effectiveness of a fully online, self-directed, scalable, psycho-educational intervention for reducing fear of hypoglycaemia: the Hypoglycaemia Prevention, Awareness of Symptoms, and Treatment (HypoPAST) programme., Methods: A 24-week, two-arm, parallel-group, hybrid type 1 randomised controlled trial, conducted remotely (online and telephone). Australian adults (≥ 18 years) with self-reported T1D and fear of hypoglycaemia will be recruited, and allocated at random (1:1) to HypoPAST or control (usual care). The primary outcome is the between-group difference in fear of hypoglycaemia (assessed using HFS-II Worry score) at 24 weeks. A sample size of N = 196 is required to detect a 9-point difference, with 90% power and allowing for 30% attrition. Multiple secondary outcomes include self-reported psychological, behavioural, biomedical, health economic, and process evaluation data. Data will be collected at baseline, 12 and 24 weeks using online surveys, 2-week ecological momentary assessments, website analytics and semi-structured interviews., Discussion: This study will provide evidence regarding the effectiveness, cost-effectiveness and acceptability of a novel, online psycho-educational programme: HypoPAST. Due to the fully online format, HypoPAST is expected to provide an inexpensive, convenient, accessible and scalable solution for reducing fear of hypoglycaemia among adults with T1D., Trial Registration: Australian and New Zealand Clinical Trials Registry (ANZCTR): ACTRN12623000894695 (21 August 2023)., (© 2024. The Author(s).)

Aims/hypothesis: The aim of this study was to investigate insulin secretion, insulin sensitivity, disposition index and insulin clearance by glucose tolerance status in individuals with cystic fibrosis (CF) and exocrine pancreatic insufficiency., Methods: In a cross-sectional study, we conducted an extended (ten samples) OGTT in individuals with pancreatic-insufficient CF (PI-CF). Participants were divided into normal glucose tolerance (NGT), early glucose intolerance (EGI), impaired glucose tolerance (IGT) and CF-related diabetes (CFRD) groups. We used three different oral minimal models to assess insulin secretion, insulin sensitivity and insulin clearance during the OGTT. We evaluated insulin secretion using total secretion (Φ total), first-phase secretion (Φ dynamic) and second-phase secretion (Φ static) from the model, and we estimated the disposition index by multiplying Φ total and insulin sensitivity., Results: Among 61 participants (NGT 21%, EGI 33%, IGT 16%, CFRD 30%), insulin secretion indices (Φ total, dynamic and static) were significantly lower in the CFRD group compared with the other groups. Insulin sensitivity declined with worsening in glucose tolerance (p value for trend <0.001) and the disposition index declined between NGT and EGI and between IGT and CFRD. Those with CFRD had elevated insulin clearance compared with NGT (p=0.019) and low insulin secretion (Φ total) was also associated with high insulin clearance (p<0.001)., Conclusions/interpretation: In individuals with PI-CF, disposition index declined with incremental impairment in glucose tolerance due to a reduction in both insulin secretion and insulin sensitivity. Moreover in CF, reduced insulin secretion was associated with higher insulin clearance., (© 2024. The Author(s).)

CF-related diabetes (CFRD) is a prevalent comorbidity in people with Cystic Fibrosis (CF), significantly impacting morbidity and mortality rates. This review article critically evaluates the current understanding of CFRD molecular mechanisms, including the role of CFTR protein, oxidative stress, unfolded protein response (UPR) and intracellular communication. CFRD manifests from a complex interplay between exocrine pancreatic damage and intrinsic endocrine dysfunction, further complicated by the deleterious effects of misfolded CFTR protein on insulin secretion and action. Studies indicate that ER stress and subsequent UPR activation play critical roles in both exocrine and endocrine pancreatic cell dysfunction, contributing to β-cell loss and insulin insufficiency. Additionally, oxidative stress and altered calcium flux, exacerbated by CFTR dysfunction, impair β-cell survival and function, highlighting the significance of antioxidant pathways in CFRD pathogenesis. Emerging evidence underscores the importance of exosomal microRNAs (miRNAs) in mediating inflammatory and stress responses, offering novel insights into CFRD's molecular landscape. Despite insulin therapy remaining the cornerstone of CFRD management, the variability in response to CFTR modulators underscores the need for personalized treatment approaches. The review advocates for further research into non-CFTR therapeutic targets, emphasizing the need to address the multifaceted pathophysiology of CFRD. Understanding the intricate mechanisms underlying CFRD will pave the way for innovative treatments, moving beyond insulin therapy to target the disease's root causes and improve the quality of life for individuals with CF., Competing Interests: Declaration of competing interest All 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 © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: The HypoCOMPaSS multi-centre trial achieved improvement in hypoglycaemia awareness and 20-fold reduction in severe hypoglycaemia (SH) in a cohort with long-standing type 1 diabetes (T1D). All participants received 'my hypo compass' (MHC) brief structured psycho-educational intervention in addition to optimisation of insulin delivery/glucose monitoring. In this 24-week, prospective, single-centre feasibility RCT, we piloted MHC as a sole intervention in comparison to standard clinical care alone (CON)., Methods: Participants with T1D and impaired hypoglycaemia awareness (IAH) (Clarke score ≥4) were recruited. MHC comprised a group/individual 1-2 h face-to-face session followed by a telephone call and second face-to-face session at 4 weeks. Outcome measures at 24 weeks were compared with baseline., Results: Fifty-two individuals provided consent for screening with 39 fulfilling eligibility criteria. Fifteen withdrew before any study intervention. Twenty-four adults with (mean ± SD) T1D duration 41.0 ± 15.1 years commenced/completed the study (100% visit attendance); 12 randomised to MHC and 12 to CON. All had IAH at baseline and at 24 weeks. Annualised SH rate following MHC was 3.8 ± 19.0 (24 weeks) versus 12.6 ± 3.5 (Baseline) and in CON group 2.0 ± 19.0 (24 weeks) versus 4.6 ± 11.5 (Baseline). 'Immediate Action' for and 'Worry' about hyperglycaemia measured by the Hyperglycaemia Avoidance Scale appeared lower following MHC. Participants attended all study visits and reflected positively on the MHC intervention., Conclusions: Feasibility of MHC implementation without additional intervention has been demonstrated. MHC education was associated with positive changes in attitudes and behaviours with the potential to reduce SH risk. MHC provides a validated, simple, well-received programme to fulfil the educational component within RCTs targeting problematic hypoglycaemia and as part of holistic clinical care., (© 2024 The Author(s). Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Aims: Impaired awareness of hypoglycaemia (IAH) increases the risk of severe hypoglycaemia in people with type 1 diabetes mellitus (T1DM). IAH can be reversed through meticulous avoidance of hypoglycaemia. Diabetic autonomic neuropathy (DAN) has been proposed as an underlying mechanism contributing to IAH; however, data are inconsistent. The aim of this study was to examine the effects of cardiac autonomic neuropathy (CAN) on IAH reversibility inT1DM., Methods: Participants with T1DM and IAH (Gold score ≥4) recruited to the HypoCOMPaSS (24-week 2 × 2 factorial randomised controlled) trial were included. All underwent screening for cardiac autonomic function testing at baseline and received comparable education and support aimed at avoiding hypoglycaemia and improving hypoglycaemia awareness. Definite CAN was defined as the presence of ≥2 abnormal cardiac reflex tests. Participants were grouped according to their CAN status, and changes in Gold score were compared., Results: Eighty-three participants (52 women [62.7%]) were included with mean age (SD) of 48 (12) years and mean HbA1c of 66 (13) mmol/mol (8.2 [3.3] %). The mean duration of T1DM was 29 (13) years. The prevalence of CAN was low with 5/83 (6%) participants having definite autonomic neuropathy with 11 (13%) classified with possible/early neuropathy. All participants, regardless of the autonomic function status, showed a mean improvement in Gold score of ≥1 (mean improvement -1.2 [95% CI -0.8, -1.6]; p < 0.001)., Conclusions: IAH can be improved in people with T1DM, and a long duration of disease, with and without cardiac autonomic dysfunction. These data suggest that CAN is not a prime driver for modulating IAH reversibility., (© 2024 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Intra-islet crosstalk has become a focus area to fully understand the regulation of insulin secretion and impaired β-cell function in type 2 diabetes (T2D). Here, we put forward evidence for insulin-like growth factor binding protein 7 (IGFBP7) as a potential protein involved in autocrine and paracrine β-cell regulation. We showed presence of IGFBP7 in granules of both human α- and β-cells and measured elevated gene expression as well as IGFBP7 protein in T2D. Insulin secretion was reduced in human islets, and the human β-cell line EndoC-βH1, after 72-h incubation with IGFBP7. Mechanistically reduced insulin secretion by IGFBP7 is attributed to reduced p21-activated kinase 1 (PAK1) protein, and decreased oxygen consumption and ATP-production. Knockdown of IGFBP7 in EndoC-βH1 cells verified reduced IGFBP7 levels in the medium, as well as improved insulin secretion. Finally, IGFBP7 knockdown in islets from T2D donors improved insulin secretion, making IGFBP7 a potential drug target in diabetes., Competing Interests: The authors declare no relationships or activities related to personal gain, financial or otherwise, that are in a conflict of interest with this work., (© 2024 The Author(s).)

