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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.)

The field of regenerative medicine offers potential therapies for Type 1 Diabetes, whereby metabolically active cellular components are combined with synthetic medical devices. These therapies are sometimes referred to as "bioartificial pancreases." For these emerging and rapidly developing therapies to be clinically translated to patients, researchers must overcome not just scientific hurdles, but also navigate complex legal, ethical and psychosocial issues. In this article, we first provide an introductory overview of the key legal, ethical and psychosocial considerations identified in the existing literature and identify areas where research is currently lacking. We then highlight two principal areas of concern in which these discrete disciplines significantly overlap: 1) individual autonomy and 2) access and equality. Using the example of beta-cell provenance, we demonstrate how, by harnessing an interdisciplinary approach we can address these key areas of concern. Moreover, we provide practical recommendations to researchers, clinicians, and policymakers which will help to facilitate the clinical translation of this cutting-edge technology for Type 1 Diabetes patients. Finally, we emphasize the importance of exploring patient perspectives to ensure their responsible and acceptable translation from bench to body., 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 © 2023 de Jongh, Thom, Cronin, Bunnik and Massey.)

Flash glucose monitoring (FGM) is increasingly used for blood glucose assessment due to ease of use and is now subsidized in Australia for blood glucose measurement for patients with Type 1 Diabetes Mellitus. Dysglycaemia is common following kidney transplantation and is associated with worse outcomes and there are data to support the use of FGM post-transplant to better detect and manage changes in blood glucose levels. There is, however, no data on patient or staff perceptions of FGM, or resource implications in this setting. We prospectively evaluated patients and nursing staff experiences of FGM compared to traditional capillary glucose measurement in the immediate post-transplant setting, along with resource utilization, cost of testing, staff time taken to test and accuracy. Twenty-one kidney transplant recipients had a FGM sensor applied in the post-operative period and results compared to capillary blood glucose monitoring (CBGM) measured at least four times a day. Six-hundred-fifty-six glucose measurements were obtained, median per patient of 30 readings (IQR 10). Pearson's correlation between FGM and CBGM readings is 0.95 (p < .001). FGM readings were lower than CBGM by an average of 1.2 mmol/L (SD 0.7). Using a 5-point preference questionnaire (with ratings varying from strongly disagree-strongly agree), both patients and nurses were highly satisfied with the usability and convenience of FGM, with all preferring FGM over CBGM. Average time to perform FGM was 3.6 s versus 64 s for CBGM. In average, cost of FGM was $58 less than traditional testing per patient. FGM is an accurate, convenient and cost-effective tool that may support optimal management of glycaemic control in the post-transplant period., (© 2023 The Authors. Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology.)

Introduction/aims: Pancreatic islet transplantation (ITx) is increasingly used in patients with brittle type 1 diabetes (T1D). If successful, ITx results in insulin-free euglycemia, but its application is limited by a need for lifelong immunosuppression. The aim of this study was to assess the long-term effects of ITx on the occurrence and course of polyneuropathy in a cohort of patients with brittle T1D., Methods: In this prospective, single-center study, 13 patients (4 males and 9 females) with brittle T1D had a baseline neurological exam with the calculation of Utah Neuropathy Scale (UNS) and a limited nerve conduction study before ITx, and about yearly after in the patients who achieved insulin independence., Results: Patients were followed for a period of 17 to 133 months. There was no significant difference between UNS and nerve conduction study parameters at baseline and at the end of follow-up, except for significant decreases in peroneal (50.34 ± 6.12 vs. 52.42 ± 6.47 ms, P = 0.005) and ulnar (27.5 ± 2.15 vs. 29.45 ± 2.10 ms, P = 0.009) F-wave latencies and an increase in ulnar sensory nerve conduction velocity (49.98 ± 6.27 vs. 47.19 ± 5.36 m/s, P = 0.04)., Discussion: If successful, ITx has a good long-term safety profile for peripheral nerve toxicity, and a favorable effect on diabetic neuropathy., (© 2023 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Aims: To compare the time required for perioperative glucose management using fully automated closed-loop versus standard insulin therapy., Methods: We performed a time-motion study to quantify the time requirements for perioperative glucose management with fully closed-loop (FCL) and standard insulin therapy applied to theoretical scenarios. Following an analysis of workflows in different periods of perioperative care in elective surgery patients receiving FCL or standard insulin therapy upon hospital admission (pre- and intra-operatively, at the intermediate care unit and general wards), the time of process-specific tasks was measured by shadowing hospital staff. Each task was measured 20 times and its average duration in combination with its frequency according to guidelines was used to calculate the cumulative staff time required for blood glucose management. Cumulative time was calculated for theoretical scenarios consisting of elective minor and major abdominal surgeries (pancreatic surgery and sleeve gastrectomy, respectively) to account for the different care settings and lengths of stay., Results: The FCL insulin therapy reduced the time required for perioperative glucose management compared to standard insulin therapy, across all assessed care periods and for both perioperative pathways (range 2.1-4.5). For a major abdominal surgery, total time required was 248.5 min using FCL versus 753.9 min using standard insulin therapy. For a minor abdominal surgery, total time required was 68.6 min and 133.2 min for FCL and standard insulin therapy, respectively., Conclusions: The use of fully automated closed-loop insulin delivery for inpatient glucose management has the potential to alleviate the workload of diabetes management in an environment with adequately trained staff., (© 2023 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Islet transplantation (IT) offers the potential to restore euglycemia for patients with type 1 diabetes mellitus (T1DM). Despite improvements in islet isolation techniques and immunosuppressive regimes, outcomes remain suboptimal with UK five-year graft survivals (5YGS) of 55% and most patients still requiring exogenous insulin after multiple islet infusions. Native islets have a significant non-endocrine component with dense extra-cellular matrix (ECM), important for islet development, cell survival and function. Collagenase isolation necessarily disrupts this complex islet microenvironment, leaving islets devoid of a supporting framework and increasing vulnerability of transplanted islets. Following portal venous transplantation, a liver injury response is potentially induced, which typically results in inflammation and ECM deposition from liver specific myofibroblasts. The impact of this response may have important impact on islet survival and function. A fibroblast response and ECM deposition at the kidney capsule and eye chamber alongside other implantation sites have been shown to be beneficial for survival and function. Investigating the implantation site microenvironment and the interactions of transplanted islets with ECM proteins may reveal therapeutic interventions to improve IT and stem-cell derived beta-cell therapy., 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 © 2023 Doherty, Khambalia, van Dellen, Jennings and Piper Hanley.)

