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Background: Youth with type 1 diabetes (T1D) are tasked with integrating their illness into their identity, a process conceptualized as illness identity. To date, longitudinal person-centered studies are lacking that substantiate qualitative research capturing illness identity as a process., Purpose: First, the current study examined patterns of stability and change among illness identity profiles in youth with T1D. Second, the study investigated how these profiles and patterns are related to background and medical characteristics, psychological, and contextual variables., Methods: This 4-wave longitudinal study (covering 3 years) included 558 adolescents and emerging adults with T1D at baseline recruited from the Belgian Diabetes Registry (age range = 14-26 years, 54% female). Latent transition analysis was used to examine (1) illness identity profiles and (2) patterns of stability and change among these profiles. Multinomial logistic regression models examined the profiles' and patterns' associations with the background and medical characteristics, psychological, and contextual variables., Results: Three illness identity profiles emerged: the more-integrated profile, the less-integrated profile, and the least-integrated profile. Although most individuals remained within their profile across 3 years, several meaningful transitions occurred as well. Age, self-esteem, diabetes distress, and psychological control were related to profile membership, whereas only illness duration was related to transitional patterns., Conclusion: The present study informed both theory and clinical practice on how illness identity is experienced by youth with T1D from a person-centered perspective. In addition, the results provided insight into which aspects are meaningfully related to illness identity integration, supporting tailored interventions for youth with T1D., (© Society of Behavioral Medicine 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Growth hormone (GH) deficiency (GHD) in children and adolescents can vary in severity and origin, with GH replacement therapy proving effective in achieving genetic target height. Optimal outcomes are seen in those treated early and with higher doses. As patients approach adult height, priorities shift towards optimizing metabolic effects, maintaining body composition, and enhancing bone mass and muscle strength. Transitioning from pediatric to adult care presents challenges, including accurately identifying candidates for continued GH therapy, reevaluating persistent GHD, and preventing treatment discontinuation. Assessing readiness for transition and self-management skills is crucial. This Policy and Practice Review provides a comprehensive overview of current policies, regulations, and guidelines pertinent to managing GHD transition in Belgium. We integrate perspectives from national academic and nonacademic clinical stakeholders in pediatric and adult endocrine care to provide an updated policy framework. This framework underscores the importance of sustained GH therapy during transition, particularly for individuals with persistent GHD, with the goal of optimizing practices and improving outcomes during this critical period., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Staels, De Schepper, Becker, Lysy, Klink, Logghe, den Brinker, Rochtus, Lapauw, Cools, Alexopoulou, Bex, Corvilain, Crenier, De Block, Donckier, Hilbrands, Ponchon, T'Sjoen, Van Den Bruel, Vandewalle and Velkeniers.)

Background: ALERTT1 showed that switching from intermittently scanned continuous glucose monitoring (isCGM) without alerts to real-time CGM (rtCGM) with alert functionality improved time in range (TIR; 70-180 mg/dL), glycated hemoglobin (HbA1c), time <54 mg/dL, and Hypoglycemia Fear Survey version II worry subscale (HFS-worry) score after six months in adults with type 1 diabetes (T1D). Moderator analyses aimed to identify certain subgroups that would benefit more from switching to rtCGM than others., Methods: Post hoc analyses of ALERTT1 evaluated the impact of 14 baseline characteristics on the difference (delta) in mean TIR, HbA1c, time <54 mg/dL, and HFS-worry score at six months between rtCGM and isCGM. Therefore, the delta was allowed to depend on each of these variables by including interactions in the moderator analysis model. Analyses were performed separately for each variable; variables with P < .10 in the univariable analysis were combined into a single model., Results: Univariable analyses showed no dependency of delta TIR, HbA1c, or time <54 mg/dL on variables other than CGM type. Only delta HFS-worry score depended on baseline HbA1c ( P = .0059), indicating less worries with rtCGM in people with baseline HbA1c <6.5% or ≥8%. Given P < .10 for dependency of delta TIR on insulin therapy type (favoring multiple daily injections), baseline HbA1c, and baseline TIR, these variables were combined into a multivariable analysis; interactions were not statistically significant., Conclusions: Except for HFS-worry score, no interactions between 14 baseline characteristics and the six-month intervention effect of rtCGM on TIR, HbA1c, or time <54 mg/dL were observed, supporting the conclusion of ALERTT1 that switching from isCGM without alerts to rtCGM with alert functionality is beneficial for a wide range of people with T1D., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: UZ Leuven received nonfinancial support for travel from Novo Nordisk, and Boehringer-Ingelheim for M.M.V. M.M.V. serves or has served on the speakers bureau for Dexcom—financial compensation for these activities has been received by KU Leuven. KU Leuven received nonfinancial support for travel from Medtronic, and financial support for travel from Roche for S.C. C.D.B. reports consulting fees and honoraria for speaking for Abbott, AstraZeneca, Boehringer-Ingelheim, A. Menarini Diagnostics, Eli Lilly, Medtronic, Novo Nordisk, and Roche. R.H. serves or has served on the advisory panel for Merck Sharp and Dohme, Boehringer-Ingelheim, and Eli Lilly. L.V.H. reports consulting fees and honoraria for speaking for Abbott, AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Medtronic, Merck Sharp and Dohme, Novo Nordisk, and Sanofi-Aventis. G.V. serves or has served on the advisory panel for Merck Sharp and Dohme, Boehringer-Ingelheim, and Eli Lilly. G.V. reports consulting fees and honoraria for speaking from Merck Sharp and Dohme, Boehringer-Ingelheim, AstraZeneca, Sanofi-Aventis, Novo Nordisk, and Eli Lilly. E.D. has served on the advisory panel for Novo Nordisk. E.D. reports speaking fees from Novo Nordisk, Boehringer-Ingelheim, Eli Lilly, and AstraZeneca. N.M. serves or has served on the advisory panel for Boehringer-Ingelheim. N.M. reports speaking fees from Merck Sharp and Dohme, Boehringer-Ingelheim, AstraZeneca, Sanofi-Aventis, Novo Nordisk, and Eli Lilly. C.V. reports consulting and speaking fees from Medtronic, Boehringer-Ingelheim, AstraZeneca, and Sanofi-Aventis. F.N. reports consulting fees and honoraria for speaking from Abbott, AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Johnson and Johnson, Medtronic, Merck Sharp and Dohme, Novo Nordisk, Roche, and Sanofi-Aventis. C.M. serves or has served on the advisory panel for Novo Nordisk, Sanofi-Aventis, Merck Sharp and Dohme, Eli Lilly, Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, and Zealand Pharma. Financial compensation for these activities has been received by KU Leuven; KU Leuven has received research support for C.M. from Medtronic, Novo Nordisk, Sanofi-Aventis, Merck Sharp and Dohme, Eli Lilly, Roche, Abbott, ActoBio Therapeutics, and Novartis; C.M. serves or has served on the speakers bureau for Novo Nordisk, Sanofi-Aventis, Merck Sharp and Dohme, Eli Lilly, Boehringer-Ingelheim, AstraZeneca, and Novartis. Financial compensation for these activities has been received by KU Leuven. P.G. serves or has served on the advisory panel for Novo Nordisk, Sanofi-Aventis, Boehringer-Ingelheim, Janssen Pharmaceuticals, Roche, Medtronic, and Bayer. Financial compensation for these activities has been received by KU Leuven. P.G. serves or has served on the speakers bureau for Merck Sharp and Dohme, Boehringer-Ingelheim, Bayer, Medtronic, Insulet, Novo Nordisk, Abbott, Roche, and Dexcom. Financial compensation for these activities has been received by KU Leuven. KU Leuven received nonfinancial support for travel from Sanofi-Aventis, A. Menarini Diagnostics, Medtronic, and Roche for P.G. All disclosures were unrelated to the present work. S.F., T.M., and B.K. have nothing to disclose.