Competing Interests: The authors declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: Severe hypoglycemia is a common and feared complication of medications used to lower blood glucose levels in individuals with diabetes. Psychoeducational interventions can prevent severe hypoglycemia in individuals with type 1 diabetes (T1D). We aim to determine the effectiveness of this approach among adults with type 2 diabetes (T2D) at elevated risk for severe hypoglycemia., Methods: Preventing Hypoglycemia in Type 2 diabetes (PHT2) is a two-arm, parallel, randomized controlled trial. Participants are eligible if they are adults with T2D receiving care at an integrated group practice in Washington state and have experienced one or more episodes of severe hypoglycemia in the prior 12 months or have impaired awareness of hypoglycemia (Gold score ≥ 4). Participants are randomized to proactive nurse care management with or without my hypo compass, an evidence-based, psychoeducational intervention combining group and individual self-management training. For this study, my hypo compass was adapted to be suitable for adults with T2D and from an in-person to a virtual intervention over videoconference and telephone. The primary outcome is any self-reported severe hypoglycemia in the 12 months following the start of the intervention. Secondary outcomes include biochemical measures of hypoglycemia, self-reported hypoglycemia awareness, fear of hypoglycemia, and emergency department visits and hospitalizations for severe hypoglycemia. The study includes a process evaluation to assess implementation fidelity and clarify the causal pathway., Conclusion: The PHT2 trial will compare the effectiveness of two approaches for reducing severe hypoglycemia in adults with T2D., Trial Registration: clinicaltrials.gov, # NCT04863872., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. JDR reported receiving grants from National Institutes of Health (NIH) and Agency for Healthcare Research and Quality (AHRQ). AJK reported receiving grants from NIH (R01 AG063391; P30 DK092924; R01 DK134446), PCORI (CDR-2019C1–16,126), the Leona M and Harry B Helmsley Charitable Trust outside the submitted work. JAMS reported receiving honoraria for consultancy with Mogrify and grants from the Cystic Fibrosis Trust and the Medical Research Council. The research group of JSp (ACBRD) has received unrestricted educational grants from Abbott Diabetes Care, Medtronic, and Sanofi Diabetes; sponsorship to host, attend, or present at educational meetings from Lilly, Medtronic, Merck Sharp & Dohme, Novo Nordisk, Roche Diabetes Care, and Sanofi Diabetes; and consultancy income from Abbott Diabetes Care, AstraZeneca, Insulet, Roche Diabetes Care, and Sanofi Diabetes. JSp owns the copyright of the HypoA-Q., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: To determine the frequency, severity, burden, and utility of hypoglycaemia symptoms among adults with type 1 diabetes (T1D) and impaired awareness of hypoglycaemia (IAH) at baseline and week 24 following the HypoCOMPaSS awareness restoration intervention., Methods: Adults (N = 96) with T1D (duration: 29 ± 12 years; 64% women) and IAH completed the Hypoglycaemia Burden Questionnaire (HypoB-Q), assessing experience of 20 pre-specified hypoglycaemia symptoms, at baseline and week 24., Results: At baseline, 93 (97%) participants experienced at least one symptom (mean ± SD 10.6 ± 4.6 symptoms). The proportion recognising each specific symptom ranged from 15% to 83%. At 24 weeks, symptom severity and burden appear reduced, and utility increased., Conclusions: Adults with T1D and IAH experience a range of hypoglycaemia symptoms. Perceptions of symptom burden or utility are malleable. Although larger scale studies are needed to confirm, these findings suggest that changing the salience of the symptomatic response may be more important in recovering protection from hypoglycaemia through regained awareness than intensifying symptom frequency or severity., (© 2023 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Background: Donor hyperglycaemia following brain death has been attributed to reversible insulin resistance. However, our islet and pancreas transplant data suggest that other mechanisms may be predominant. We aimed to determine the relationships between donor insulin use and markers of beta-cell death and beta-cell function in pancreas donors after brain death., Methods: In pancreas donors after brain death, we compared clinical and biochemical data in 'insulin-treated' and 'not insulin-treated donors' (IT vs. not-IT). We measured plasma glucose, C-peptide and levels of circulating unmethylated insulin gene promoter cell-free DNA (INS-cfDNA) and microRNA-375 (miR-375), as measures of beta-cell death. Relationships between markers of beta-cell death and islet isolation outcomes and post-transplant function were also evaluated., Results: Of 92 pancreas donors, 40 (43%) required insulin. Glycaemic control and beta-cell function were significantly poorer in IT donors versus not-IT donors [median (IQR) peak glucose: 8 (7-11) vs. 6 (6-8) mmol/L, p = .016; C-peptide: 3280 (3159-3386) vs. 3195 (2868-3386) pmol/L, p = .046]. IT donors had significantly higher levels of INS-cfDNA [35 (18-52) vs. 30 (8-51) copies/ml, p = .035] and miR-375 [1.050 (0.19-1.95) vs. 0.73 (0.32-1.10) copies/nl, p = .05]. Circulating donor miR-375 was highly predictive of recipient islet graft failure at 3 months [adjusted receiver operator curve (SE) = 0.813 (0.149)]., Conclusions: In pancreas donors, hyperglycaemia requiring IT is strongly associated with beta-cell death. This provides an explanation for the relationship of donor IT with post-transplant beta-cell dysfunction in transplant recipients., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