Introduction: Simultaneous pancreas-kidney transplantation (SPKT) has demonstrated favorable impact on the progression of chronic complications in type-1 diabetes (T1D) and terminal chronic kidney disease (CKD). However, some CKD mineral and bone disorders (CKD-MBD) may persist, even after transplantation. There are only a few studies addressing the long-term progression of bone mineral density (BMD) in these patients. Our aim was to assess baseline BMD and long-term progression and consequences in patients with T1D undergoing SPKT., Methods: A retrospective cohort included patients undergoing SPKT in our tertiary center between 2000 and 2017. BMD progression was assessed on dual X-ray absorptiometry (DXA). Only patients with baseline data and a minimum follow-up of 2 years were included., Results: Seventy-three patients were included, 53.4% male, with a median age at SPKT of 35 years (interquartile range [IQR] 31; 39). At transplantation, the median T-scores for the lumbar spine (LS) and femoral neck (FN) were -1.6 (IQR -2.6; -1.1) and --2.1 (IQR -2.7; -1.6), respectively. Seventy-five percent of patients presented low BMD (osteopenia or osteoporosis) in the LS and 90% in the FN, with 33% osteoporosis in the LS and 36% in the FN. On multivariate analysis, male gender (odds ratio [OR] 10.82, 95% confidence interval (CI) 2.88-40.70) and low body-mass index (BMI) (OR 0.73, 95% CI 0.55-0.97) were significantly associated with lumbar but not femoral osteoporosis. At long-term follow-up, BMD significantly improved in the LS (ΔT-score +0.41, P<0.001) and FN (ΔT-score +0.29, P=0.01), at a median 4 years after SPKT. Twelve (16.4%) and 9 (12.3%) patients showed persistent FN and LS osteoporosis, respectively. Multivariate linear regression showed that high BMI was predictive of improvement in BMD., Conclusions: This study demonstrated severe skeletal fragility in T1D patients with terminal CKD undergoing SPKT, more than a quarter of whom showed osteoporosis. The significant improvement in BMD may result from metabolic correction by SPKT and from physiological skeleton mineralization, which continues in this age group. BMD progression was positively associated with BMI, due to improved nutritional balance after transplantation., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Intrahepatic transplantation of islets of Langerhans (ITx) is a treatment option for individuals with complicated type 1 diabetes and profoundly unstable glycemic control, but its therapeutic success is hampered by deterioration of graft function over time. To improve ITx strategies, technologies to noninvasively monitor the fate and survival of transplanted islets over time are of great potential value. We used [68Ga]Ga-NODAGA-exendin-4 (68Ga-exendin) positron emission tomography (PET)/computed tomography (CT) imaging to demonstrate the feasibility of quantifying β-cell mass in intrahepatic islet grafts in 13 individuals with type 1 diabetes, nine after ITx with functional islet grafts and four control patients not treated with ITx. β-Cell function was measured by mixed-meal tolerance test. With dynamic 68Ga-exendin PET/CT images, we determined tracer accumulation in hepatic hotspots, and intrahepatic fat was assessed using MRI and spectroscopy. Quantification of hepatic hotspots showed a significantly higher uptake of 68Ga-exendin in the ITx group compared with the control group (median 0.55 [interquartile range 0.51-0.63] vs. 0.43 [0.42-0.45]). GLP-1 receptor expression was found in transplanted islets by immunohistochemistry. Intrahepatic fat was not detected in a majority of the individuals. Our study provides the first clinical evidence that radiolabeled exendin imaging can be used to monitor viable transplanted islets after intraportal ITx., Article Highlights: This clinical study researched the potential of radiolabeled exendin to follow the fate and survival of intrahepatic islet grafts. Is it feasible to quantitatively detect intrahepatic islet transplants with [68Ga]Ga-NODAGA-exendin-4 (68Ga-exendin) positron emission tomography (PET) imaging? Our study findings indicate that the imaging technique 68Ga-exendin PET can be used to monitor viable islet mass after intrahepatic islet transplantation in humans. Alongside functional measures, 68Ga-exendin PET imaging could significantly aid in the evaluation of strategies designed to improve islet engraftment, survival, and function., (© 2023 by the American Diabetes Association.)

Background: Simultaneous pancreas-kidney transplantation (SPKT) is the treatment of choice for type 1 diabetes patients with end-stage renal disease. Donor characteristics are determinants of graft and patient survival. We aimed to study the impact of donor age on outcomes in SPKT., Methods: We retrospectively studied 254 patients submitted to SPKT between 2000 and 2021. Patients were classified as "younger donor" (donor age <40 years) and "older donor" (donor age ≥40 years)., Results: Fifty-three patients received grafts from older donors. Pancreas graft survival rates at 1, 5, 10, and 15 years were 89%, 83%, 77%, and 73% in the younger donor group, respectively, and 77%, 73%, 67%, and 62% in the older donor group, respectively (P = .052). Older donors and previous major adverse cardiovascular events (MACEs) were associated with pancreas graft failure at 15 years. Kidney transplant survival (1, 5, 10, and 15 years) was lower in the older donor cohort (94%, 92%, 69%, 60% vs 97%, 94%, 89%, and 84%, respectively; P = .004). Older donor, recipient age, and previous MACE predicted kidney graft failure at 15 years. Patient survival rates at 1, 5, 10, and 15 years were 98%, 95%, 91%, and 81% in the younger donor group, respectively, versus 92%, 90%, 84%, and 72% in the older donor group, respectively (P = .127)., Conclusions: The kidney graft survival rate was lower in the older donor group, whereas pancreas graft survival and patient survival did not differ significantly. Multivariate analysis showed that a donor age of ≥40 years was an independent predictor of pancreas and kidney graft failure at 15 years in SPKT patients., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A child diagnosed with type 1 diabetes mellitus during her middle childhood developed severe subcutaneous insulin resistance as her illness progressed. This resulted in recurrent episodes of diabetic ketoacidosis and hypoglycaemia, eventually leading to intravenous insulin dependence. Despite intensive investigations, an organic cause was not found.The patient was in her late adolescence when she eventually received her pancreas transplant alone, the youngest patient in the UK. This case highlights severe peripheral insulin resistance as an important indication for whole organ pancreas transplantation in the paediatric population, as well as early recognition in the failure of conventional medical therapy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Long-term success in beta-cell replacement remains limited by the toxic effects of calcineurin inhibitors (CNI) on beta-cells and renal function. We report a multi-modal approach including islet and pancreas-after-islet (PAI) transplant utilizing calcineurin-sparing immunosuppression. Ten consecutive non-uremic patients with Type 1 diabetes underwent islet transplant with immunosuppression based on belatacept (BELA; n = 5) or efalizumab (EFA; n = 5). Following islet failure, patients were considered for repeat islet infusion and/or PAI transplant. 70% of patients (four EFA, three BELA) maintained insulin independence at 10 years post-islet transplant, including four patients receiving a single islet infusion and three patients undergoing PAI transplant. 60% remain insulin independent at mean follow-up of 13.3 ± 1.1 years, including one patient 9 years after discontinuing all immunosuppression for adverse events, suggesting operational tolerance. All patients who underwent repeat islet transplant experienced graft failure. Overall, patients demonstrated preserved renal function, with a mild decrease in GFR from 76.5 ± 23.1 mL/min to 50.2 ± 27.1 mL/min ( p = 0.192). Patients undergoing PAI showed the greatest degree of renal impairment following initiation of CNI (56% ± 18.7% decrease in GFR). In our series, repeat islet transplant is ineffective at maintaining long-term insulin independence. PAI results in durable insulin independence but is associated with impaired renal function secondary to CNI dependence., 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 © 2023 Wisel, Posselt, Szot, Nunez, Santos-Parker, Gardner, Worner, Roll, Syed, Kelly, Ward, Tavakol, Johnson, Masharani and Stock.)

