y Shared senior authorship.The objective was to determine whether metabolic goals have been achieved with locally isolated and transported preparations over the first 3 years of the UK's nationally funded integrated islet transplant program. Twenty islet recipients with C-peptide negative type 1 diabetes and recurrent severe hypoglycemia consented to the study, including standardized meal tolerance tests. Participants received a total of 35 infusions (seven recipients: single graft; 11 recipients: two grafts: two recipients: three grafts). Graft function was maintained in 80% at [median (interquartile range)] 24 (13.5-36) months postfirst transplant. Severe hypoglycemia was reduced from 20 (7-50) episodes/patient-year pretransplant to 0.3 (0-1.6) episodes/patient-year posttransplant (p < 0.001). Resolution of impaired hypoglycemia awareness was confirmed [pretransplant: Gold score 6 (5-7); 24 (13.5-36) months: 3 (1.5-4.5); p < 0.03]. Target HbA 1c of <7.0% was attained/maintained in 70% of recipients [pretransplant: 8.0 (7.0-9.6

OBJECTIVEMaintenance of endogenous pancreatic b-cell function could be an important goal in the management of type 1 diabetes. However, the impact of stimulated C-peptide level on overall glycemic control is unknown. The relationship between C-peptide and parameters of glucose control was therefore characterized in a cohort with rapidly changing b-cell function following islet transplantation. RESEARCH DESIGN AND METHODSStandardized mixed-meal tolerance test was undertaken in 12 consecutive islet recipients at 1-6-month intervals, with graft function determined by 90-min stimulated C-peptide. Continuous glucose monitoring was undertaken in the week preceding each assessment and the relationship between C-peptide and glucose control evaluated by mixed Poisson regression. RESULTS Recipients completed 5 (1-14) [median (range)] clinical assessments over 18(1-51) months posttransplant encompassing a wide range of stimulated C-peptide levels (7-2,622 pmol/L). Increasing b-cell function across predefined C-peptide groups was associated with reduced insulin dose, HbA 1c , mean glucose (low [<200 pmol/L] 10.7 vs. excellent [>1,000 pmol/L] 7.5 mmol/L), and glucose SD (low, 4.4 vs. excellent, 1.4 mmol/L). Highly statistically significant continuous associations between stimulated C-peptide and mean interstitial glucose (lower by 2.5% [95% CI 1.5-3.5%] per 100 pmol/L higher C-peptide), glucose SD, time outside glucose target range, and measures of hyper-/hypoglycemia risk were confirmed. CONCLUSIONSRepeated assessment of islet transplant recipients has enabled modeling of the relationship between endogenous b-cell function and measures of glycemic control providing quantitative estimates of likely impact of an acute change in b-cell function in individuals with type 1 diabetes.

IntroductionSevere hypoglycaemia (SH), when blood glucose falls too low to support brain function, is the most feared acute complication of insulin therapy for type 1 diabetes mellitus (T1DM). 10% of people with T1DM contribute nearly 70% of all episodes, with impaired awareness of hypoglycaemia (IAH) a major risk factor. People with IAH may be refractory to conventional approaches to reduce SH, with evidence for cognitive barriers to hypoglycaemia avoidance. This paper describes the protocol for the Hypoglycaemia Awareness Restoration Programme for People with Type 1 Diabetes and Problematic Hypoglycaemia Persisting Despite Optimised Self-care (HARPdoc) study, a trial to assess the impact on hypoglycaemia experience of a novel intervention that addresses cognitive barriers to hypoglycaemia avoidance, compared with an existing control intervention, recommended by the National Institute of Health and Care Excellence.Methods and analysisA randomised parallel two-arm trial of two group therapies: HARPdoc versus Blood Glucose Awareness Training, among 96 adults with T1DM and problematic hypoglycaemia, despite attendance at education with or without technology use, in four centres providing specialist T1DM services. The primary outcome will be the SH rate at 12 and/or 24 months after randomisation to either course. Secondary outcomes include rates of SH requiring parenteral therapy, involving unconsciousness or needing emergency services; hypoglycaemia awareness status, overall diabetes control and quality of life measures. An implementation study to evaluate how the interventions are delivered and how implementation impacts on clinical effectiveness is planned as a parallel study, with its own protocol.Ethics and disseminationThe protocol was approved by the London Dulwich Research Ethics Committee, the Health Research Authority, National Health Service R&D and the Institutional Review Board of the Joslin Diabetes Center in the USA. Study findings will be disseminated to study participants and through peer-reviewed publications and conference presentations, including user groups.Trial registration numberNCY02940873; Pre-results.