The field of transplantation has witnessed the emergence of Advanced Therapy Medicinal Products (ATMPs) as highly promising solutions to address the challenges associated with organ and tissue transplantation. ATMPs encompass gene therapy, cell therapy, and tissue-engineered products, hold immense potential for breakthroughs in overcoming the obstacles of rejection and the limited availability of donor organs. However, the development and academic research access to ATMPs face significant bottlenecks that hinder progress. This opinion paper emphasizes the importance of addressing bottlenecks in the development and academic research access to ATMPs by implementing several key strategies. These include the establishment of streamlined regulatory processes, securing increased funding for ATMP research, fostering collaborations and partnerships, setting up centralized ATMP facilities, and actively engaging with patient groups. Advocacy at the policy level is essential to provide support for the development and accessibility of ATMPs, thereby driving advancements in transplantation and enhancing patient outcomes. By adopting these strategies, the field of transplantation can pave the way for the introduction of innovative and efficacious ATMP therapies, while simultaneously fostering a nurturing environment for academic research., Competing Interests: Authors MM, KP-K, and PK were employed by Kugelmeiers Ltd. 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 © 2023 Piemonti, Scholz, de Jongh, Kerr-Conte, van Apeldoorn, Shaw, Engelse, Bunnik, Mühlemann, Pal-Kutas, Scott, Magalon, Kugelmeier and Berishvili.)

Associations between islet graft function and well-being in islet transplant recipients requiring exogenous insulin remain unclear. This cross-sectional analysis compared person-reported outcome measures in 15 adults with type 1 diabetes whose islet transplants were classified according to Igls criteria as "Good" ( n = 5), "Marginal" ( n = 4) and "Failed" ( n = 6) graft function. At a mean of 6.2 years post-first islet transplant, 90% reduction in severe hypoglycaemia was maintained in all groups, with HbA1c (mean ± SD mmol/mol) 49 ± 4 in recipients with "Good" function; 56 ± 5 ("Marginal"); and 69 ± 25 ("Failed"). Self-reported impaired awareness of hypoglycaemia persisted in all groups but those with "Good" function were more likely to experience symptoms during hypoglycaemia. "Marginal" function was associated with greater fear of hypoglycaemia (HFS-II score: "Marginal": 113 [95, 119]; "Failed": 63 [42, 93] ( p = 0.082); "Good": 33 [29, 61]) and severe anxiety (GAD7: "Marginal"): 21 [17, 21]; "Failed": 6 [6, 6] "Good": 6 [3, 11]; ( p = 0.079)), diabetes distress and low mood. Despite clear evidence of ongoing clinical benefit, Igls criteria 'Marginal' function is associated with sub-optimal well-being, including greater fear of hypoglycaemia and severe anxiety. This study provides person-reported validation that "Good" and "Marginal" graft function are differentiated by general and diabetes-specific subjective well-being, suggesting those with "Marginal" function may benefit from further intervention, including re-transplantation., Competing Interests: JSp has served on advisory boards for Janssen, Medtronic, Omnipod, Roche Diabetes Care, and Sanofi Diabetes; received unrestricted educational grants and in-kind support from Abbott Diabetes Care, AstraZeneca, Medtronic, Roche Diabetes Care, and Sanofi Diabetes; received sponsorship to attend educational meetings from Medtronic, Roche Diabetes Care and Sanofi Diabetes, and consultancy income or speaker fees from Abbott Diabetes Care, AstraZeneca, Insulet, Medtronic, Novo Nordisk, Roche Diabetes Care and Sanofi Diabetes. In all cases, JSp’s research group (ACBRD) has been the beneficiary. JAMS has served on an Advisory Board for Mogrify. 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 © 2023 Bond, Malik, Bashir, Stocker, Buckingham, Speight and Shaw.)

Aims: The purpose of the study was to further elucidate the pathophysiology of cystic fibrosis (CF)-related diabetes (CFRD) and potential drivers of hypoglycaemia. Hence, we aimed to describe and compare beta cell function (insulin and proinsulin) and alpha cell function (glucagon) in relation to glucose tolerance in adults with CF and to study whether hypoglycaemia following oral glucose challenge may represent an early sign of islet cell impairment., Methods: Adults with CF (≥18 years) were included in a cross-sectional study using an extended (-10, -1, 10, 20, 30, 45, 60, 90, 120, 150, and 180 min) or a standard (-1, 30, 60, and 120 min) oral glucose tolerance test (OGTT). Participants were classified according to glucose tolerance status and hypoglycaemia was defined as 3-hour glucose <3.9 mmol/L in those with normal glucose tolerance (NGT) and early glucose intolerance (EGI)., Results: Among 93 participants, 67 underwent an extended OGTT. In addition to worsening in insulin secretion, the progression to CFRD was associated with signs of beta cell stress, as the fasting proinsulin-to-insulin ratio incrementally increased (p-value for trend=0.013). The maximum proinsulin level (pmol/L) was positively associated with the nadir glucagon, as nadir glucagon increased 6.2% (95% confidence interval: 1.4-11.3%) for each unit increase in proinsulin. Those with hypoglycaemia had higher 60-min glucose, 120-min C-peptide, and 180-min glucagon levels (27.8% [11.3-46.7%], 42.9% [5.9-92.85%], and 80.3% [14.9-182.9%], respectively) and unaltered proinsulin-to-insulin ratio compared to those without hypoglycaemia., Conclusions: The maximum proinsulin concentration was positively associated with nadir glucagon during the OGTT, suggesting that beta cell stress is associated with abnormal alpha cell function in adults with CF. In addition, hypoglycaemia seemed to be explained by a temporal mismatch between glucose and insulin levels rather than by an impaired glucagon response., Competing Interests: Author TA holds stocks in the company Novo Nordisk. 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 © 2023 Nielsen, Mathiesen, Møller, Krogh-Madsen, Katzenstein, Pressler, Shaw, Ritz, Rickels, Stefanovski, Almdal and Faurholt-Jepsen.)