Purpose: To report outcomes of cataract surgery in type 1 diabetes mellitus (T1DM) compared with type 2 diabetes mellitus (T2DM) and patients without diabetes mellitus (DM)., Setting: Academic tertiary referral university hospital eye center, Aurora, Colorado., Design: Retrospective chart review using the University of Colorado Cataract Outcomes Database for all cataract surgeries between 2014 and 2020., Methods: Demographics, ocular history, and postoperative outcomes were compared across groups using general linear and logistic regression modeling with estimating equations to account for some patients having 2 eyes included., Results: 8117 patients and 13 383 eyes were included. Compared with T2DM eyes undergoing cataract surgery (n = 3115), T1DM eyes (n = 233) were more likely to have a history of diabetic retinopathy (DR) (60.5% vs 23.6%, P < .0001), of which proliferative DR was the most common (63.1% vs 42.4%, P < .0001). T1DM eyes were also more likely to have a history of retinal detachment (RD) (9.0% vs 2.9%, P < .0001) and prior vitrectomy surgery (12.9% vs 4.0%, P < .0001). Despite having similar preoperative corrected distance visual acuity (CDVA) as T2DM eyes (logMAR 0.52 vs 0.44, P = .092), T1DM eyes had worse CDVA after cataract surgery (logMAR 0.27 vs 0.15, P = .0003). In a multivariate analysis, a history of proliferative DR and prior RD were significant predictors of worse postoperative CDVA ( P < .0001) but type of DM was not ( P = .894)., Conclusions: T1DM eyes have worse visual outcomes after cataract surgery compared with T2DM eyes. Worse postoperative visual acuity was associated with worse preoperative DR and history of RD rather than type of DM., (Copyright © 2023 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)

Background: Allogeneic islet transplantation is a validated therapy in type 1 diabetes; however, there is decline of transplanted islet graft function over time and the mechanisms underlying this decline are unclear. We evaluated the distinct association between primary graft function (PGF) and 5-year islet transplantation outcomes., Methods: In this retrospective, multicentre, observational cohort study, we enrolled all patients from the Collaborative Islet Transplant Registry who received islet transplantation alone (ITA recipients) or islet-after-kidney transplantation (IAK recipients) between Jan 19, 1999, and July 17, 2020, with a calculable PGF (exposure of interest), measured 28 days after last islet infusion with a validated composite index of islet graft function (BETA-2 score). The primary outcome was cumulative incidence of unsuccessful islet transplantation, defined as an HbA 1c of 7·0% (53 mmol/mol) or higher, or severe hypoglycaemia (ie, requiring third-party intervention to correct), or a fasting C-peptide concentration of less than 0·2 ng/mL. Secondary outcomes were graft exhaustion (fasting C-peptide <0·3 ng/mL); inadequate glucose control (HbA 1c ≥7·0% [53 mmol/mol] or severe hypoglycaemia); and requirement for exogenous insulin therapy (≥14 consecutive days). Associations between PGF and islet transplantation outcomes were explored with a competing risk analysis adjusted for all covariates suspected or known to affect outcomes. A predictive model based on PGF was built and internally validated by using bootstraps resampling method., Findings: In 39 centres worldwide, we enrolled 1210 patients with a calculable PGF (of those without missing data, mean age 47 years [SD 10], 712 [59·5%] were female, and 865 (97·9%) were White), who received a median of 10·8 thousand islet-equivalents per kg of bodyweight (IQR 7·4-13·5). 986 (82·4%) were ITA recipients and 211 (17·6%) were IAK recipients. Of 1210 patients, 452 (37·4%) received a single islet infusion and 758 (62·6%) received multiple islet infusions. Mean PGF was 14·3 (SD 8·8). The 5-year cumulative incidence of unsuccessful islet transplantation was 70·7% (95% CI 67·2-73·9), and was inversely and linearly related to PGF, with an adjusted subhazard ratio (sHR) of 0·77 (95% CI 0·72-0·82) per 5-unit increase of BETA-2 score (p<0·0001). Secondary endpoints were similarly related to PGF. The model-adjusted median C-statistic values of PGF for predicting 5-year cumulative incidences of unsuccessful islet transplantation, graft exhaustion, inadequate glucose control, and exogenous insulin therapy were 0·70 (range 0·69-0·71), 0·76 (0·74-0·77), 0·65 (0·64-0·66), and 0·72 (0·71-0·73), respectively., Interpretation: This global multicentre study reports a linear and independent association between PGF and 5-year clinical outcomes of islet transplantation. The main study limitations are its retrospective design and the absence of analysis of complications., Funding: Public Health Service Research, National Institutes of Health, Juvenile Diabetes Research Foundation International, Agence National de la Recherche, Fondation de l'Avenir, and Fonds de Dotation Line Renaud-Loulou Gasté., Competing Interests: Declaration of interests CB, EP and FB were employed by The EMMES Company. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Competing Interests: SF collaborates with, and receives funding from, Novo Nordisk, Cell Therapy Programme, Copenhagen, Denmark.

Background: Nail-patella syndrome (NPS) is a rare autosomal dominant disorder caused by a mutation in LIM-homeodomain transcription factor 1-beta (LMX1B) and characterized by nail dystrophy, skeletal changes, glaucoma, and kidney disease with up to 30% of patients progressing to kidney failure. Autoimmune diseases, including thyroid disease, have been reported previously in patients with NPS., Case-Diagnosis/treatment: We report the case of a pediatric patient with NPS with kidney failure, hypothyroidism, and type 1 diabetes mellitus. The patient's pedigree and identification of a kidney specific mutation in LMX1B was a result of whole exome sequencing. Clinical data was obtained from retrospective chart review and included the 1-year post-transplant follow-up period. At 15 years of age, our patient received a simultaneous kidney-pancreas transplantation, from a 3 HLA antigen mismatched deceased donor. The donor was CMV + , EBV - and our patient was CMV - , EBV - at time of transplant. Our patient maintained normal kidney function and euglycemia without insulin therapy at 1 year post-transplant., Conclusions: The patient's hypothyroidism, diabetes mellitus, and kidney failure may all be related to LMX1B mutation. Further study is needed to clarify the genetic link between these processes. Simultaneous kidney-pancreas transplantation can be used to successfully treat diabetes mellitus and kidney failure in a pediatric patient., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Intrahepatic islet transplantation for type 1 diabetes is limited by the need for multiple infusions and poor islet viability posttransplantation. The development of alternative transplantation sites is necessary to improve islet survival and facilitate monitoring and retrieval. We tested a clinically proven biodegradable temporizing matrix (BTM), a polyurethane-based scaffold, to generate a well-vascularized intracutaneous "neodermis" within the skin for islet transplantation. In murine models, BTM did not impair syngeneic islet renal-subcapsular transplant viability or function, and it facilitated diabetes cure for over 150 days. Furthermore, BTM supported functional neonatal porcine islet transplants into RAG-1-/- mice for 400 days. Hence, BTM is nontoxic for islets. Two-photon intravital imaging used to map vessel growth through time identified dense vascular networks, with significant collagen deposition and increases in vessel mass up to 30 days after BTM implantation. In a preclinical porcine skin model, BTM implants created a highly vascularized intracutaneous site by day 7 postimplantation. When syngeneic neonatal porcine islets were transplanted intracutaneously, the islets remained differentiated as insulin-producing cells, maintained normal islet architecture, secreted c-peptide, and survived for over 100 days. Here, we show that BTM facilitates formation of an islet-supportive intracutaneous neodermis in a porcine preclinical model, as an alternative islet-transplant site., Article Highlights: Human and porcine pancreatic islets were transplanted into a fully vascularized biodegradable temporizing matrix (Novosorb) that creates a unique intracutaneous site outside of the liver in a large-animal preclinical model. The intracutaneous prevascularized site supported pancreatic islet survival for 3 months in a syngeneic porcine-transplant model. Pancreatic (human and porcine) islet survival and function were demonstrated in an intracutaneous site outside of the liver for the first time in a large-animal preclinical model., (© 2023 by the American Diabetes Association.)