The premise of this study was to gain more insight into whether type 1 diabetes (T1D) can impact how youth perceive parents and peers. To address limitations of previous observational studies comparing youth with T1D to control youth, propensity weighting was used to mimic a randomized controlled trial. A total of 558 youth with T1D and 426 control youth (14-26y) completed questionnaires on parental responsiveness, psychological control, overprotection, friend support, extreme peer orientation, and a host of background and psychological functioning variables. The groups were statistically weighted to become as comparable as possible except for disease status. The analysis plan and hypotheses were preregistered on the open science framework. Youth with T1D perceived their mothers to be more overprotective, perceived fewer friend support, and were less extremely oriented toward peers than control youth. There were no group differences for paternal overprotection and paternal and maternal responsiveness and psychological control. Mothers of youth with T1D seem at risk to practice overprotective parenting and clinicians could play an important role in making mothers aware of this risk. However, the absence of group differences for the maladaptive parenting dimension of psychological control and adaptive dimension of responsiveness are reassuring and testify to the resilient nature of youth with T1D and their families. Additionally, there is accumulating evidence that T1D could interfere with engaging in supportive friendships., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Comparing Continuous With Flash Glucose Monitoring In Adults With Type 1 Diabetes (ALERTT1) examined whether switching from first-generation intermittently scanned continuous glucose monitoring (isCGM) without alerts to real-time continuous glucose monitoring (rtCGM) with alert functionality offers additional benefits to adults with type 1 diabetes. The extension of the randomised ALERTT1 trial assessed the effect of switching from isCGM to rtCGM up to 24 months., Methods: In this 6-month, double-arm, parallel-group, non-masked, randomised, controlled trial, done across six hospitals in Belgium, 254 adults aged 18 years or older with type 1 diabetes previously using isCGM were randomly assigned (1:1) to rtCGM with alerts (intervention; n=127) or isCGM without alerts (control; n=127). Upon completion of the 6-month trial, the control group switched to rtCGM (is-rtCGM group), and the intervention group continued rtCGM (rt-rtCGM group). The extension focused on within-group changes in time in range (TIR; 3·9-10·0 mmol/L; primary outcome), HbA 1c , time in clinically significant hypoglycaemia (<3·0 mmol/L), and Hypoglycaemia Fear Survey worry (HFS-worry) score (all prespecified key secondary outcomes). Mean within-group change versus the start of rtCGM is reported, with a positive value referring to a lower value at start of rtCGM. This trial is registered at ClinicalTrials.gov (NCT03772600)., Findings: 119 participants were assigned to the is-rtCGM group of whom 112 (94%) completed the 24-month trial, and 123 participants were assigned to the rt-rtCGM group of whom 117 (95%) completed the 24-month trial. TIR increased from 51·8% (95% CI 49·1-54·5) at start of rtCGM (month 6) to 63·5% (60·7-66·3) at month 12 in the is-rtCGM group, and remained stable up to month 24 (change 11·7 percentage points [pp] [9·4-14·0; p<0·0001). In the rt-rtCGM group, TIR increased from 52·5% (95% CI 49·8-55·1) at start of rtCGM (month 0) to 63·0% (60·3-65·8) at month 12, also remaining stable up to month 24 (change 10·5 pp [8·2-12·8]; p<0·0001). HbA 1c decreased from 7·4% (57 mmol/mol; month 6) to 6·9% (52 mmol/mol) at month 24 (change -0·54 pp [95% CI -0·64 to -0·44]; -5 mmol/mol [95% CI -6 to -4]; p<0·0001) in the is-rtCGM group, and from 7·4% (57 mmol/mol; month 0) to 7·0% (53 mmol/mol) at month 24 (change -0·43 pp [95% CI -0·53 to -0·33]; -4 mmol/mol [95% CI -5 to -3]; p<0·0001) in the rt-rtCGM group. The change in HFS-worry score was -2·67 (month 24 vs month 6; p=0·0008) in the is-rtCGM group and -5·17 points (month 24 vs month 0; p<0·0001) in the rt-rtCGM group. Time in clinically significant hypoglycaemia was unchanged in both groups after month 12. Severe hypoglycaemia decreased from 31·0 to 3·3 per 100 patient-years after switching to rtCGM., Interpretation: Glycaemic control and hypoglycaemia worry improved significantly up to 24 months after switching from isCGM without alerts to rtCGM with alerts, supporting the use of rtCGM in the care of adults with type 1 diabetes., Funding: Dexcom., Competing Interests: Declaration of interests MMV received non-financial support for travel from Novo Nordisk and Boehringer-Ingelheim via UZ Leuven. MMV serves, or has served, on the speakers bureau for Dexcom; financial compensation for this activity has been received by KU Leuven. SC received research support from Roche Diabetes Care, Novo Nordisk, and Sanofi via KU Leuven. CDB reports consulting fees and honoraria for speaking for Abbott, AstraZeneca, Boehringer-Ingelheim, A Menarini Diagnostics, Indigo Diabetes, Insulet, Eli Lilly, Medtronic, Novo Nordisk, and Roche, and served on the advisory panel for Eli Lilly, Indigo Diabetes, and Novo Nordisk. RH serves, or has served, on the advisory panel for Merck Sharp and Dohme, Boehringer-Ingelheim, and Eli Lilly. LVH reports consulting fees and honoraria for speaking for Abbott, AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Medtronic, Merck Sharp and Dohme, Novo Nordisk, Sanofi-Aventis, and Roche. GV serves, or has served, on the advisory panel for Merck Sharp and Dohme, Boehringer-Ingelheim, and Eli Lilly. GV reports consulting fees and honoraria for speaking from Merck Sharp and Dohme, Boehringer-Ingelheim, AstraZeneca, Sanofi-Aventis, Novo Nordisk, and Eli Lilly. ED has served on the advisory panel for Novo Nordisk. ED reports speaking fees from Novo Nordisk, Boehringer-Ingelheim, Eli Lilly, and AstraZeneca. NM serves, or has served, on the advisory panel for Boehringer-Ingelheim. NM reports speaking fees from Merck Sharp and Dohme, Boehringer-Ingelheim, AstraZeneca, Sanofi-Aventis, Novo Nordisk, and Eli Lilly. CV reports consulting and speaking fees from Medtronic, Boehringer Ingelheim, AstraZeneca, and Sanofi Aventis. FN reports consulting fees and honoraria for speaking from Abbott, AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Johnson and Johnson, Medtronic, Merck Sharp and Dohme, Novo Nordisk, Roche, and Sanofi-Aventis. CM serves, or has served, on the advisory panel for Novo Nordisk, Sanofi, Merck Sharp and Dohme, Eli Lilly and Company, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, Imcyse, Insulet, Zealand Pharma, Avotres, Mannkind, Sandoz, and Vertex. Financial compensation for these activities has been received by KU Leuven; KU Leuven has received research support for CM from Medtronic, Imcyse, Novo Nordisk, Sanofi, and ActoBio Therapeutics; CM serves or has served on the speakers bureau for Novo Nordisk, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, AstraZeneca, and Novartis. Financial compensation for these activities has been received by KU Leuven. PG serves, or has served, on the advisory panel for Novo Nordisk, Sanofi-Aventis, Boehringer-Ingelheim, Janssen Pharmaceuticals, Roche, Medtronic, Abbott and Bayer. Financial compensation for these activities has been received by KU Leuven. PG serves, or has served, on the speakers bureau for Merck Sharp and Dohme, Boehringer-Ingelheim, Bayer, Medtronic, Insulet, Novo Nordisk, Abbott, Roche, VitalAire, and Dexcom. Financial compensation for these activities has been received by KU Leuven. KU Leuven received non-financial support for PG for travel from Sanofi-Aventis, A Menarini Diagnostics, Novo Nordisk, Medtronic, and Roche. All disclosures were unrelated to the present work. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Intraportal (IP) islet cell transplants can restore metabolic control in type 1 diabetes patients, but limitations raise the need for establishing a functional beta cell mass (FBM) in a confined extrahepatic site. This study reports on function and composition of omental (OM) implants after placement of islet cell grafts with similar beta cell mass as in our IP-protocol (2-5.10 6 beta cells/kg body weight) on a scaffold. Four of seven C-peptide-negative recipients achieved low beta cell function (hyperglycemic clamp [HGC] 2-8 percent of controls) until laparoscopy, 2-6 months later, for OM-biopsy and concomitant IP-transplant with similar beta cell dose. This IP-transplant increased HGC-values to 15-40 percent. OM-biopsies reflected the composition of initial grafts, exhibiting varying proportions of endocrine-cell-enriched clusters with more beta than alpha cells and leucocyte pole, non-endocrine cytokeratin-positive clusters surrounded by leucocytes, and scaffold remnants with foreign body reaction. OM-implants on a polyglactin-thrombin-fibrinogen-scaffold presented larger endocrine clusters with infiltrating endothelial cells and corresponded to the higher HGC-values. No activation of cellular immunity to GAD/IA2 was measured post-OM-transplant. Establishment of a metabolically adequate FBM in omentum may require a higher beta cell number in grafts but also elimination of their immunogenic non-endocrine components as well as local conditioning that favors endocrine cell engraftment and function., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Patients fulfilling criteria for euthanasia can choose to donate their organs after circulatory death [donors after euthanasia (DCD V)]. This study assesses the outcome of islet cell isolation from DCD V pancreases. A procedure for DCD V procurement provided 13 pancreases preserved in Institut Georges Lopez-1 preservation solution and following acirculatory warm ischemia time under 10 minutes. Islet cell isolation outcomes are compared with those from reference donors after brain death (DBD, n = 234) and a cohort of donors after controlled circulatory death (DCD III, n = 29) procured under the same conditions. Islet cell isolation from DCD V organs resulted in better in vitro outcome than for selected DCD III or reference DBD organs. A 50% higher average beta cell number before and after culture and a higher average beta cell purity (35% vs 24% and 25%) was observed, which led to more frequent selection for our clinical protocol (77% of isolates vs 50%). The functional capacity of a DCD V islet cell preparation was illustrated by its in vivo effect following intraportal transplantation in a type 1 diabetes patient: injection of 2 million beta cells/kg body weight (1,900 IEQ/kg body weight) at 39% insulin purity resulted in an implant with functional beta cell mass that represented 30% of that in non-diabetic controls. In conclusion, this study describes procurement and preservation conditions for donor organs after euthanasia, which allow preparation of cultured islet cells, that more frequently meet criteria for clinical use than those from DBD or DCD III organs.