Aims/hypothesis: The aims of this study were to assess cognitions relating to hypoglycaemia in adults with type 1 diabetes and impaired awareness of hypoglycaemia before and after the multimodal HypoCOMPaSS intervention, and to determine cognitive predictors of incomplete response (one or more severe hypoglycaemic episodes over 24 months)., Methods: This analysis included 91 adults with type 1 diabetes and impaired awareness of hypoglycaemia who completed the Attitudes to Awareness of Hypoglycaemia (A2A) questionnaire before, 24 weeks and 24 months after the intervention, which comprised a short psycho-educational programme with optimisation of insulin therapy and glucose monitoring., Results: The age and diabetes duration of the participants were 48±12 and 29±12 years, respectively (mean±SD). At baseline, 91% reported one or more severe hypoglycaemic episodes over the preceding 12 months; this decreased to <20% at 24 weeks and after 24 months (p=0.001). The attitudinal barrier 'hyperglycaemia avoidance prioritised' (η 2 p =0.250, p=0.001) decreased from baseline to 24 weeks, and this decrease was maintained at 24 months (mean±SD=5.3±0.3 vs 4.3±0.3 vs 4.0±0.3). The decrease in 'asymptomatic hypoglycaemia normalised' from baseline (η 2 p =0.113, p=0.045) was significant at 24 weeks (1.5±0.3 vs 0.8±0.2). Predictors of incomplete hypoglycaemia response (one or more further episodes of severe hypoglycaemia) were higher baseline rates of severe hypoglycaemia, higher baseline scores for 'asymptomatic hypoglycaemia normalised', reduced change in 'asymptomatic hypoglycaemia normalised' scores at 24 weeks, and lower baseline 'hypoglycaemia concern minimised' scores (all p<0.05)., Conclusions/interpretation: Participation in the HypoCOMPaSS RCT was associated with improvements in hypoglycaemia-associated cognitions, with 'hyperglycaemia avoidance prioritised' most prevalent. Incomplete prevention of subsequent severe hypoglycaemia episodes was associated with persistence of the cognition 'asymptomatic hypoglycaemia normalised'. Understanding and addressing cognitive barriers to hypoglycaemia avoidance is important in individuals prone to severe hypoglycaemia episodes., Clinical Trials Registration: www.isrctn.org : ISRCTN52164803 and https://eudract.ema.europa.eu : EudraCT2009-015396-27., (© 2022. The Author(s).)

Appropriate glucose-stimulated insulin secretion (GSIS) by pancreatic β-cells is an essential component of blood glucose homeostasis. Configuration of β-cells as 3D pseudoislets (PI) improves the GSIS response compared to 2D monolayer (ML) culture. The aim of this study was to determine the underlying mechanisms. MIN6 β-cells were grown as ML or PI for 5 days. Human islets were isolated from patients without diabetes. Function was assessed by GSIS and metabolic capacity using the Seahorse bioanalyser. Connexin 36 was downregulated using inducible shRNA. Culturing MIN6 as PI improved GSIS. MIN6 PI showed higher glucose-stimulated oxygen consumption (OCR) and extracellular acidification (ECAR) rates. Further analysis showed the higher ECAR was, at least in part, a consequence of increased glycolysis. Intact human islets also showed glucose-stimulated increases in both OCR and ECAR rates, although the latter was smaller in magnitude compared to MIN6 PI. The higher rates of glucose-stimulated ATP production in MIN6 PI were consistent with increased enzyme activity of key glycolytic and TCA cycle enzymes. There was no impact of connexin 36 knockdown on GSIS or ATP production. Configuration of β-cells as PI improves GSIS by increasing the metabolic capacity of the cells, allowing higher ATP production in response to glucose.

Aims: Many individuals with type 1 diabetes retain residual β-cell function, with increased endogenous insulin secretion associated with reduced hyperglycaemia, hypoglycaemia and glycaemic variability. However, it is unknown when these improvements occur during the day. Dysglycaemia is common in overnight and postprandial periods and associated with diabetes complications. Therefore, this study aimed to determine the influence of residual β-cell function upon nocturnal and postprandial glycaemic control in established type 1 diabetes., Methods: Under free-living conditions, 66 participants wore a blinded continuous glucose monitor (CGM), kept a food diary, and completed a stimulated urine C-peptide creatinine (UCPCR) test. Nocturnal, and postprandial CGM outcomes (participant means and discrete event analysis) were compared between UCPCR groups: undetectable (Cpep und ), low (Cpep low : 0.001-0.19 nmol/mmol) and high (Cpep high : ≥0.2 nmol/mmol)., Results: Greater β-cell function was associated with incremental improvements in glycaemia. Cpep high spent significantly greater time in normoglycaemia than Cpep und overnight (76 ± 20% vs. 58 ± 20%, p = 0.005) and 0-300 mins postprandially (68 ± 22% vs. 51 ± 22%, p = 0.045), while also having reducing nocturnal variability (SD 1.12 ± 0.41 vs. 1.52 ± 0.43 mmol/L, p = 0.010). Analysis of individual events, controlling for diabetes duration, BMI, basal insulin, use of a continuous or flash glucose monitor and (for postprandial) meal type, carbohydrate and bolus insulin intake, replicated the group findings, additionally demonstrating Cpep und had increased hyperglycaemia versus Cpep low overnight and increased postprandial hypoglycaemic events compared with Cpep high . For all participants, breakfast had a significantly higher incremental area under the curve than lunch and dinner., Conclusions: Residual β-cell function is associated with improved nocturnal and postprandial glycaemic control. These data may be of clinical importance for identifying specific periods and individuals where further glycaemic management strategies would be beneficial., (© 2022 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