Background: Previously we performed clinical encapsulated neonatal porcine islet transplantation under comprehensive regulation, and demonstrated the efficacy and safety. To analyze the patients' quality of life (QOL), we assessed patients' opinions 10 years after islet xenotransplantation., Methods: Twenty-one type 1 diabetic patients received microencapsulated neonatal porcine islet transplants in Argentina were enrolled. Seven patients were enrolled in efficacy and safety study and 14 patients were enrolled in safety studies. Patients' opinions related to the current and pre-transplant status of diabetes control, blood glucose levels, severe hypoglycemia, and hyperglycemia required hospitalization were analyzed. In addition, opinions related to islet xenotransplantation were assessed., Results: At the time of this survey, average HbA1c was still significantly lower compared to pre-transplantation (8.5 ± 0.9 (%) at pre-transplant and 7.4 ± 0.5(%) at the survey, p < .05) and average insulin dose were also lower (0.95 ± 0.32 (IU/kg) at pre-transplant and 0.73 ± 0.27 (IU) at the survey). The majority of patients improved diabetes control (71%), blood glucose levels (76%), severe hypoglycemia (86%) and hyperglycemia required hospitalization (76%), and no patients deteriorated in all of the categories when compared with pre-transplantation. No patients had cancer, or psychological problem, and one patient had a serious adverse event. The majority of patients wanted to recommend this treatment to other patients (76%) and receive booster transplantation (85.7%)., Conclusions: The majority of patients had positive opinions related to the encapsulated porcine islet xenotransplantation 10 years after transplantation., (© 2023 The Authors. Xenotransplantation published by John Wiley & Sons Ltd.)

Background: Duodenal graft perforation (DGP) is a serious complication after pancreas transplantation (PTx) and can lead to pancreas graft loss. Here, we investigated whether the placement of a decompression tube (DT) for the duodenal graft during PTx is clinically useful for preventing DGP., Methods: This study included 54 patients who received PTx for type 1 diabetes at our institution between 2000 and 2020. Among these cases, 28 included DT placement (51.9%; DT group), and the remaining 26 without DT placement (non-DT group) were used as historical controls for comparison to the cases with DT placement., Results: Among all 54 cases, DGP occurred in 7 (13.0%). The DGP incidence did not significantly differ between the DT group (10.7%, 3/28 cases) and the non-DT group (15.4%, 4/26 cases) (P = .6994). Logistic regression analysis showed that DT placement did not affect DGP risk. Notably, 5 cases in the DT group (17.9%) exhibited adverse effects that were likely the result of DT placement, including bleeding from tube contact (2 cases), enterocutaneous fistula at the DT placement site (2 cases), and intraabdominal abscess around the DT site (1 case). Pancreas graft survival after PTx did not significantly differ between the DT and non-DT groups (P = .6260)., Conclusions: The DT group did not exhibit superior outcomes compared with the non-DT group. This result suggests that DT placement did not have a clinical impact on DGP prevention after PTx., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: We wanted to compare glycemic control post pancreas transplantation with newer therapeutic options., Methods: We conducted a retrospective analysis of pancreas transplantation at our institution from January 1, 2008, through September 30, 2021. All patients who underwent pancreatic transplantation were 18 years and older. We compared pre-transplant glycemic control of those patients, whether self-monitoring or continuous glucose monitor to their post-transplant glycemic control. Outcomes were assessed by HgbA1C level at evaluation (eval), pretransplant (pre), within the first 5 months posttransplant (post) and 1 year post transplant (1 year)., Results: One hundred and thirty-four patients underwent pancreas transplantation during the 14-year study period. Overall, 1-year patient and graft survival were 95% and 88%. The mean HgbA1C (%) for eval and pre were 8.5(SD ± 1.7) and 8.3(SD ± 1.7), which was significantly higher than post, and 1 year at 5.1(SD ± .6, p < .01) and 5.2(SD ± .6, p < .01). Of those, 38 patients presented with continuous glucose monitors (CGM) +/- pump. Their mean HgbA1C(%) was 8.2(SD ± 1.5) at eval 8.1(SD ± 1.3). These were also significantly higher than post 5.0(SD ± .6, p < .01), and 1 year 5.1(SD ± .5, p < .01)., Conclusion: Pancreas transplant provides superior glycemic control to continuous glucose monitoring and remains the optimal therapy for appropriately selected patients with diabetes., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: ABO-incompatible transplantation has improved accessibility of kidney, heart, and liver transplantation. Pancreatic islet transplantation continues to be ABO-matched, yet ABH antigen expression within isolated human islets or novel human embryonic stem cell (hESC)-derived islets remain uncharacterized., Methods: We evaluated ABH glycans within human pancreata, isolated islets, hESC-derived pancreatic progenitors, and the ensuing in vivo mature islets following kidney subcapsular transplantation in rats. Analyses include fluorescence immunohistochemistry and single-cell analysis using flow cytometry., Results: Within the pancreas, endocrine and ductal cells do not express ABH antigens. Conversely, pancreatic acinar tissues strongly express these antigens. Acinar tissues are present in a substantial portion of cells within islet preparations obtained for clinical transplantation. The hESC-derived pancreatic progenitors and their ensuing in vivo-matured islet-like clusters do not express ABH antigens., Conclusions: Clinical pancreatic islet transplantation should remain ABO-matched because of contaminant acinar tissue within islet preparations that express ABH glycans. Alternatively, hESC-derived pancreatic progenitors and the resulting in vivo-matured hESC-derived islets do not express ABH antigens. These findings introduce the potential for ABO-incompatible cell replacement treatment and offer evidence to support scalability of hESC-derived cell therapies in type 1 diabetes., Competing Interests: A.M.J.S. is supported through a Canada Research Chair (Tier 1) in Regenerative Medicine and Transplant Surgery, and through grant support from the Juvenile Diabetes Research Foundation, Diabetes Canada, the Canadian Donation and Transplant Research Program, the Diabetes Research Institute Foundation of Canada, the Alberta Diabetes Foundation, and the Canadian Stem Cell Network. B.A.M.-G. is supported by the Patronato del Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran (INCMNSZ), the Fundacion para la Salud y la Educacion Dr. Salvador Zubirán (FunSaEd), and the CHRISTUS Excellence and Innovation Center. A.M.J.S. serves as a consultant to ViaCyte Inc. The other authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To determine C-peptide measures and levels associated with positive glycemic control outcomes following islet transplant (ITx) in type 1 diabetes., Research Design and Methods: We evaluated Collaborative Islet Transplant Registry (CITR) islet-alone recipients with pretransplant C-peptide <0.1 nmol/L and mean follow-up of 4.6 ± 1.1 years (n = 677). Receiver operating characteristic area under the curve (ROC-AUC) was used to evaluate the predictive value of fasting and stimulated glucose and C-peptide measures for seven primary outcomes: 1) absence of severe hypoglycemic events (ASHEs); 2) HbA1c <7.0%; 3) HbA1c <7.0% and ASHEs; 4) HbA1c ≤6.5%; 5) HbA1c ≤6.5% and ASHEs; 6) insulin independence; and 7) ASHEs, HbA1c ≤6.5%, and insulin independence (the optimal outcome). Measures with the highest ROC-AUC were selected for determination of optimal cut points., Results: Fasting C-peptide was highly predictive for ASHE (ROC-AUC 0.906; optimal cut point 0.070 nmol/L) and the optimal outcome (ROC-AUC 0.845; optimal cut point 0.33 nmol/L). Mixed-meal tolerance test (MMTT)-stimulated C-peptide-to-glucose ratio (CPGR) outperformed both fasting and stimulated C-peptide for all outcomes except ASHE. The optimal cut point for the optimal outcome was 0.12 nmol/mmol for MMTT-stimulated CPGR and 0.97 nmol/L for MMTT-stimulated C-peptide., Conclusions: Fasting C-peptide reliably predicts ITx primary outcomes. MMTT-stimulated CPGR provides marginally better prediction for composite ITx outcomes, including insulin independence. In the absence of an MMTT, a fasting C-peptide ≥0.33 nmol/L is a reassuring measure of optimal islet graft function. C-peptide targets represent excellent and easily determinable means to predict glycemic control outcomes after ITx and should be considered as potential goals of β-cell replacement., (© 2023 by the American Diabetes Association.)

