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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), HbA1c, time in clinically significant hypoglycaemia (

Purpose Real-time continuous glucose monitoring (RT-CGM) provides information on glycemic variability (GV), time in range (TIR), and guidance to avoid hypoglycemia, thereby complimenting HbA1c for diabetes management. We investigated whether GV and TIR were independently associated with chronic and acute diabetes complications. Methods Between September 2014 and January 2017, 515 subjects with type 1 diabetes using sensor-augmented pump therapy were followed for 24 months. The link between baseline HbA1c and CGM-derived glucometrics (TIR [70-180 mg/dL], coefficient of variation [CV], and SD) obtained from the first 2 weeks of RT-CGM use and the presence of complications was investigated. Complications were defined as: composite microvascular complications (presence of neuropathy, retinopathy, or nephropathy), macrovascular complications, and hospitalization for hypoglycemia and/or ketoacidosis. Results Individuals with microvascular complications were older (P < 0.001), had a longer diabetes duration (P < 0.001), a higher HbA1c (7.8 ± 0.9 vs 7.5 ± 0.9%, P < 0.001), and spent less time in range (60.4 ± 12.2 vs 63.9 ± 13.8%, P = 0.022) compared with those without microvascular complication. Diabetes duration (odds ratio [OR] = 1.12 [1.09-1.15], P < 0.001) and TIR (OR = 0.97 [0.95-0.99], P = 0.005) were independent risk factors for composite microvascular complications, whereas SD and CV were not. Age (OR = 1.08 [1.03-1.14], P = 0.003) and HbA1c (OR = 1.80 [1.02-3.14], P = 0.044) were risk factors for macrovascular complications. TIR (OR = 0.97 [0.95-0.99], P = 0.021) was the only independent risk factor for hospitalizations for hypoglycemia or ketoacidosis. Conclusions Lower TIR was associated with the presence of composite microvascular complications and with hospitalization for hypoglycemia or ketoacidosis. TIR, SD, and CV were not associated with macrovascular complications.

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 Methods: Post hoc analyses of ALERTT1 evaluated the impact of 14 baseline characteristics on the difference (delta) in mean TIR, HbA1c, time Results: Univariable analyses showed no dependency of delta TIR, HbA1c, or time 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

AIM: To evaluate the ability of ladarixin (LDX, 400 mg twice-daily for three cycles of 14 days on/14 days off), an inhibitor of the CXCR1/2 chemokine receptors, to maintain C-peptide production in adult patients with newly diagnosed type 1 diabetes. MATERIALS AND METHODS: A double-blind, randomized (2:1), placebo-controlled study was conducted in 45 males and 31 females (aged 18-46 years) within 100 days of the first insulin administration. The primary endpoint was the area under the curve (AUC) for C-peptide in response to a 2-hour mixed meal tolerance test (AUC[0-120 min] ) at week 13 ± 1. Secondary endpoints included C-peptide AUC(15-120 min) , HbA1c, daily insulin requirement, severe hypoglycaemic events (SHE), the proportion of subjects achieving HbA1c less than 7.0% without SHE and maintaining a residual beta cell function. Follow-up assessments were scheduled at weeks 13 ± 1, 26 ± 2 and 52 ± 2. RESULTS: In total, 26/26 (100%, placebo) and 49/50 (98%, LDX) patients completed week 13. The mean change from baseline to week 13 in C-peptide AUC(0-120 min) was -0.144 ± 0.449 nmol/L with placebo and 0.003 ± .322 nmol/L with LDX. The difference was not significant (0.149 nmol/L, 95% CI -0.04 to 0.33; P = .122). At week 26, the proportion of patients with HbA1c less than 7.0% without SHE was transiently higher in the LDX group (81% vs. 54%, P = .024). Otherwise, no significant secondary endpoint differences were noted. Transient metabolic benefit was seen at week 26 in favour of the LDX group in the prespecified subpopulation with fasting C-peptide less than the median value at screening. CONCLUSIONS: In newly diagnosed patients with type 1 diabetes, short-term LDX treatment had no appreciable effect on preserving residual beta cell function. ispartof: DIABETES OBESITY & METABOLISM vol:24 issue:9 pages:1840-1849 ispartof: location:England status: published

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 July 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