The UK islet allotransplant program is nationally funded to deliver one or two transplants over 12 months to individuals with type 1 diabetes and recurrent severe hypoglycemia. Analyses were undertaken 10 years after program inception to evaluate associations between transplanted mass; single versus two transplants; time between two transplants and graft survival (stimulated C-peptide >50 pmol/L) and function. In total, 84 islet transplant recipients were studied. Uninterrupted graft survival over 12 months was attained in 23 (68%) single and 47 (94%) (p = .002) two transplant recipients (separated by [median (IQR)] 6 (3-8) months). 64% recipients of one or two transplants with uninterrupted function at 12 months sustained graft function at 6 years. Total transplanted mass was associated with Mixed Meal Tolerance Test stimulated C-peptide at 12 months (p < .01). Despite 1.9-fold greater transplanted mass in recipients of two versus one islet infusion (12 218 [9291-15 417] vs. 6442 [5156-7639] IEQ/kg; p < .0001), stimulated C-peptide was not significantly higher. Shorter time between transplants was associated with greater insulin dose reduction at 12 months (beta -0.35; p = .02). Graft survival over the first 12 months was greater in recipients of two versus one islet transplant in the UK program, although function at 1 and 6 years was comparable. Minimizing the interval between 2 islet infusions may maximize cumulative impact on graft function., (© 2021 The Authors. American Journal of Transplantation published by Wiley periodicals LLC on behalf of the The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Pancreas and islet transplantation outcomes are negatively impacted by injury to the endocrine cells from acute stress during donor death, organ procurement, processing, and transplant procedures. Here, we report a novel electron microscopy scoring system, the Newcastle Pancreas Endocrine Stress Score (NPESS)., Methods: NPESS was adapted and expanded from our previously validated method for scoring pancreatic exocrine acinar cells, yielding a 4-point scale (0-3) classifying ultrastructural pathology in endocrine cell nuclei, mitochondria, endoplasmic reticulum, cytoplasmic vacuolization, and secretory granule depletion, with a maximum additive score of 15. We applied NPESS in a cohort of deceased organ donors after brainstem (DBD) and circulatory (DCD) death with a wide range of cold ischemic times (3.6-35.9 h) including 3 donors with type 1 and 3 with type 2 diabetes to assess islets in situ (n = 30) in addition to pancreata (n = 3) pre- and postislet isolation., Results: In DBD pancreata, NPESS correlated with cold ischemic time (head: r = 0.55; P  = 0.02) and mirrored exocrine score (r = 0.48; P  = 0.01). When stratified by endocrine phenotype, cells with granules of heterogeneous morphology had higher scores than α, β, and δ cells ( P  < 0.0001). Cells of mixed endocrine-exocrine morphology were observed in association with increased NPESS ( P  = 0.02). Islet isolation was associated with improved NPESS (in situ: 8.39 ± 0.77 [Mean ± SD]; postisolation: 5.44 ± 0.31; P  = 0.04)., Conclusions: NPESS provides a robust method for semiquantitative scoring of subcellular ultrastructural changes in human pancreatic endocrine cells in situ and following islet isolation with utility for unbiased evaluation of acute stress in organ transplantation research., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Type 1 diabetes is characterised by autoimmune-mediated destruction of pancreatic β-cell mass. With the advent of insulin therapy a century ago, type 1 diabetes changed from a progressive, fatal disease to one that requires lifelong complex self-management. Replacing the lost β-cell mass through transplantation has proven successful, but limited donor supply and need for lifelong immunosuppression restricts widespread use. In this Review, we highlight incremental advances over the past 20 years and remaining challenges in regenerative medicine approaches to restoring β-cell mass and function in type 1 diabetes. We begin by summarising the role of endocrine islets in glucose homoeostasis and how this is altered in disease. We then discuss the potential regenerative capacity of the remaining islet cells and the utility of stem cell-derived β-like cells to restore β-cell function. We conclude with tissue engineering approaches that might improve the engraftment, function, and survival of β-cell replacement therapies., Competing Interests: Declaration of interests LDS holds a licensed patent on nanoparticles for autoimmune tolerance, with patent applications pending on scaffolds for islet transplantation and local immune monitoring. MOH receives funding and consulting fees from Crinetics. JAMS has received hororaria for chairing academic meetings organised by Novo Nordisk and for participating in a Medtronic Scientific Advisory Board. NAJK declares no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by pancreatic islet β cell loss and dysfunction resulting in insulin deficiency and hyperglycemia. During a presymptomatic phase of established β cell autoimmunity, β cell loss may first be evident through assessment of β cell secretory capacity, a measure of functional β cell mass. Reduction in pancreatic islet β cell reserve eventually manifests as impaired first-phase insulin response to glucose and abnormal glucose tolerance, which progresses until the functional capacity for β cell secretion can no longer meet the demand for insulin to control glycemia. A functional β cell mass of ∼25% of normal may be required to avoid symptomatic T1D but is already associated with dysregulated glucagon secretion. With symptomatic T1D, stimulated C-peptide levels >0.60 ng/mL (0.200 pmol/mL) indicate the presence of clinically meaningful residual β cell function for contributing to glycemic control, although even higher residual C-peptide appears necessary for evidencing glucose-dependent islet β and α cell function that may contribute to maintaining (near)normal glycemia. β cell replacement by islet transplantation can restore a physiologic reserve capacity for insulin secretion, confirming thresholds for functional β cell mass required for independence from insulin therapy., (© 2021 New York Academy of Sciences.)