Background: Information about the impact of diabetic neuropathy (DN) on outcomes after pancreas transplantation (PT) is scarce. We assessed the independent relationship between DN markers with both graft survival and incident cardiovascular disease (CVD) after transplantation., Methods: A cohort study in individuals with type 1 diabetes and end-stage kidney disease who underwent PT between 1999 and 2015 was conducted. DN was assessed with vibration perception thresholds (VPTs) and orthostatic hypotension (pre-PT and 6 mo, 2-3, 5-6, and 8-10 y after transplantation). Pretransplantation and posttransplantation DN markers were related with graft failure/dysfunction and incident CVD during follow-up., Results: We included 187 participants (70% men, age 39.9 ± 7.1 y, diabetes duration 27.1 y), with a median follow-up of 11.3 y. Abnormal VPTs (≥25 V) were observed in 53%. After transplantation, VPTs improved (22.4 ± 8.4 pretransplant versus 16.1 ± 6.1 V at 8-10 y post-PT; P < 0.001); additionally, the prevalence of abnormal VPTs decreased (53% pretransplant versus 24.4% at 8-10 y; P < 0.001). After adjusting for age, sex, diabetes duration, blood pressure, body mass index, and previous CVD, pretransplant VPTs ≥25 V were independently associated with pancreas graft failure/dysfunction (hazard ratio [HR], 2.01 [1.01-4.00]) and incident CVD (HR, 2.57 [1.17-5.64]). Furthermore, persistent abnormal VPTs after 6 mo posttransplantation were associated with the worst outcomes (HR, 2.80 [1.25-6.23] and HR, 3.19 [1.14-8.96], for graft failure/dysfunction and incident CVD, respectively)., Conclusions: In individuals with type 1 diabetes and end-stage kidney disease, PT was associated with an improvement of VPTs. This simple and widely available DN study was independently associated with pancreas graft function and CVD posttransplantation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: While obesity is prevalent among patients with type I diabetes mellitus (T1DM), the effects of metabolic surgery on patients with T1DM have not been adequately investigated. The study aims to investigate the perioperative outcomes and the improvement of comorbidity 1 year following metabolic surgery amongst this patient population., Methods: In this study, we evaluated the effects of sleeve gastrectomy (SG) and Roux-Y gastric bypass (RYGB) on patients with T1DM and insulin resistance., Results: One hundred forty-nine patients (SG n = 91 and RYGB n = 58) with obesity, T1DM, and insulin resistance were analyzed. There was no significant difference in BMI reduction and %EWL 1 year after surgery between the two groups. In the SG group, BMI reduction was 6.5 kg/m 2 versus 5.9 kg/m 2 in the RYGB group (p=0.406). The %EWL was 68.2 ± 25.2 in the RYGB group and 64.3 ± 21.5 in SG (p=0.332). There was also no significant difference in weight loss between the two groups (14.9 ± 5.4 kg in SG vs. 14.2 ± 7 kg in RYGB; p=0.548). In all patients, insulin requirements decreased after surgery, and in 22% of patients, insulin requirements were equivalent to those of normal-weight individuals. There was a significantly higher rate of remission of reflux in RYGB patients than in SG patients (94·44% vs 29·41; p<0.001)., Conclusion: Patients with obesity and T1DM may benefit from metabolic surgery. Both methods produce satisfactory results in this group of patients regarding daily insulin requirements and treatment of obesity-related diseases. However, the decision of which procedure should be carried out still depends on the patient's general condition and the surgeon's technical ability., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The field of cell therapy of type 1 diabetes is a particularly interesting example in the scenario of regenerative medicine. In fact, β-cell replacement has its roots in the experience of islet transplantation, which began 40 years ago and is currently a rapidly accelerating field, with several ongoing clinical trials using β cells derived from stem cells. Type 1 diabetes is particularly suitable for cell therapy as it is a disease due to the deficiency of only one cell type, the insulin-producing β cell, and this endocrine cell does not need to be positioned inside the pancreas to perform its function. On the other hand, the presence of a double immunological barrier, the allogeneic one and the autoimmune one, makes the protection of β cells from rejection a major challenge. Until today, islet transplantation has taught us a lot, pioneering immunosuppressive therapies, graft encapsulation, tissue engineering, and test of different implant sites and has stimulated a great variety of studies on β-cell function. This review starts from islet transplantation, presenting its current indications and the latest published trials, to arrive at the prospects of stem cell therapy, presenting the latest innovations in the field., (© 2022 S. Karger AG, Basel.)

Aim: Major challenges to islet transplantation in Type 1 diabetes include host-inflammation, which results in failure to maintain survival and functions of transplanted islets. Therefore, this study investigated the applications of encapsulating the bile acid ursodeoxycholic acid (UDCA) with transplanted islets within improved nano-gel systems for Type 1 diabetes treatment. Materials & methods: Islets were harvested from healthy mice, encapsulated using UDCA-nano gel and transplanted into the diabetic mice, while the control group was transplanted encapsulated islets without UDCA. The two groups' survival plot, blood glucose, and inflammation and bile acid profiles were analyzed. Results & conclusion: UDCA-nano gel enhanced survival, glycemia and normalized bile acids' profile, which suggests improved islets functions and potential adjunct treatment for insulin therapy.

Aims/hypothesis: This study sought to provide up-to-date pooled global estimates of diabetes-related amputation incidence from 2010 to 2020., Methods: Embase and Medline databases were searched for studies reporting the incidence rate (IR) of diabetes-related amputations from 2010 to 2020. IR estimates of diabetes-related amputations with associated 95% confidence interval (CI) per 100,000 individuals with diabetes were calculated., Results: 23 studies were included, reporting 505,390 diabetes-related lower extremity amputations. IR of minor amputations was 139.97 (95% CI 88.18-222.16) per 100,000 individuals with diabetes, among patients with type 1 diabetes was 148.59 (95% CI 65.00-339.68) and in type 2 diabetes was 75.53 (95% CI 29.94-190.54). IR of major amputations was 94.82 (95% CI 56.62-158.80) per 100,000 individuals with diabetes, among patients with type 1 diabetes was 100.76 (95% CI 53.71-189.01) and among type 2 diabetes was 40.58 (95% CI 11.03-149.28). There were 83.84 annual amputations (95% CI 41.67-168.65) per 100,000 women with diabetes and 178.04 (95% CI 81.16-390.55) per 100,000 men., Conclusions: Globally, annual incidence of diabetes-related amputations from 2010 to 2020 has shown to disproportionately affect men and individuals with type 1 diabetes mellitus, although its incidence is not uniform across countries., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Islet transplantation is an effective treatment for type 1 diabetes (T1D). However, a shortage of donors and the need for immunosuppressants are major issues. The ideal solution is to develop a source of insulin-secreting cells and an immunoprotective method. No bioartificial pancreas (BAP) devices currently meet all of the functions of long-term glycemic control, islet survival, immunoprotection, discordant xenotransplantation feasibility, and biocompatibility. We developed a device in which porcine islets were encapsulated in a highly stable and permeable hydrogel and a biocompatible immunoisolation membrane. Discordant xenotransplantation of the device into diabetic mice improved glycemic control for more than 200 days. Glycemic control was also improved in new diabetic mice "relay-transplanted" with the device after its retrieval. The easily retrieved devices exhibited almost no adhesion or fibrosis and showed sustained insulin secretion even after the two xenotransplantations. This device has the potential to be a useful BAP for T1D., Competing Interests: This work was partially supported by research funds from Mochida Pharmaceutical Co., Ltd. Sodium alginate was provided by Mochida Pharmaceutical Co., Ltd. M.S., S.F., and K.A. are inventors on Japan patent PCT/JP2020/025,324. This patent covers the synthesis of chemically modified sodium alginate and the effectiveness of transplantation devices containing the alginate gels, which is also a topic of this manuscript., (© 2022 The Authors.)