Allogeneic islet transplantation is a standard of care treatment for patients with labile type 1 diabetes in many countries around the world, including Japan, the United Kingdom, Australia, much of continental Europe, and parts of Canada. The United States is now endorsing islet cell treatment for type 1 diabetes, but the FDA has chosen to consider islets as a biologic that requires licensure, making the universal implementation of the procedure in the clinic very challenging and opening the manufacture of islet grafts to private companies. The commercialization of human tissues raises significant legal and ethical issues and ironically leads to a situation where treatments developed as a result of the scientific and economic efforts of academia over several decades become exploited exclusively by for-profit entities., (© 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Background: People with type 1 diabetes can continuously monitor their glucose levels on demand (intermittently scanned continuous glucose monitoring [isCGM]), or in real time (real-time continuous glucose monitoring [rtCGM]). However, it is unclear whether switching from isCGM to rtCGM with alert functionality offers additional benefits. Therefore, we did a trial comparing rtCGM and isCGM in adults with type 1 diabetes (ALERTT1)., Methods: We did a prospective, double-arm, parallel-group, multicentre, randomised controlled trial in six hospitals in Belgium. Adults with type 1 diabetes who previously used isCGM were randomly assigned (1:1) to rtCGM (intervention) or isCGM (control). Randomisation was done centrally using minimisation dependent on study centre, age, gender, glycated haemoglobin (HbA 1c ), time in range (sensor glucose 3·9-10·0 mmol/L), insulin administration method, and hypoglycaemia awareness. Participants, investigators, and study teams were not masked to group allocation. Primary endpoint was mean between-group difference in time in range after 6 months assessed in the intention-to-treat sample. This trial is registered with ClinicalTrials.gov, NCT03772600., Findings: Between Jan 29 and Jul 30, 2019, 269 participants were recruited, of whom 254 were randomly assigned to rtCGM (n=127) or isCGM (n=127); 124 and 122 participants completed the study, respectively. After 6 months, time in range was higher with rtCGM than with isCGM (59·6% vs 51·9%; mean difference 6·85 percentage points [95% CI 4·36-9·34]; p<0·0001). After 6 months HbA 1c was lower (7·1% vs 7·4%; p<0·0001), as was time <3·0 mmol/L (0·47% vs 0·84%; p=0·0070), and Hypoglycaemia Fear Survey version II worry subscale score (15·4 vs 18·0; p=0·0071). Fewer participants on rtCGM experienced severe hypoglycaemia (n=3 vs n=13; p=0·0082). Skin reaction was more frequently observed with isCGM and bleeding after sensor insertion was more frequently reported by rtCGM users., Interpretation: In an unselected adult type 1 diabetes population, switching from isCGM to rtCGM significantly improved time in range after 6 months of treatment, implying that clinicians should consider rtCGM instead of isCGM to improve the health and quality of life of people with type 1 diabetes., Funding: Dexcom., Competing Interests: Declaration of interests UZ Leuven received non-financial support for travel from Novo Nordisk for MMV. KU Leuven received non-financial support for travel from Medtronic, and financial support for travel from Roche for SC. CDB reports consulting fees and honoraria for speaking for Abbott, AstraZeneca, Boehringer Ingelheim, A Menarini Diagnostics, Eli Lilly, Medtronic, Novo Nordisk, and Roche. RH serves or has served on the advisory panel for Merck Sharp and Dohme, Boehringer Ingelheim, and Eli Lilly. LVH reports consulting fees and honoraria for speaking for Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Medtronic, Merck Sharp and Dohme, Novo Nordisk, and Sanofi-Aventis. GV serves or has served on the advisory panel for Merck Sharp and Dohme, Boehringer-Ingelheim, and Eli Lilly; reports consulting fees and honoraria for speaking from Merck Sharp and Dohme, Boehringer Ingelheim, AstraZenica, Sanofi-Aventis, Novo Nordisk, and Eli Lilly. ED has served on the advisory panel for Novo Nordisk; ED reports speaking fees from Novo Nordisk, Boehringer-Ingelheim, Eli Lilly, and AstraZenica. NM serves or has served on the advisory panel for Boehringer-Ingelheim; and reports speaking fees from Merck Sharp and Dohme, Boehringer-Ingelheim, AstraZenica, Sanofi-Aventis, Novo Nordisk, and Eli Lilly. CV reports consulting and speaking fees from Medtronic, Boehringer Ingelheim, Astra Zeneca, and Sanofi Aventis. FN reports consulting fees and honoraria for speaking from Abbott, AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Johnson and Johnson, Medtronic, Merck Sharp and Dohme, Novo Nordisk, Roche, and Sanofi-Aventis. CM serves or has served on the advisory panel for Novo Nordisk, Sanofi-Aventis, Merck Sharp and Dohme, Eli Lilly, Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, and Zealand Pharma (financial compensation for these activities has been received by KU Leuven; KU Leuven has received research support for CM from Medtronic, Novo Nordisk, Sanofi-Aventis, Merck Sharp and Dohme, Eli Lilly, Roche, Abbott, ActoBio Therapeutics, and Novartis); serves or has served on the speakers' bureau for Novo Nordisk, Sanofi-Aventis, Merck Sharp and Dohme, Eli Lilly, Boehringer Ingelheim, AstraZeneca, and Novartis (financial compensation for these activities has been received by KU Leuven). PG serves or has served on the advisory panel for Novo Nordisk, Sanofi-Aventis, Boehringer-Ingelheim, Janssen Pharmaceuticals, Roche, Medtronic, and Bayer (financial compensation for these activities has been received by KU Leuven). PG serves or has served on the speakers bureau for Merck Sharp and Dohme, Boehringer-Ingelheim, Bayer, Medtronic, Insulet, Novo Nordisk, Abbott, and Roche (financial compensation for these activities has been received by KU Leuven and KU Leuven received for PG non-financial support for travel from Sanofi-Aventis, A Menarini Diagnostics, Medtronic, and Roche); and received a grant for a senior clinical research fellowship from Fonds Wetenschappelijk Onderzoek Flanders. SC received a doctoral grant for strategic basic research from Fonds Wetenschappelijk Onderzoek Flanders. All disclosures are unrelated to the present work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Detection of amyloid in intraportal islet implants of type 1 diabetes patients has been proposed as cause in their functional decline. The present study uses cultured adult human islets devoid of amyloid to examine conditions of its formation. After intraportal injection in patients, amyloid deposits <15 µm diameter were identified in 5%-12% of beta cell containing aggregates, 3-76 months posttransplant. Such deposits also formed in glucose-controlling islet implants in the kidney of diabetic mice but not in failing implants. Alginate-encapsulated islets formed amyloid during culture when functional, and in all intraperitoneal implants that corrected diabetes in mice, exhibiting larger sizes than in functioning nonencapsulated implants. After intraperitoneal injection in a patient, retrieved single capsules presented amyloid near living beta cells, whereas no amyloid occurred in clustered capsules with dead cells. Amyloid was also demonstrated in functional human stem cell-generated beta cell implants in subcutaneous devices of mice. Deposits up to 35 µm diameter were localized in beta cell-enriched regions and related to an elevated IAPP over insulin ratio in the newly generated beta cells. Amyloid in device-encapsulated human stem cell-generated beta cell implants marks the formation of a functional beta cell mass but also an imbalance between its activated state and its microenvironment., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background and Aims: The management of chronic inflammatory bowel diseases in youth is challenging. We aimed to determine health literacy (HL), quality of life (QoL) and clinical outcomes in young adults from the BELgian CROhn's disease registry (BELCRO) in comparison to type 1 diabetes mellitus (DM) as a control. Methods: In this prospective and observational study, young adults with Crohn's disease (CD) diagnosed < 18 years and with > 5 years disease duration and a comparable group of patients with DM completed validated HL, QoL and work productivity and activity impairment questionnaires (HLS-EU-Q16, EQ-5D-5L and WPAI). HL was scored as sufficient (13-16), problematic (9-12) or inadequate (0-8). QoL was dichotomized into "no problems" (EQ-5D level 1) or "problems" (EQ-5D levels 2 to 5). Non-parametric (Mann-Whitney U ) analyses and Spearman correlations were performed. Results: A total of 52 CD (median [IQR] age of 25.0 [23.8-27.0], 64% male) and 50 DM (age 20.0 [19.0-22.0], 50% male) patients were included. HL was 14.0 [11.0-16.0] for CD and 14.0 [11.3-14.8] for DM ( p = 0.6) with similar proportions of sufficient (60 vs. 68%, p = 0.4), problematic (34 vs. 26%, p = 0.3) and inadequate HL (both 6%, p = 1). Although QoL was comparable for CD and DM (77.0 [68.8-82.0] vs. 75.0 [65.0-80.0] %, p =0.4), CD had a trend for higher pain/discomfort (50 vs. 32%, p = 0.06). HL and QoL correlated in CD ( r = 0.6, p < 0.001) and DM patients ( r = 0.6, p < 0.001). Fewer CD patients with recent hospitalization/surgery had sufficient HL (31 vs. 69%, p = 0.01) and had lower QoL (70.0 [60.0-77.0] vs. 80.0 [70.0-85.0], p = 0.04) compared to those without. Conclusions: Selected young Belgian adults suffering from CD for >5 years have similar and sufficient HL compared to DM patients. However, CD patients requiring hospitalization/surgery have lower HL, which indicates the need for targeted educational programs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Carels, Wauters, Outtier, Baert, Bossuyt, Colard, De Looze, Ferrante, Goegebuer, Hauser, Hilbrands, Hoffman, Keymeulen, Paquot, Ruytjens, Simoens, Thienpont, Verreth, Verstockt, Vermeire and Veereman.)