Background: The pancreas is small and irregular in shape in people with type 2 diabetes. If these abnormalities are caused by the disease state itself rather than being a predisposing factor, remission of type 2 diabetes should restore normal pancreas morphology. The objective of this study was to determine whether changes in pancreas volume and shape occurred during 2 years of remission., Methods: For this post-hoc analysis, we included a subset of adult participants of the Diabetes Remission Clinical Trial (DiRECT), who had type 2 diabetes and were randomly assigned to a weight management intervention or routine diabetes management. Intervention group participants were categorised as responders (HbA 1c <6·5% [48 mmol/mol] and fasting blood glucose <7·0 mmol/L, off all anti-diabetes medication) and non-responders, who were classified as remaining diabetic. Data on pancreas volume and irregularity of pancreas border at baseline, 5 months, 12 months, and 24 months after intervention were compared between responders and non-responders; additional comparisons were made between control group participants with type 2 diabetes and a non-diabetic comparator (NDC) group, who were matched to the intervention group by age, sex, and post-weight-loss weight, to determine the extent of any normalisation. We used a mixed-effects regression model based on repeated measures ANOVA with correction for potential confounding. Magnetic resonance techniques were employed to quantify pancreas volume, the irregularity of the pancreas borders, and intrapancreatic fat content. β-cell function and biomarkers of tissue growth were also measured., Findings: Between July 25, 2015, and Aug 5, 2016, 90 participants with type 2 diabetes in the DiRECT subset were randomly assigned to intervention (n=64) or control (n=26) and were assessed at baseline; a further 25 non-diabetic participants were enrolled into the NDC group. At baseline, mean pancreas volume was 61·7 cm 3 (SD 16·0) in all participants with type 2 diabetes and 79·8 cm 3 (14·3) in the NDC group (p<0·0001). At 24 months, pancreas volume had increased by 9·4 cm 3 (95% CI 6·1 to 12·8) in responders compared with 6·4 cm 3 (2·5 to 10·3) in non-responders (p=0·0008). Pancreas borders at baseline were more irregular in participants with type 2 diabetes than in the NDC group (fractal dimension 1·138 [SD 0·027] vs 1·097 [0·025]; p<0·0001) and had normalised by 24 months in responders only (1·099 [0·028]). Intrapancreatic fat declined by 1·02 percentage points (95% CI 0·53 to 1·51) in 32 responders and 0·51% (-0·17 to 1·19) in 13 non-responders (p=0·23)., Interpretation: These data show for the first time, to our knowledge, reversibility of the abnormal pancreas morphology of type 2 diabetes by weight loss-induced remission., Funding: Diabetes UK., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Insulin is routinely used to manage hyperglycaemia in organ donors and during the peri-transplant period in islet transplant recipients. However, it is unknown whether donor insulin use (DIU) predicts beta-cell dysfunction after islet transplantation. We reviewed data from the UK Transplant Registry and the UK Islet Transplant Consortium; all first-time transplants during 2008-2016 were included. Linear regression models determined associations between DIU, median and coefficient of variation (CV) peri-transplant glucose levels and 3-month islet graft function. In 91 islet cell transplant recipients, DIU was associated with lower islet function assessed by BETA-2 scores (β [SE] -3.5 [1.5], P = .02), higher 3-month post-transplant HbA1c levels (5.4 [2.6] mmol/mol, P = .04) and lower fasting C-peptide levels (-107.9 [46.1] pmol/l, P = .02). Glucose at 10 512 time points was recorded during the first 5 days peri-transplant: the median (IQR) daily glucose level was 7.9 (7.0-8.9) mmol/L and glucose CV was 28% (21%-35%). Neither median glucose levels nor glucose CV predicted outcomes post-transplantation. Data on DIU predicts beta-cell dysfunction 3 months after islet transplantation and could help improve donor selection and transplant outcomes., (© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Context: Although diabetes affects 40% to 50% of adults with cystic fibrosis, remarkably little is known regarding the underlying mechanisms leading to impaired pancreatic β-cell insulin secretion. Efforts toward improving the functional β-cell deficit in cystic fibrosis-related diabetes (CFRD) have been hampered by an incomplete understanding of whether β-cell function is intrinsically regulated by cystic fibrosis transmembrane conductance regulator (CFTR). Definitively excluding meaningful CFTR expression in human β-cells in situ would contribute significantly to the understanding of CFRD pathogenesis., Objective: To determine CFTR messenger ribonucleic acid (mRNA) and protein expression within β-cells in situ in the unmanipulated human pancreas of donors without any known pancreatic pathology., Design: In situ hybridization for CFTR mRNA expression in parallel with insulin immunohistochemical staining and immunofluorescence co-localization of CFTR with insulin and the ductal marker, Keratin-7 (KRT7), were undertaken in pancreatic tissue blocks from 10 normal adult, nonobese deceased organ donors over a wide age range (23-71 years) with quantitative image analysis., Results: CFTR mRNA was detectable in a mean 0.45% (range 0.17%-0.83%) of insulin-positive cells. CFTR protein expression was co-localized with KRT7. One hundred percent of insulin-positive cells were immunonegative for CFTR., Conclusions: For the first time, in situ CFTR mRNA expression in the unmanipulated pancreas has been shown to be present in only a very small minority (<1%) of normal adult β-cells. These data signal a need to move away from studying endocrine-intrinsic mechanisms and focus on elucidation of exocrine-endocrine interactions in human cystic fibrosis., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Reparixin is an inhibitor of CXCR1/2 chemokine receptor shown to be an effective anti-inflammatory adjuvant in a pilot clinical trial in allotransplant recipients., Research Design and Methods: A phase 3, multicenter, randomized, double-blind, parallel-assignment study (NCT01817959) was conducted in recipients of islet allotransplants randomized (2:1) to reparixin or placebo in addition to immunosuppression. Primary outcome was the area under the curve (AUC) for C-peptide during the mixed-meal tolerance test at day 75 ± 5 after the first and day 365 ± 14 after the last transplant. Secondary end points included insulin independence and standard measures of glycemic control., Results: The intention-to-treat analysis did not show a significant difference in C-peptide AUC at both day 75 (27 on reparixin vs. 18 on placebo, P = 0.99) and day 365 (24 on reparixin vs. 15 on placebo, P = 0.71). There was no statistically significant difference between treatment groups at any time point for any secondary variable. Analysis of patient subsets showed a trend for a higher percentage of subjects retaining insulin independence for 1 year after a single islet infusion in patients receiving reparixin as compared with patients receiving placebo (26.7% vs. 0%, P = 0.09) when antithymocyte globulin was used as induction immunosuppression., Conclusions: In this first double-blind randomized trial, islet transplantation data obtained with reparixin do not support a role of CXCR1/2 inhibition in preventing islet inflammation-mediated damage., (© 2020 by the American Diabetes Association.)

β-Cell dysfunction in type 2 diabetes (T2D) is associated with loss of cellular identity and mis-expression of alternative islet hormones, including glucagon. The molecular basis for these cellular changes has been attributed to dysregulation of core β-cell transcription factors, which regulate β-cell identity through activating and repressive mechanisms. The TLE1 gene lies near a T2D susceptibility locus and, recently, the glucagon repressive actions of this transcriptional coregulator have been demonstrated in vitro. We investigated whether TLE1 expression is disrupted in human T2D, and whether this is associated with increased islet glucagon-expressing cells. Automated image analysis following immunofluorescence in donors with (n = 7) and without (n = 7) T2D revealed that T2D was associated with higher islet α/β cell ratio (Control: 0.7 ± 0.1 vs T2D: 1.6 ± 0.4; P < .05) and an increased frequency of bihormonal (insulin+/glucagon+) cells (Control: 0.8 ± 0.2% vs T2D: 2.0 ± 0.4%, P < .05). In nondiabetic donors, the majority of TLE1-positive cells were mono-hormonal β-cells (insulin+/glucagon-: 98.2 ± 0.5%; insulin+/glucagon+: 0.7 ± 0.2%; insulin-/glucagon+: 1.1 ± 0.4%; P < .001). TLE1 expression was reduced in T2D (Control: 36 ± 2.9% vs T2D: 24 ± 2.6%; P < .05). Reduced islet TLE1 expression was inversely correlated with α/β cell ratio (r = -0.55; P < .05). TLE1 knockdown in EndoC-βH1 cells was associated with a 2.5-fold increase in glucagon gene mRNA and mis-expression of glucagon in insulin-positive cells. These data support TLE1 as a putative regulator of human β-cell identity, with dysregulated expression in T2D associated with increased glucagon expression potentially reflecting β- to α-cell conversion., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Despite major advances in structured education, insulin delivery and glucose monitoring, diabetes self-management remains an unremitting challenge. Insulin therapy is inextricably linked to risk of dangerous hypoglycaemia and sustained hyperglycaemia remains a leading cause of renal failure. This review sets out to demystify transplantation for diabetes multidisciplinary teams, facilitating consideration and incorporation within holistic overall person-centred management. Deceased and living donor kidney, whole pancreas and isolated islet transplant procedures, indications and potential benefits are described, in addition to outcomes within the integrated UK transplant programme., (© 2019 Diabetes UK.)