Background: The prevalence of obesity in patients with type 1 diabetes mellitus (T1DM) has been increasing. Metabolic bariatric surgery (MBS) has proven to be effective in treating patients with T2DM. However, evidence for the benefit of the procedure for patients with T1DM is still limited, particularly in terms of glycemic control, demonstrating the need for a systematic review investigating this., Method: A systematic review was performed in accordance with the PRISMA guidelines. Outcome measures such as weight loss, remission of comorbidities, pre- and post-intervention insulin requirements, and HbA1c levels were extracted., Results: Thirty studies were included with a total of 706 patients (F = 524, M = 74, N/A = 60). The mean age was 40.01 years. The mean weight and body mass index (BMI) were 112.76 kg and 40.88 kg/m 2 (24-58.9) respectively. The common procedure performed was RYGB (n = 497 (70.4%)), followed by SG (n = 131 (18.6%)). The mean decrease of insulin requirements was 92.3 IU/day (36.2-174) preoperatively to a mean of 35.8 IU/day (5-75) post-operatively. No significant trend was found for changes in HbA1c levels. The main side effects were episodes of hypoglycemia and diabetic ketoacidosis (DKA); there was no mortality. The mean %EWL was 74.57% (60-90.5%) at ≥ 6 follow-up months. Reductions in comorbidities such as hypertension and cardiovascular disease (CVD) were recorded in multiple studies., Conclusion: Patients with obesity and T1DM can expect significant weight loss, potential resolution of comorbidities, and reduction of insulin requirements, but it does not usually result in improved glycemic control. Based on current review, best choice of bariatric surgery in such patients cannot yet be established., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Type 1 diabetes is a disease resulting from autoimmune destruction of the insulin-producing beta cells in the pancreas. When type 1 diabetes develops into severe secondary complications, in particular end-stage nephropathy, or life-threatening severe hypoglycemia, the best therapeutic approach is pancreas transplantation, or more recently transplantation of the pancreatic islets of Langerhans. Islet transplantation is a cell therapy procedure, that is minimally invasive and has a low morbidity, but does not display the same rate of functional success as the more invasive pancreas transplantation because of suboptimal engraftment and survival. Another issue is that pancreas or islet transplantation (collectively known as beta cell replacement therapy) is limited by the shortage of organ donors and by the need for lifelong immunosuppression to prevent immune rejection and recurrence of autoimmunity. A bioartificial pancreas is a construct made of functional, insulin-producing tissue, embedded in an anti-inflammatory, immunomodulatory microenvironment and encapsulated in a perm-selective membrane allowing glucose sensing and insulin release, but isolating from attacks by cells of the immune system. A successful bioartificial pancreas would address the issues of engraftment, survival and rejection. Inclusion of unlimited sources of insulin-producing cells, such as xenogeneic porcine islets or stem cell-derived beta cells would further solve the problem of organ shortage. This article reviews the current status of clinical islet transplantation, the strategies aiming at developing a bioartificial pancreas, the clinical trials conducted in the field and the perspectives for further progress., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2022 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

There is a critical need for therapeutic approaches that combine renewable sources of replacement beta cells with localized immunomodulation to counter recurrence of autoimmunity in type 1 diabetes (T1D). However, there are few examples of animal models to study such approaches that incorporate spontaneous autoimmunity directed against human beta cells rather than allogenic rejection. Here, we address this critical limitation by demonstrating rejection and survival of transplanted human stem cell-derived beta-like cells clusters (sBCs) in a fully immune competent mouse model with matching human HLA class I and spontaneous diabetes development. We engineered localized immune tolerance toward transplanted sBCs via inducible cell surface overexpression of PD-L1 (iP-sBCs) with and without deletion of all HLA class I surface molecules via beta-2 microglobulin knockout (iP-BKO sBCs). NOD.HLA-A2.1 mice, which lack classical murine MHC I and instead express human HLA-A*02:01, underwent transplantation of 1,000 human HLA-A*02:01 sBCs under the kidney capsule and were separated into HLA-A2 positive iP-sBC and HLA-class I negative iP-BKO sBC groups, each with +/- doxycycline (DOX) induced PD-L1 expression. IVIS imaging showed significantly improved graft survival in mice transplanted with PD-L1 expressing iP-sBC at day 3 post transplantation compared to controls. However, luciferase signal dropped below in vivo detection limits by day 14 for all groups in this aggressive immune competent diabetes model. Nonetheless, histological examination revealed significant numbers of surviving insulin + /PD-L1 + sBCs cells for DOX-treated mice at day 16 post-transplant despite extensive infiltration with high numbers of CD3 + and CD45 + immune cells. These results show that T cells rapidly infiltrate and attack sBC grafts in this model but that significant numbers of PD-L1 expressing sBCs manage to survive in this harsh immunological environment. This investigation represents one of the first in vivo studies recapitulating key aspects of human autoimmune diabetes to test immune tolerance approaches with renewable sources of beta cells., Competing Interests: HR is or has been a consultant and islets SAB member to Sigilon therapeutics, a SAB member at Prellis Biologics and consultant to Eli Lilly and Minutia. 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 © 2022 Santini-González, Castro-Gutierrez, Becker, Rancourt, Russ and Phelps.)