Aims/hypothesis: Numerous clinical studies have investigated the anti-CD3ɛ monoclonal antibody otelixizumab in individuals with type 1 diabetes, but limited progress has been made in identifying the optimal clinical dose with acceptable tolerability and safety. The aim of this study was to evaluate the association between dose-response, safety and tolerability, beta cell function preservation and the immunological effects of otelixizumab in new-onset type 1 diabetes., Methods: In this randomised, single-blind, placebo-controlled, 24 month study, conducted in five centres in Belgium via the Belgian Diabetes Registry, participants (16-27 years old, <32 days from diagnosis of type 1 diabetes) were scheduled to receive placebo or otelixizumab in one of four dose cohorts (cumulative i.v. dose 9, 18, 27 or 36 mg over 6 days; planned n = 40). Randomisation to treatment was by a central computer system; only participants and bedside study personnel were blinded to study treatment. The co-primary endpoints were the incidence of adverse events, the rate of Epstein-Barr virus (EBV) reactivation, and laboratory measures and vital signs. A mixed-meal tolerance test was used to assess beta cell function; exploratory biomarkers were used to measure T cell responses., Results: Thirty participants were randomised/28 were analysed (placebo, n = 6/5; otelixizumab 9 mg, n = 9/8; otelixizumab 18 mg, n = 8/8; otelixizumab 27 mg, n = 7/7; otelixizumab 36 mg, n = 0). Dosing was stopped at otelixizumab 27 mg as the predefined EBV reactivation stopping criteria were met. Adverse event frequency and severity were dose dependent; all participants on otelixizumab experienced at least one adverse event related to cytokine release syndrome during the dosing period. EBV reactivation (otelixizumab 9 mg, n = 2/9; 18 mg, n = 4/8: 27 mg, n = 5/7) and clinical manifestations (otelixizumab 9 mg, n = 0/9; 18 mg, n = 1/8; 27 mg, n = 3/7) were rapid, dose dependent and transient, and were associated with increased productive T cell clonality that diminished over time. Change from baseline mixed-meal tolerance test C-peptide weighted mean AUC 0-120 min following otelixizumab 9 mg was above baseline for up to 18 months (difference from placebo 0.39 [95% CI 0.06, 0.72]; p = 0.023); no beta cell function preservation was observed at otelixizumab 18 and 27 mg., Conclusions/interpretation: A metabolic response was observed with otelixizumab 9 mg, while doses higher than 18 mg increased the risk of unwanted clinical EBV reactivation. Although otelixizumab can temporarily compromise immunocompetence, allowing EBV to reactivate, the effect is dose dependent and transient, as evidenced by a rapid emergence of EBV-specific T cells preceding long-term control over EBV reactivation., Trial Registration: ClinicalTrials.gov NCT02000817., Funding: The study was funded by GlaxoSmithKline. Graphical abstract.