Objective: The HypoCOMPaSS study was designed to test the hypothesis that successful avoidance of biochemical hypoglycemia without compromising overall glycemic control would restore sufficient hypoglycemia awareness to prevent recurrent severe hypoglycemia in the majority of participants with established type 1 diabetes. Before starting the study, we planned to investigate associations between baseline characteristics and recurrent severe hypoglycemia over 2 years' follow-up., Research Design and Methods: A total of 96 adults with type 1 diabetes and impaired awareness of hypoglycemia participated in a 24-week 2 × 2 factorial randomized controlled trial comparing insulin delivery and glucose monitoring modalities, with the goal of rigorous biochemical hypoglycemia avoidance. The analysis included 71 participants who had experienced severe hypoglycemia in the 12-month prestudy with confirmed absence (complete responder) or presence (incomplete responder) of severe hypoglycemia over 24 months' follow-up., Results: There were 43 (61%) complete responders and 28 (39%) incomplete responders experiencing mean ± SD 1.5 ± 1.0 severe hypoglycemia events/person-year. At 24 months, incomplete responders spent no more time with glucose ≤3 mmol/L (1.4 ± 2.1% vs. 3.0 ± 4.8% for complete responders; P = 0.26), with lower total daily insulin dose (0.45 vs. 0.58 units/24 h; P = 0.01) and greater impairment of hypoglycemia awareness (Clarke score: 3.8 ± 2.2 vs. 2.0 ± 1.9; P = 0.01). Baseline severe hypoglycemia rate (16.9 ± 16.3 vs. 6.4 ± 10.8 events/person-year; P = 0.002) and fear of hypoglycemia were higher in incomplete responders. Peripheral neuropathy was more prevalent in incomplete responders (11 [39%] vs. 2 [4.7%]; P < 0.001) with a trend toward increased autonomic neuropathy., Conclusions: Recurrent severe hypoglycemia was associated with higher preintervention severe hypoglycemia rate, fear of hypoglycemia, and concomitant neuropathy., (© 2019 by the American Diabetes Association.)

Background: Glucose monitoring is an essential aspect of self-care for people with type 1 diabetes. With technologies developing rapidly, valid assessment of user experiences and satisfaction is needed. Our aim was to develop a novel measure: the Glucose Monitoring Experiences Questionnaire (GME-Q). Methods: Questionnaire design was informed by exploratory and cognitive debriefing interviews. The GME-Q was included in a large online survey enabling psychometric validation. Results: The interview sample included 17 adults (aged [mean ± SD] 46 ± 11 years, 53% women) with type 1 diabetes duration of 26 ± 14 years. The proposed conceptual framework included three domains: "Effectiveness", "Intrusiveness", and "Convenience", assessed with 25 items plus a single, overview item. The validation sample included 589 adults (aged 44 ± 15 years; 64% women) with type 1 diabetes (duration: 22 ± 14 years, self-monitoring blood glucose [SMBG] using finger-prick devices: median [IQR] 6 [4-7] daily checks). Questionnaire acceptability was indicated: 98% ( n  = 578) completion rate. After deleting 3 redundant items, principal components analysis supported a 22-item questionnaire with 3 domains ("Effectiveness" [9 items]; "Intrusiveness" [6 items]; "Convenience" [7 items]), accounting for 55% of variance, with good internal consistency reliability (α = 0.83-0.88). Subscales correlated significantly ( r s  = ±0.44-0.66, P  < 0.001) with the single, overview item, together explaining 51% of the total variance in the single item score. Associations with demographic and clinical characteristics supported convergent and discriminant validity. Conclusions: Overall, the 22-item GME-Q is a brief, acceptable, valid, and reliable measure of satisfaction with glucose monitoring in adults with type 1 diabetes using SMBG, and this needs to be assessed among those using continuous glucose monitoring.

Background: In the HypoCOMPaSS trial, adults with long-standing type 1 diabetes and problematic hypoglycemia were randomized to compare insulin pump (continuous subcutaneous insulin infusion; CSII) with multiple daily injections (MDI) and real-time continuous glucose monitoring (RT-CGM) with conventional self-monitoring of blood glucose (SMBG). Our aim was to investigate participants' satisfaction with these technologies at 6-month randomized, controlled trial (RCT) endpoint and at 2-year follow-up. Methods: Participants completed the Insulin Treatment Satisfaction Questionnaire subscales "device delivery" and "hypoglycemia control"; and Glucose Monitoring Experience Questionnaire, assessing "convenience", "effectiveness", "intrusiveness", and "total satisfaction." We assessed change over time and between-group differences by insulin and monitoring modalities. Results: Participants ( N  = 96) were 64% women, aged 49 ± 12 years, with a diabetes duration of 29 ± 12 years. At 6 months, participants reported improvements compared with baseline (all P  < 0.001) in satisfaction with insulin "delivery device" ( r =  0.39) and "hypoglycemia control" ( r  = 0.52), and trends toward significance in perceived "effectiveness" ( r =  0.42) and "intrusiveness" ( r  = 0.27) of monitoring device (but not "convenience", P  = 0.139). All improvements were sustained at 2 years. At 6 months, the only difference between arms was that greater satisfaction with insulin "delivery device" was reported in the CSII group compared with MDI ( P  < 0.001, r  = 0.40). No between-group differences were observed at 2 years. Conclusions: Overall, significant improvements in participant satisfaction with diabetes technologies were observed over the 6-month RCT, in all domains except "convenience," and maintained at 2 years. Although HypoCOMPaSS demonstrated noninferiority of SMBG versus CGM, and MDI versus CSII in terms of biomedical outcomes, detailed assessments confirm that participants' satisfaction with delivery device was greater in those allocated to CSII than MDI.

Background: All human islets used in research and for the clinical treatment of diabetes are subject to ischemic damage during pancreas procurement, preservation, and islet isolation. A major factor influencing islet function is exposure of pancreata to cold ischemia during unavoidable windows of preservation by static cold storage (SCS). Improved preservation methods may prevent this functional deterioration. In the present study, we investigated whether pancreas preservation by gaseous oxygen perfusion (persufflation) better preserved islet function versus SCS., Methods: Human pancreata were preserved by SCS or by persufflation in combination with SCS. Islets were subsequently isolated, and preparations in each group matched for SCS or total preservation time were compared using dynamic glucose-stimulated insulin secretion as a measure of β-cell function and RNA sequencing to elucidate transcriptomic changes., Results: Persufflated pancreata had reduced SCS time, which resulted in islets with higher glucose-stimulated insulin secretion compared to islets from SCS only pancreata. RNA sequencing of islets from persufflated pancreata identified reduced inflammatory and greater metabolic gene expression, consistent with expectations of reducing cold ischemic exposure. Portions of these transcriptional responses were not associated with time spent in SCS and were attributable to pancreatic reoxygenation. Furthermore, persufflation extended the total preservation time by 50% without any detectable decline in islet function or viability., Conclusions: These data demonstrate that pancreas preservation by persufflation rather than SCS before islet isolation reduces inflammatory responses and promotes metabolic pathways in human islets, which results in improved β cell function.