Background: Preliminary studies show promise for extrahepatic islet transplantation (ITx). However, clinical comparisons with intraportal ITx outcomes remain limited., Methods: This single-center cohort study evaluates patients receiving extrahepatic or intraportal ITx between 1999 and 2018. Primary outcome was stimulated C-peptide level. Secondary outcomes were fasting plasma glucose, BETA-2 scores, and fasting C-peptide level. Multivariable logistic modeling evaluated factors independently associated with a composite variable of early graft failure and primary nonfunction within 60 d of ITx., Results: Of 264 patients, 9 (3.5%) received extrahepatic ITx (gastric submucosal = 2, subcutaneous = 3, omental = 4). Group demographics were similar at baseline (age, body mass index, diabetes duration, and glycemic control). At 1-3 mo post-first infusion, patients receiving extrahepatic ITx had significantly lower stimulated C-peptide (0.05 nmol/L versus 1.2 nmol/L, P < 0.001), higher fasting plasma glucose (9.3 mmol/L versus 7.3 mmol/L, P < 0.001), and lower BETA-2 scores (0 versus 11.6, P < 0.001) and SUITO indices (1.5 versus 39.6, P < 0.001) compared with those receiving intraportal ITx. Subjects receiving extrahepatic grafts failed to produce median C-peptide ≥0.2 nmol/L within the first 60 d after transplant. Subsequent intraportal infusion following extrahepatic transplants achieved equivalent outcomes compared with patients receiving intraportal transplant alone. Extrahepatic ITx was independently associated with early graft failure/primary non-function (odds ratio 1.709, confidence interval 73.8-39 616.0, P < 0.001), whereas no other factors were independently predictive., Conclusions: Using current techniques, intraportal islet infusion remains the gold standard for clinical ITx, with superior engraftment, graft function, and glycemic outcomes compared with extrahepatic transplantation of human islets., Competing Interests: A.M.J.S. serves as a consultant to ViaCyte Inc., Diagon Inc., Protokinetix Inc., and Pelican Therapeutics Inc. The other authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Simultaneous pancreas-kidney (SPK) transplant is the primary option in patients with type 1 diabetes mellitus who develop end-stage kidney disease. Pancreas retransplant (PRt) has become an alternative in patients who experience pancreas graft failure (PGF). There is a lack of evidence regarding PRt in international registers. There are small series of published research with indeed heterogeneous results. We aim to compare PRt outcomes with primary SPK transplant in our center., Methods: The study was designed as a descriptive study of a cohort of 234 patients who received SPK transplant and received another PRt because of PGF at Reina Sofía University Hospital between 1988 and 2021. Kaplan-Meier analysis was performed to calculate patient and allograft survival., Results: Of these 234 SPK transplants, 53 pancreas grafts (22.6%) were lost initially. In total, 15 PRts were performed. The major cause of first PGF was surgical, whereas the medical cause was the most frequent in the PRt group. There were 60 deaths in the SPK group compared with only 1 in the PRt group. In Kaplan-Meier analysis, the PRt group showed worse survival than the SPK group, with statistically significant difference between groups (P = .05). Patient survival was not different between both groups., Conclusions: PRt constitutes a viable option for recipients who experience PGF in the absence of formal contraindication. Although graft retransplant survival seems to be inferior to first graft in our series, these results are difficult to compare because of the scarce number of procedures performed., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Simultaneous pancreas-kidney (SPK) transplantation is the treatment of choice in patients with type 1 diabetes and end-stage renal disease, because it improves survival and quality of life. Currently, enteric exocrine drainage is the most commonly used method. Intestinal complications continue to be a major cause of posttransplant morbidity despite improvements in surgical technique. This study analyzed early and late intestinal complications related to SPK transplantation., Materials and Methods: We performed a retrospective analysis of 100 adult patients undergoing SPK transplantation between January 2009 and December 2019. We performed systemic venous drainage and exocrine enteric drainage with duodenojejunostomy. Statistical analysis was performed using SPSS v2. This study was performed in accordance with the Declaration of Istanbul and the 1964 Declaration of Helsinki. Informed consent was obtained from all participants involved in the study., Results: Intestinal complications were reported in 18 patients. Ten patients (10%) had the following early intestinal complications including: ileus (n = 4), intestinal obstruction (n = 2), graft volvulus (n = 1), duodenal graft fistula (n = 1), and jejunal fistula after pancreas transplantation (n = 1). Two cases required relaparotomy: graft repositioning with Roux-en-Y conversion (n = 1) and Y-roux conversion (n = 1). Eight patients had repeated episodes of intestinal obstruction (8%), of whom 2 required surgery for resolution with 100% postoperative mortality., Conclusions: SPK transplantation with enteric drainage via duodenojejunostomy has a low rate of short- and long-term postoperative intestinal complications. Surgery in patients with recurrent intestinal obstruction has a high mortality risk and should be performed in reference transplant centers., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The prevalence of diabetes mellitus (DM) continues to increase among patients undergoing total hip arthroplasty (THA). It is unclear how insulin use is correlated with risk for adverse outcomes., Methods: A cohort of 146,526 patients undergoing primary THA were identified in the 2005-2017 National Surgical Quality Improvement Program database. Patients were classified as insulin-dependent diabetic (IDDM), non-insulin-dependent diabetic (NIDDM), or not diabetic. Multivariate analyses were used., Results: Compared to patients without diabetes, patients with NIDDM were at increased risk for 4 of 17 perioperative adverse outcomes studied. Patients with IDDM were at increased risk for those 4 and 8 additional adverse outcomes (12 of the 17 studied)., Conclusion: These findings have important implications for preoperative risk stratification and quality improvement initiatives.

Insulin represents a life-saving treatment in patients with type 1 diabetes, and technological advancements have improved glucose control in an increasing number of patients. Despite this, adequate control is often still difficult to achieve and insulin remains a therapy and not a cure for the disease. β-cell replacement strategies can potentially restore pancreas endocrine function and aim to maintain normoglycemia; both pancreas and islet transplantation have greatly progressed over the last decades and, in subjects with extreme glycemic variability and diabetes complications, represent a concrete and effective treatment option. Some issues still limit the adoption of this approach on a larger scale. One is represented by the strict selection criteria for the recipient who can benefit from a transplant and maintain the lifelong immunosuppression necessary to avoid organ rejection. Second, with regard to islet transplantation, up to 40% of islets can be lost during hepatic engraftment. Recent studies showed very preliminarily but promising results to overcome these hurdles: the ability to induce β-cell maturation from stem cells may represent a solution to the organ shortage, and the creation of semi-permeable membranes that envelope or package cells in either micro- or macro- encapsulation strategies, together with engineering cells to be hypo-immunogenic, pave the way for developing strategies without immunosuppression. The aim of this review is to describe the state of the art in β-cell replacement with a focus on its efficacy and clinical benefits, on the actual limitations and still unmet needs, and on the latest findings and future directions., (© The Author(s) 2022. Published by Oxford University Press.)

The development of new therapeutic approaches to treat type 1 diabetes mellitus (T1D) relies on the precise understanding and deciphering of insulin-secreting β-cell biology, as well as the mechanisms responsible for their autoimmune destruction. β-cell or islet transplantation is viewed as a potential long-term therapy for the millions of patients with diabetes. To advance the field of insulin-secreting cell transplantation, two main research areas are currently investigated by the scientific community: (1) the identification of the developmental pathways that drive the differentiation of stem cells into insulin-producing cells, providing an inexhaustible source of cells; and (2) transplantation strategies and engineered transplants to provide protection and enhance the functionality of transplanted cells. In this review, we discuss the biology of pancreatic β-cells, pathology of T1D and current state of β-cell differentiation. We give a comprehensive view and discuss the different possibilities to engineer enhanced insulin-secreting cell/islet transplantation from a translational perspective., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Pancreas transplantation in patients with type 2 diabetes (T2D) remains relatively uncommon compared with pancreas transplantation in patients with type 1 diabetes (T1D); however, several studies have suggested similar outcomes between T2D and T1D, and the practice has become increasingly common. Despite this growing interest in pancreas transplantation in T2D, no study has systematically summarized the data to date. We systematically reviewed the literature on pancreas transplantation in T2D patients including patient and graft survival, glycemic control outcomes, and comparisons with outcomes in T2D kidney transplant alone and T1D pancreas transplant recipients. We searched biomedical databases from January 1, 2000, to January 14, 2021, and screened 3314 records, of which 22 full texts and 17 published abstracts met inclusion criteria. Full-text studies were predominantly single center (73%), whereas the remaining most often studied the Organ Procurement and Transplantation Network database. Methodological quality was mixed with frequent concern for selection bias and concern for inconsistent definitions of both T2D and pancreas graft survival across studies. Overall, studies generally reported favorable patient survival, graft survival, and glycemic control outcomes for pancreas transplantation in T2D and expressed a need to better characterize the T2D patients who would benefit most from pancreas transplantation. We suggest guidance for future studies, with the aim of supporting the safe and evidence-based treatment of end-stage T2D and judicious use of scarce resources., Competing Interests: The authors declare no conflict of interests., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Twenty-year follow-up of the first reported simultaneous pancreas-kidney transplant from living donor between identical twins., Case: We present a case of a patient after the world's first simultaneous pancreas and kidney transplant between identical twins. The transplant was performed because of diabetes mellitus type (DM1) related renal failure. Now in her sixties, the patient has had exceptional prolonged bi-graft function without immunosuppression. She is free from DM1 recurrence, does not take insulin, and her creatinine level has stayed with the normal limit., Conclusions: Simultaneous pancreas and kidney transplant can be performed successfully with excellent long-term outcomes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Simultaneous pancreas-kidney transplantation (SPK) carries about a 7%-22% risk of technical failure, but the impact of early pancreas allograft loss on subsequent kidney graft and patient survival is not well-defined. We examined national transplant registry data for type 1 diabetic patients who received SPK between 2000 and 2021. Associations of transplant type (i.e., SPK, deceased-donor kidney transplant [DDKA], living-donor kidney transplant [LDKA]) with kidney graft failure and patient survival were estimated by multivariable inverse probability of treatment-weighted accelerated failure-time models. Compared to SPK recipients with a functioning pancreas graft 3 months posttransplant (SPK,P+), LDKA had 18% (Time Ratio [TR] 0.82, 95%CI: 0.70-0.95) less graft survival time and 18% (TR 0.82, 95%CI: 0.68-0.97) less patient survival time, DDKA had 23% (TR 0.77, 95%CI: 0.68-0.87) less graft survival time and 29% (TR 0.71, 95%CI: 0.62-0.81) less patient survival time, and SPK with early pancreas graft loss had 34% (TR 0.66, 95%CI: 0.56-0.78) less graft survival time and 34% (TR 0.66, 95%CI: 0.55-0.79) less patient survival time. In conclusion, SPK,P+ recipients have better kidney allograft and patient survival compared with LDKA and DDKA. Early pancreas graft failure results in inferior kidney and patient survival time compared to kidney transplant alone., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ji, Wang, Hu, Ibrahim, Lentine, Merzkani, Murad, Al-Hosni, Parsons, Wellen, Chang and Alhamad.)