Background: Clinical islet transplantation is generally conducted within 72 hours after isolating sufficient beta-cell mass. A preparation that does not meet the sufficient dose can be cultured until this is reached after combination with subsequent ones. This retrospective study examines whether metabolic outcome is influenced by culture duration., Methods: Forty type 1 diabetes recipients of intraportal islet cell grafts under antithymocyte globulin induction and mycophenolate mofetil-tacrolimus maintenance immunosuppression were analyzed. One subgroup (n = 10) was transplanted with preparations cultured for ≥96 hours; in the other subgroup (n = 30) grafts contained similar beta-cell numbers but included isolates that were cultured for a shorter duration. Both subgroups were compared by numbers with plasma C-peptide ≥0.5 ng/mL, low glycemic variability associated with C-peptide ≥1.0 ng/mL, and with insulin independence., Results: The subgroup with all cells cultured ≥96 hours exhibited longer C-peptide ≥0.5 ng/mL (103 versus 48 mo; P = 0.006), and more patients with low glycemic variability and C-peptide ≥1.0 ng/mL, at month 12 (9/10 versus 12/30; P = 0.005) and 24 (7/10 versus 6/30; P = 0.007). In addition, 9/10 became insulin-independent versus 15/30 (P = 0.03). Grafts with all cells cultured ≥96 hours did not contain more beta cells but a higher endocrine purity (49% versus 36%; P = 0.03). In multivariate analysis, longer culture duration and older recipient age were independently associated with longer graft function., Conclusions: Human islet isolates with insufficient beta-cell mass for implantation within 72 hours can be cultured for 96 hours and longer to combine multiple preparations in order to reach the desired beta-cell dose and therefore result in a better metabolic benefit.