β-cell replacement therapy, available currently as pancreas or islet transplantation, has developed without a clear definition of graft functional and clinical outcomes. The International Pancreas and Islet Transplant Association and European Pancreas and Islet Transplantation Association held a workshop to develop consensus for an International Pancreas and Islet Transplant Association and European Pancreas and Islet Transplant Association Statement on the definition of function and failure of current and future forms of β-cell replacement therapy. There was consensus that β-cell replacement therapy could be considered as a treatment for β-cell failure, regardless of etiology and without requiring undetectable C-peptide, accompanied by glycemic instability with either problematic hypoglycemia or hyperglycemia. Glycemic control should be assessed at a minimum by glycated hemoglobin (HbA1c) and the occurrence of severe hypoglycemia. Optimal β-cell graft function is defined by near-normal glycemic control (HbA1c ≤6.5% [48 mmol/mol]) without severe hypoglycemia or requirement for insulin or other antihyperglycemic therapy, and with an increase over pretransplant measurement of C-peptide. Good β-cell graft function requires HbA1c less than 7.0% (53 mmol/mol) without severe hypoglycemia and with a significant (>50%) reduction in insulin requirements and restoration of clinically significant C-peptide production. Marginal β-cell graft function is defined by failure to achieve HbA1c less than 7.0% (53 mmol/mol), the occurrence of any severe hypoglycemia, or less than 50% reduction in insulin requirements when there is restoration of clinically significant C-peptide production documented by improvement in hypoglycemia awareness/severity, or glycemic variability/lability. A failed β-cell graft is defined by the absence of any evidence for clinically significant C-peptide production. Optimal and good function are considered successful clinical outcomes.

Objective: Severe hypoglycemia is a feared complication of type 1 diabetes; yet, few trials have targeted prevention using optimized self-management (educational, therapeutic, and technological support). We aimed to investigate whether improved awareness and reduced severe hypoglycemia, achieved during an intensive randomized clinical trial (RCT), were sustained after return to routine care., Research Design and Methods: Ninety-six adults with type 1 diabetes (29 ± 12 years' duration) and impaired awareness of hypoglycemia at five U.K. tertiary referral diabetes centers were recruited into a 24-week 2 × 2 factorial RCT (HypoCOMPaSS). Participants were randomized to pump (continuous subcutaneous insulin infusion [CSII]) or multiple daily injections (MDIs) and real-time continuous glucose monitoring (RT-CGM) or self-monitoring of blood glucose (SMBG), with equal education/attention to all groups. At 24 weeks, participants returned to routine care with follow-up until 24 months, including free choice of MDI/CSII; RT-CGM vs. SMBG comparison continued to 24 months. Primary outcome was mean difference (baseline to 24 months [between groups]) in hypoglycemia awareness., Results: Improvement in hypoglycemia awareness was sustained (Gold score at baseline 5.1 ± 1.1 vs. 24 months 3.7 ± 1.9; P < 0.0001). Severe hypoglycemia rate was reduced from 8.9 ± 12.8 episodes/person-year over the 12 months prestudy to 0.4 ± 0.8 over 24 months ( P < 0.0001). HbA 1c improved (baseline 8.2 ± 3.2% [66 ± 12 mmol/mol] vs. 24 months 7.7 ± 3.1% [61 ± 10 mmol/mol]; P = 0.003). Improvement in treatment satisfaction and reduced fear of hypoglycemia were sustained. There were no significant differences between interventions at 24 months., Conclusions: Optimized insulin replacement and glucose monitoring underpinned by hypoglycemia-focused structured education should be provided to all with type 1 diabetes complicated by impaired awareness of hypoglycemia., (© 2018 by the American Diabetes Association.)

Replacement of pancreatic β-cells through deceased donor islet transplantation is a proven therapy for preventing recurrent life-threatening hypoglycemia in type 1 diabetes. Although near-normal glucose levels and insulin independence can be maintained for many years following successful islet transplantation, restoration of normal functional β-cell mass has remained elusive. It has recently been proposed that dedifferentiation/plasticity towards other endocrine phenotypes may play an important role in stress-induced β-cell dysfunction in type 2 diabetes. Here we report loss of end-differentiated β-cell phenotype in 2 intraportal islet allotransplant recipients. Despite excellent graft function and sustained insulin independence, all examined insulin-positive cells had lost expression of the end-differentiation marker, urocortin-3, or appeared to co-express the α-cell marker, glucagon. In contrast, no insulin + /urocortin-3 - cells were seen in nondiabetic deceased donor control pancreatic islets. Loss of end-differentiated phenotype may facilitate β-cell survival during the stresses associated with islet isolation and culture, in addition to sustained hypoxia following engraftment. As further refinements in islet isolation and culture are made in parallel with exploration of alternative β-cell sources, graft sites, and ultimately fully vascularized bioengineered insulin-secreting microtissues, differentiation status immunostaining provides a novel tool to assess whether fully mature β-cell phenotype has been maintained., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Studies in animal models of type 2 diabetes have shown that glucagon-like peptide 1 (GLP-1) receptor agonists prevent β-cell loss. Whether GLP-1 mediates β-cell survival via the key lysosomal-mediated process of autophagy is unknown. In this study, we report that treatment of INS-1E β-cells and primary islets with glucolipotoxicity (0.5 mmol/L palmitate and 25 mmol/L glucose) increases LC3 II, a marker of autophagy. Further analysis indicates a blockage in autophagic flux associated with lysosomal dysfunction. Accumulation of defective lysosomes leads to lysosomal membrane permeabilization and release of cathepsin D, which contributes to cell death. Our data further demonstrated defects in autophagic flux and lysosomal staining in human samples of type 2 diabetes. Cotreatment with the GLP-1 receptor agonist exendin-4 reversed the lysosomal dysfunction, relieving the impairment in autophagic flux and further stimulated autophagy. Small interfering RNA knockdown showed the restoration of autophagic flux is also essential for the protective effects of exendin-4. Collectively, our data highlight lysosomal dysfunction as a critical mediator of β-cell loss and shows that exendin-4 improves cell survival via restoration of lysosomal function and autophagic flux. Modulation of autophagy/lysosomal homeostasis may thus define a novel therapeutic strategy for type 2 diabetes, with the GLP-1 signaling pathway as a potential focus., (© 2017 by the American Diabetes Association.)