Outcomes after islet transplantation continue to improve but etiology of graft failure remains unclear. De novo donor‐specific human leukocyte antigen (HLA) antibodies (DSA) posttransplant are increasingly recognized as a negative prognostic marker. Specific temporal associations between DSA and graft function remain undefined particularly in programs undertaking multiple sequential transplants. Impact of de novo DSA on graft function over 12 months following first islet transplant was determined prospectively in consecutive recipients taking tacrolimus/mycophenolate immunosuppression at a single center. Mixed‐meal tolerance test was undertaken in parallel with HLA antibody assessment pretransplant and 1–3 months posttransplant. Sixteen participants received a total of 26 islet transplants. Five (19%) grafts were associated with de novo DSA. Five (31%) recipients were affected: three post–first transplant; two post–second transplant. DSA developed within 4 weeks of all sensitizing grafts and were associated with decreased stimulated C‐peptide (median [interquartile range]) at 3 months posttransplant (DSA negative: 613(300–1090); DSA positive 106(34–235) pmol/L [p = 0.004]). De novo DSA directed against most recent islet transplant were absolutely associated with loss of graft function despite maintained immunosuppression at 12 months in the absence of a rescue nonsensitizing transplant. Alemtuzumab induction immunosuppression was associated with reduced incidence of de novo DSA formation (p = 0.03).

Impaired awareness of hypoglycaemia (IAH) is a major risk for severe hypoglycaemia in insulin treatment of type 1 diabetes (T1D). To explore the hypothesis that unhelpful health beliefs create barriers to regaining awareness, we conducted a multi-centre, randomised, parallel, two-arm trial (ClinicalTrials.gov NCT02940873) in adults with T1D and treatment-resistant IAH and severe hypoglycaemia, with blinded analysis of 12-month recall of severe hypoglycaemia at 12 and/or 24 months the primary outcome. Secondary outcomes included cognitive and emotional measures. Adults with T1D, IAH and severe hypoglycaemia despite structured education in insulin adjustment, +/− diabetes technologies, were randomised to the “Hypoglycaemia Awareness Restoration Programme despite optimised self-care” (HARPdoc, n = 49), a psychoeducation programme uniquely focussing on changing cognitive barriers to avoiding hypoglycaemia, or the evidence-based “Blood Glucose Awareness Training” (BGAT, n = 50), both delivered over six weeks. Median [IQR] severe hypoglycaemia at baseline was 5[2–12] per patient/year, 1[0–5] at 12 months and 0[0–2] at 24 months, with no superiority for HARPdoc (HARPdoc vs BGAT incident rate ratios [95% CI] 1.25[0.51, 3.09], p = 0.62 and 1.26[0.48, 3.35], p = 0.64 respectively), nor for changes in hypoglycaemia awareness scores or fear. Compared to BGAT, HARPdoc significantly reduced endorsement of unhelpful cognitions (Estimated Mean Difference for Attitudes to Awareness scores at 24 months, −2.07 [−3.37,−0.560], p = 0.01) and reduced scores for diabetes distress (−6.70[−12.50,−0.89], p = 0.02); depression (−1.86[−3.30, −0.43], p = 0.01) and anxiety (−1.89[−3.32, −0.47], p = 0.01). Despite positive impact on cognitive barriers around hypoglycaemia avoidance and on diabetes-related and general emotional distress scores, HARPdoc was not more effective than BGAT at reducing severe hypoglycaemia.