We report a recurrent CNOT1 de novo missense mutation, GenBank: NM&#95;016284.4; c.1603C>T (p.Arg535Cys), resulting in a syndrome of pancreatic agenesis and abnormal forebrain development in three individuals and a similar phenotype in mice. CNOT1 is a transcriptional repressor that has been suggested as being critical for maintaining embryonic stem cells in a pluripotent state. These findings suggest that CNOT1 plays a critical role in pancreatic and neurological development and describe a novel genetic syndrome of pancreatic agenesis and holoprosencephaly., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims/hypothesis: HLA-A*24 carriership hampers achievement of insulin independence in islet allograft recipients. However, less than half of those who fail to achieve insulin independence carry the allele. We investigated whether genetic polymorphism at the recipients' zinc transporter 8-encoding SLC30A8 gene (rs13266634) could complement their HLA-A*24 status in predicting functional graft outcome., Methods: We retrospectively analysed data of a hospital-based patient cohort followed for 18 months post transplantation. Forty C-peptide-negative type 1 diabetic individuals who received >2 million beta cells (>4000 islet equivalents) per kg body weight in one or two intraportal implantations under similar immunosuppression were genotyped for SLC30A8. Outcome measurements included achievement and maintenance of graft function. Metabolic benefit was defined as <25% CV of fasting glycaemia in the presence of >331 pmol/l C-peptide, in addition to achievement of insulin independence and maintenance of C-peptide positivity., Results: In multivariate analysis, HLA-A*24 positivity, presence of SLC30A8 CT or TT genotypes and BMI more than or equal to the group median (23.9 kg/m 2 ) were independently associated with failure to achieve insulin independence (p = 0.015-0.046). The risk increased with the number of factors present (p < 0.001). High BMI interacted with SLC30A8 T allele carriership to independently predict difficulty in achieving graft function with metabolic benefit (p = 0.015). Maintenance of C-peptide positivity was mainly associated with older age at the time of implantation. Only HLA-A*24 carriership independently predicted failure to maintain acceptable graft function once achieved (p = 0.012)., Conclusions/interpretation: HLA-A*24, the SLC30A8 T allele and high BMI are associated with poor graft outcome and should be considered in the interpretation of future transplantation trials., Trial Registration: ClinicalTrials.gov NCT00798785 and NCT00623610.

Background: Induction therapy with a T cell-depleting agent followed by mycophenolate mofetil and tacrolimus is presently the most frequently used immune suppression (IS) regimen in islet transplantation. This study assesses its safety and tolerability in nonuremic type 1 diabetic recipients., Methods: Fifty-one patients (age, between 29 and 63 years) with high glycemic variability and problematic hypoglycemia received intraportal islet grafts under anti-thymocyte globulin-mycophenolate mofetil-tacrolimus protocol. They were followed up for over 48 months for function of the implant and adverse events., Results: Severe hypoglycemia and diabetic ketoacidosis were absent in patients with functioning graft. Immune suppressive therapy was maintained for 48 months in 29 recipients with sustained function (group A), whereas 16 patients stopped earlier due to graft failure (group B) and in 6 for other reasons. Group A was significantly older at the time of implantation and achieved higher graft function at posttransplantation month 6 under similar dose of IS. Prevalence of IS-related side effects was similar in groups A and B, occurring predominantly during the first year posttransplantation. IS-related serious adverse events (SAE) were reported in 47% of patients, with 4 presenting with cytomegalovirus infection and 4 (age, 42-59 years) diagnosed with cancer. Except in 1 patient with cancer, all SAEs resolved after appropriate treatment., Conclusions: These risk/benefit data serve as a basis for clinical decision-making before entering an intraportal islet transplantation protocol. A longer benefit is observed in recipients of higher age (≥40 years), but it is not associated with more side effects and SAE.

Background: Pancreatic agenesis is an extremely rare cause of neonatal diabetes mellitus and has enabled the discovery of several key transcription factors essential for normal pancreas and beta cell development., Case Presentation: We report a case of a Caucasian female with complete pancreatic agenesis occurring together with semilobar holoprosencephaly (HPE), a more common brain developmental disorder. Clinical findings were later confirmed by autopsy, which also identified agenesis of the gallbladder. Although the sequences of a selected set of genes related to pancreas agenesis or HPE were wild-type, the patient's phenotype suggests a genetic defect that emerges early in embryonic development of brain, gallbladder and pancreas., Conclusions: Developmental defects of the pancreas and brain can occur together. Identifying the genetic defect may identify a novel key regulator in beta cell development.

Objective: We investigated whether changes in islet autoantibody profile and presence of HLA risk markers, reported to predict rapid β-cell loss in pre-type 1 diabetes, associate with poor functional outcome in islet allograft recipients., Research Design and Methods: Forty-one patients received ≥2.3 million β-cells/kg body wt in one to two intraportal implantations. Outcome after 6-18 months was assessed by C-peptide (random and stimulated), insulin dose, and HbA1c., Results: Patients carrying HLA-A*24-positive or experiencing a significant autoantibody surge within 6 months after the first transplantation (n = 19) had lower C-peptide levels (P ≤ 0.003) and higher insulin needs (P < 0.001) despite higher HbA1c levels (P ≤ 0.018). They became less often insulin independent (16% vs. 68%, P = 0.002) and remained less often C-peptide positive (47% vs. 100%, P < 0.001) than recipients lacking both risk factors. HLA-A*24 positivity or an autoantibody surge predicted insulin dependence (P = 0.007)., Conclusions: HLA-A*24 and early autoantibody surge after islet implantation associate with poor functional graft outcome., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Regulatory T cells expressing the transcription factor Foxp3 require acquisition of a specific hypomethylation pattern to ensure optimal functional commitment, limited lineage plasticity, and long-term maintenance of tolerance. A better understanding of the molecular mechanisms involved in the generation of these epigenetic changes in vivo will contribute to the clinical exploitation of Foxp3(+) Treg. Here, we show that both in vitro and in vivo generated antigen-specific Foxp3(+) Treg can acquire Treg-specific epigenetic characteristics and prevent skin graft rejection in an animal model.