Background: Neonatal porcine pancreatic cell clusters (NPCCs) have been proposed as an alternative source of β cells for islet transplantation because of their low cost and growth potential after transplantation. However, the delayed glucose lowering effect due to the immaturity of NPCCs and immunologic rejection remain as a barrier to NPCC's clinical application. Here, we demonstrate accelerated differentiation and immune-tolerant NPCCs by in vitro chemical treatment and microencapsulation., Methods: NPCCs isolated from 3-day-old piglets were cultured in F-10 media and then microencapsulated with alginate on day 5. Differentiation of NPCCs is facilitated by media supplemented with activin receptor-like kinase 5 inhibitor II, triiodothyronine and exendin-4 for 2 weeks. Marginal number of microencapsulated NPCCs to cure diabetes with and without differentiation were transplanted into diabetic mice and observed for 8 weeks., Results: The proportion of insulin-positive cells and insulin mRNA levels of NPCCs were significantly increased in vitro in the differentiated group compared with the undifferentiated group. Blood glucose levels decreased eventually after transplantation of microencapsulated NPCCs in diabetic mice and normalized after 7 weeks in the differentiated group. In addition, the differentiated group showed nearly normal glucose tolerance at 8 weeks after transplantation. In contrast, neither blood glucose levels nor glucose tolerance were improved in the undifferentiated group. Retrieved graft in the differentiated group showed greater insulin response to high glucose compared with the undifferentiated group., Conclusion: in vitro differentiation of microencapsulated immature NPCCs increased the proportion of insulin-positive cells and improved transplant efficacy in diabetic mice without immune rejection.

Background: The long-term outcomes of both pancreas and islet allotransplantation have been compromised by difficulties in the detection of early graft dysfunction at a time when a clinical intervention can prevent further deterioration and preserve allograft function. The lack of standardized strategies for monitoring pancreas and islet allograft function prompted an international survey established by an International Pancreas and Islet Transplant Association/European Pancreas and Islet Transplant Association working group., Methods: A global survey was administered to 24 pancreas and 18 islet programs using Redcap. The survey addressed protocolized and for-cause immunologic and metabolic monitoring strategies following pancreas and islet allotransplantation. All invited programs completed the survey., Results: The survey identified that in both pancreas and islet allograft programs, protocolized clinical monitoring practices included assessing body weight, fasting glucose/C-peptide, hemoglobin A1c, and donor-specific antibody. Protocolized monitoring in islet transplant programs relied on the addition of mixed meal tolerance test, continuous glucose monitoring, and autoantibody titers. In the setting of either suspicion for rejection or serially increasing hemoglobin A1c/fasting glucose levels postpancreas transplant, Doppler ultrasound, computed tomography, autoantibody titers, and pancreas graft biopsy were identified as adjunctive strategies to protocolized monitoring studies. No additional assays were identified in the setting of serially increasing hemoglobin A1c levels postislet transplantation., Conclusions: This international survey identifies common immunologic and metabolic monitoring strategies utilized for protocol and for cause following pancreas and islet transplantation. In the absence of any formal studies to assess the efficacy of immunologic and metabolic testing to detect early allograft dysfunction, it can serve as a guidance document for developing monitoring algorithms following beta-cell replacement., Competing Interests: J.S.O. is an investigator in multicenter trials supported by CareDx, Natera, and Vertex. He is a principal investigator of a single-center trial supported by Veloxis. The other authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The advisory panel for US Food and Drug Administration (FDA) recently endorsed pancreatic islet cell transplantation (ICT) therapy for suboptimally controlled type 1 diabetes (T1D), and FDA approval is under consideration. An important part of regulatory approval includes the patient perspective, through discrete choice. We developed a discrete-choice instrument and used it to determine how 90 people with T1D weigh the risks and benefits of ICT to inform regulatory decisions., Methods: Sawtooth software created a random, full-profile, balanced-overlap experimental design for a measure with 8 attributes of ICT risks/benefits, each with 3 to 5 levels. We asked 18 random task pairs, sociodemographics, diabetes management, and hypoglycemia questions. Analysis was performed using random parameters logistic regression technique., Results: The strongest preference was for avoiding the highest chance (15%) of serious procedure-related complications (β = -2.03, P < 0.001). The strongest positive preference was for gaining 5-y insulin independence (β = 1.75, P < 0.001). The desire for 5-y HbA1C-defined clinical treatment success was also strong (β = 1.39, P < 0.001). Subgroup analysis suggested strong gender differences with women showing much higher preferences for all benefits (68% higher for 5-y insulin independence), and men were generally more risk averse than women. Those with high versus low diabetes distress showed 3 times stronger preference for 5-y insulin independence but also twice preference to avoid risks of serious complications., Conclusions: Despite showing the most preference for avoiding serious ICT complications, people with T1D had a strong preference for achieving ICT benefits, especially insulin independence. We identified important attributes of ICT and demonstrated that patients are willing to make these trade-offs, showing support for the introduction of ICT., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Bariatric and metabolic surgery is an effective treatment for patients with severe obesity and obesity-related diseases. In patients with type 2 diabetes, it provides marked improvement in glycemic control and even remission of diabetes. In patients with type 1 diabetes, bariatric surgery may offer improvement in insulin sensitivity and other cardiometabolic risk factors, as well as amelioration of the mechanical complications of obesity. Because of these positive outcomes, there are increasing numbers of patients with diabetes who undergo bariatric surgical procedures each year. Prior to surgery, efforts should be made to optimize glycemic control. However, there is no need to delay or withhold bariatric surgery until a specific glycosylated hemoglobin target is reached. Instead, treatment should focus on avoidance of early postoperative hyperglycemia. In general, oral glucose-lowering medications and noninsulin injectables are not favored to control hyperglycemia in the inpatient setting. Hyperglycemia in the hospital is managed with insulin, aiming for perioperative blood glucose concentrations between 80 and 180 mg/dL. Following surgery, substantial changes of the antidiabetic medication regimens are common. Patients should have a clear understanding of the modifications made to their treatment and should be followed closely thereafter. In this review article, we describe practical recommendations for the perioperative management of diabetes in patients with type 2 or type 1 diabetes undergoing bariatric surgery. Specific recommendations are delineated based on the different treatments that are currently available for glycemic control, including oral glucose-lowering medications, noninsulin injectables, and a variety of insulin regimens., (Copyright © 2022 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)