Background: Transplant patients on tacrolimus therapy exhibit a reduced glomerular filtration rate (GFR). The type of graft and immune treatment protocol may influence the extent and reversibility of this side effect., Methods: The present single-center study is conducted in 48 nonuremic type 1 diabetic recipients of an intraportal islet-cell graft under maintenance immunosuppression (IS) with tacrolimus and mycophenolate mofetil. Estimated GFR (eGFR) and albuminuria were followed up to 5 years posttransplantation., Results: Mean eGFR values decreased by 19 mL/min/1.73 m after 1 to 2 weeks of IS (P<0.0001) and then remained stable throughout the complete treatment period. The decrease was related to predose trough tacrolimus concentrations or doses and disappeared upon its discontinuation; it was also associated with the presence of albuminuria at the time of transplantation. Tacrolimus treatment resulted in a reduction of albuminuria; its discontinuation restored albuminuria to the initial levels., Conclusions: The use of tacrolimus in our islet-cell transplant protocol caused an initial 20% reduction in eGFR, which was reversible following its discontinuation, at least within the 5-year follow-up period. The associated reduction in albuminuria was also reversible, compatible with a tacrolimus-induced preglomerular vasoconstriction. These observations support further use of our tacrolimus regimen in this patient population.

Early demonstrations that mice could be tolerized to transplanted tissues with short courses of immunosuppressive therapy and that with regard to tolerance to self, CD4+FOXP3+ regulatory T cells (Tregs) appeared to play a critical role, have catalyzed strategies to harness FOXP3-dependent processes to control rejection in human transplantation. This review seeks to examine the scientific underpinning for this new approach to finesse immunosuppression.

Objective: Previous work has shown a correlation between β-cell number in cultured islet cell grafts and their ability to induce C-peptide secretion after intraportal implantation in C-peptide-negative type1 diabetic patients. In this cross-sectional study, we examined the minimal functional β-cell mass (FBM) in the implant that induces metabolic improvement., Research Design and Methods: Glucose clamps assessed FBM in 42 recipients with established implants. C-peptide release during each phase was expressed as percentage of healthy control values. Its relative magnitude during a second hyperglycemic phase was most discriminative and therefore selected as a parameter to be correlated with metabolic effects., Results: Recipients with functioning β-cell implants exhibited average FBM corresponding to 18% of that in normal control subjects (interquartile range 10-33%). Its relative magnitude negatively correlated with HbA1c levels (r = -0.47), daily insulin dose (r = -0.75), and coefficient of variation of fasting glycemia (CVfg) (r = -0.78, retained in multivariate analysis). A correlation between FBM and CVfg <25% appeared from the receiver operating characteristic curve (0.97 [95% CI 0.93-1.00]). All patients with FBM >37% exhibited CVfg <25% and a >50% reduction of their pretransplant CVfg; this occurred in none with FBM <5%. Implants with FBM >18% reduced CVfg from a median pretransplant value of 46 to <25%., Conclusions: Glucose clamping assesses the degree of restoration in FBM achieved by islet cell implants. Values >37% of normal control subjects appear needed to reduce glycemic variability in type 1 diabetic recipients. Further studies should examine whether the test can help guide decisions on additional islet cell transplants and on adjusting or stopping immunotherapy.

Background: Islet transplantation has been reported to induce allosensitization in the majority of type 1 diabetic recipients of fresh or shortly incubated islet grafts prepared from one to three donors., Methods: We examined the appearance of human leukocyte antigen (HLA) antibodies after withdrawal of immunosuppressants in 35 type 1 diabetic recipients of islet cell grafts prepared from a median of 6 donors (range, 2-11), cultured for longer periods, and characterized for their cellular composition. Immunosuppression consisted of antithymocyte globulin induction followed by mycophenolate mofetil plus calcineurin inhibitors (n=28, with 7 also receiving steroids) or sirolimus with (n=3) or without calcineurin inhibitors (n=4). Both the complement-dependent cytotoxicity (CDC) assay (class I) and the solid-phase flow-based Luminex method (class I and II) were used to identify HLA antibodies., Results: Immunosuppressant withdrawal resulted in CDC positivity for class I antibodies in only 6% of patients. However, the majority became positive for class I antibodies (72%) or class II antibodies (72%) in the Luminex assay; positivity was not correlated to a higher number of donors or HLA mismatches, but with a lower β-cell purity; use of steroids reduced de novo positivity for Luminex class I antibodies., Conclusion: Allosensitization to cultured human islet cell grafts was low when assessed by CDC assay but high in Luminex. No correlation was found with the number of donors but risk was higher for grafts with lower β-cell purity.

The success of clinical organ transplantation relies on life-long use of immunosuppressive drugs that target immune responses associated with graft rejection. Preclinical studies in mice have convincingly demonstrated that robust, long-term transplantation tolerance can be achieved after a short-term treatment with T-cell coreceptor and costimulation blockade even for a fully mismatched graft. Such therapeutically induced tolerance requires the induction of Foxp3⁺ Tregs, which are essential for both the development and maintenance of the tolerant state. Recent advances in understanding the molecular and epigenetic mechanisms underlying the induction and stabilization of Foxp3 expression, thus guiding Foxp3⁺ Treg differentiation, have revealed novel therapeutic targets in animal models that can be translated to harness Foxp3⁺ Tregs from within the patient. Such in vivo induced Foxp3⁺ Tregs can also induce the tolerant state. Pharmacological compounds are available to exploit these targets and their further development holds great promise for clinical translation.

CD4(+)Foxp3(+) regulatory T cells (Treg) are essential for immune homeostasis and maintenance of self-tolerance. They are produced in the thymus and also generated de novo in the periphery in a TGF-β-dependent manner. Foxp3(+) Treg are also required to achieve tolerance to transplanted tissues when induced by coreceptor or costimulation blockade. Using TCR-transgenic mice to avoid issues of autoimmune pathology, we show that Foxp3 expression is both necessary and sufficient for tissue tolerance by coreceptor blockade. Moreover, the known need in tolerance induction for TGF-β signaling to T cells can wholly be explained by its role in induction of Foxp3, as such signaling proved dispensable for the suppressive process. We analyzed the relative contribution of TGF-β and Foxp3 to the transcriptome of TGF-β-induced Treg and showed that TGF-β elicited a large set of downregulated signature genes. The number of genes uniquely modulated due to the influence of Foxp3 alone was surprisingly limited. Retroviral-mediated conditional nuclear expression of Foxp3 proved sufficient to confer transplant-suppressive potency on CD4(+) T cells and was lost once nuclear Foxp3 expression was extinguished. These data support a dual role for TGF-β and Foxp3 in induced tolerance, in which TGF-β stimulates Foxp3 expression, for which sustained expression is then associated with acquisition of tolerance.

Autoreactive cytotoxic CD8 T-cells (CTLs) play a key pathogenic role in the destruction of insulin-producing beta-cells resulting in type 1 diabetes. However, knowledge regarding their targets is limited, restricting the ability to monitor the course of the disease and immune interventions. In a multi-step discovery process to identify novel CTL epitopes in human preproinsulin (PPI), PPI was digested with purified human proteasomes, and resulting COOH-fragments aligned with algorithm-predicted HLA-binding peptides to yield nine potential HLA-A1, -A2, -A3 or -B7-restricted candidates. An UV-exchange method allowed the generation of a repertoire of multimers including low-affinity HLA-binding peptides. These were labeled with quantum dot-fluorochromes and encoded in a combinatorial fashion, allowing parallel and sensitive detection of specific, low-avidity T-cells. Significantly increased frequencies of T-cells against four novel PPI epitopes (PPI(4-13)/B7, PPI(29-38)/A2, PPI(76-84)/A3 and PPI(79-88)/A3) were detected in stored blood of patients with recent onset diabetes but not in controls. Changes in frequencies of circulating CD8 T-cells against these novel epitopes were detected in blood of islet graft recipients at different time points after transplantation, which correlated with clinical outcome. In conclusion, our novel strategy involving a sensitive multiplex detection technology and requiring minimal volumes of stored blood represents a major improvement in the direct ex-vivo characterization and enumeration of immune cells in the pathogenesis of type 1 diabetes., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: The safety of any immune modulating agent in type 1 diabetes mellitus (T1DM) involves its selectivity on autoimmunity and its preservation of recall and tumour immunity., Methods: We performed lymphocyte proliferation tests on seven recent onset diabetic patients treated with anti-CD3 (Otelixizumab; ChAglyCD3) and five recent onset diabetic patients treated with placebo, on average 2 years after therapy., Results: Proliferative responses towards common viral, bacterial and yeast antigens upon in vitro stimulation with a range of recall antigens in anti-CD3-treated T1DM patients were highly similar to those in placebo-treated T1DM patients. Similarly, T-cell responses towards autoantigens were equally low between the two groups, several years after diagnosis of T1DM. The proliferative response upon stimulation with the human suppressor protein p53 was invariably high in both anti-CD3- and placebo-treated patients, implying preserved anti-tumour immunity in anti-CD3 treatment., Conclusions: As long-term focus on side effects is key, we demonstrate in this sub-cohort of recent onset T1DM patients treated with Otelixizumab that recall immunity is preserved in spite of high-dose anti-CD3 treatment, adding to the safety of anti-CD3 treatment as an immune-modulatory agent in the treatment of T1DM., (Copyright © 2011 John Wiley & Sons, Ltd.)

Background: Several simple measures of graft function after islet transplantation have been proposed but a comparative evaluation is lacking. Here, we compared the performance of five indices of β-cell function: β-score, transplant estimated function (TEF), homeostasis model assessment (HOMA) 2-B%, C-peptide/glucose ratio, and Secretory Units of Islets in Transplantation (SUIT)., Methods: Two cohorts of transplanted patients were analyzed. Cohort 1 consisted of 14 recipients with type 1 diabetes of islet transplantation whereas cohort 2 consisted of 21 recipients with type 1 diabetes of cultured islet cell graft. The five surrogate indices were compared against the first- and second-phase insulin response to arginine in cohort 1, and against the C-peptide response to a hyperglycemic clamp in cohort 2., Results: We found that the performances of the five surrogate indices were close one to each other in cohort 1. The correlation coefficients ranged 0.62 to 0.67 and 0.62 to 0.68 against the first- and second-phase insulin response to arginine, respectively. In cohort 2, we found that the β-score, TEF, C-peptide/glucose ratio, and SUIT were reasonably well correlated with the clamp response (correlation coefficients were in the range 0.71-0.81), whereas HOMA2-B% showed a modest performance (r=0.54). HOMA2-B% could not be evaluated in one patient whose fasting glucose concentration level was below the lower bound indicated by the HOMA calculator (3 mmol/L). SUIT could not be evaluated in three patients whose fasting glucose concentration was below the glucose threshold of the SUIT formula (3.43 mmol/L)., Conclusion: In summary, no single index outperformed the others. Nevertheless, when the benefit to cost ratio is considered, TEF stands out for its good performance at a very low cost.

Objective: The metabolic outcome of islet cell transplants in type 1 diabetic patients is variable. This retrospective analysis examines whether differences in recipient characteristics at the time of transplantation are correlated with inadequate graft function., Research Design and Methods: Thirty nonuremic C-peptide-negative type 1 diabetic patients had received an intraportal islet cell graft of comparable size under an ATG-tacrolimus-mycophenolate mofetil regimen. Baseline patient characteristics were compared with outcome parameters during the first 6 posttransplant months (i.e., plasma C-peptide, glycemic variability, and gain of insulin independence). Correlations in univariate analysis were further examined in a multivariate model., Results: Patients that did not become insulin independent exhibited significantly higher counts of B-cells as well as a T-cell autoreactivity against insulinoma-associated protein 2 (IA2) and/or GAD. In one of them, a liver biopsy during posttransplant year 2 showed B-cell accumulations near insulin-positive beta-cell aggregates. Higher baseline total lymphocytes and T-cell autoreactivity were also correlated with lower plasma C-peptide levels and higher glycemic variability., Conclusions: Higher total and B-cell counts and presence of T-cell autoreactivity at baseline are independently associated with lower graft function in type 1 diabetic patients receiving intraportal islet cells under ATG-tacrolimus-mycophenolate mofetil therapy. Prospective studies are needed to assess whether control of these characteristics can help increase the function of islet cell grafts during the first year posttransplantation.