Background: The 6-month multicenter randomized controlled ALERTT1 trial showed improvement of time in range (TIR; 70-180 mg/dL) , HbA1c, time Methods: In this partial cross-over extension trial, the control group (n=127) switched as planned from isCGM to rtCGM from month 6 to month 24. The experimental group (n=127) continued rtCGM until month 24. Primary outcome was TIR. Key secondary outcomes were HbA1c, time Results: People in the trial were on average 42.9 years old; mean HbA1c was 7.4%. A minority used an insulin pump (n=49) or were hypo unaware (n=44) . TIR increased from 51.8% to 63.5% at month 12 in the former isCGM group (Δ 11.7% [9.6-13.8] P Conclusion: In adults with T1D, switching from isCGM to rtCGM is beneficial up to 24 months, adding further evidence that rtCGM with alerts is superior to isCGM without alerts. Disclosure M.M.Visser: Other Relationship; Boehringer Ingelheim International GmbH, Dexcom, Inc., Dexcom, Inc., Novo Nordisk. N.Myngheer: Advisory Panel; AstraZeneca, Speaker's Bureau; AstraZeneca, Novo Nordisk. C.F.Vercammen: Other Relationship; AstraZeneca. F.Nobels: Advisory Panel; Abbott Diabetes, AstraZeneca. B.Keymeulen: None. C.Mathieu: Advisory Panel; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Imcyse, Insulet Corporation, Medtronic, Novo Nordisk, Sanofi, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca. P.Gillard: Advisory Panel; Bayer AG, Novo Nordisk, Speaker's Bureau; Abbott Diabetes, Bayer AG, Dexcom, Inc., Insulet Corporation, Medtronic, Novo Nordisk, Roche Diabetes Care, Sanofi. S.Charleer: None. S.Fieuws: None. C.De block: Advisory Panel; Abbott Diagnostics, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Novo Nordisk, Research Support; Indigo Diabetes, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk. R.Hilbrands: None. L.Van huffel: Advisory Panel; Roche Diagnostics, Other Relationship; Medtronic, Speaker's Bureau; Abbott Diabetes, AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk. T.Maes: None. G.Vanhaverbeke: Advisory Panel; Abbott Diabetes, AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck Sharp & Dohme Corp., Speaker's Bureau; Novo Nordisk, Sanofi. E.L.Dirinck: None. Funding Dexcom, San Diego, CA, USA (OUS-2018-011)

Patients with heterotaxy syndrome (HS) can present with an associated complete dorsal pancreas agenesis (DPA). They are considered to be at increased risk for developing diabetes due to a reduced functional beta cell mass (FBM) as well as for chronic pancreatitis leading to unmanageable pain. We report the case of a young woman with chronic pancreatitis due to HS and associated DPA. She presented with a severe persisting upper abdominal pain refractory to nonsurgical treatment. Unlike in previously reported cases, she had a high FBM (ie, 150% of normoglycemic controls) as determined by hyperglycemic clamp. She underwent a total pancreatectomy followed within 24 hours by an intraportal autologous islet cell transplant containing 4 × 106 beta cells (4700 islet equivalent)/kg body weight. After surgery, the pain resolved, eliminating the need for analgesics. The intraportal implant established an adequate FBM (72% of controls at posttransplant month 2), achieving glycemic control without need for insulin administration. A hyperglycemic clamp can assess the utility and efficacy of an intraportal islet cell autotransplant following total pancreatectomy in patients with HS and complete DPA.

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, 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 AUC0–120 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.

AIMS: To investigate whether single use of 4 mm needles combined with education about injection technique and lipohypertrophy affects HbA1c, hypoglycaemia and glucose variability. METHODS: Insulin-injecting people with diabetes recruited from nine Belgian diabetes centres were prospectively followed for 6 months. They were provided 4 mm pen needles and education concerning injection technique using an online platform (BD and Me™) based on the international Forum for Injection Technique & Therapy Recommendations focused on avoidance of lipohypertrophy zones and reduction of needle reuse. RESULTS: A total of 171 people with diabetes were included of which 146 completed the study. At baseline, lipohypertrophy was present in 63.0% of those who completed the study, with 51.4% injecting in zones of lipohypertrophy, 37.0% incorrectly rotating and 95.9% reusing needles. After the intervention, 7.5% still injected in a lipohypertrophy zone, 4.1% rotated incorrectly and needle reuse decreased to 21.2%. The number of participants with severe hypoglycaemias (from 15.8% to 4.1%, p < 0.001), unexplained hypoglycaemias (from 46.6% to 16.4%, p < 0.001) and high glucose variability (from 64.4% to 29.5%, p < 0.001) was significantly reduced. HbA1c and total daily insulin dose remained stable. CONCLUSION: The combination of 4 mm pen needles and online education on injection techniques significantly reduced the number of people with severe hypoglycaemic episodes, unexplained hypoglycaemia and high glucose variability but did not improve HbA1c control nor lower insulin needs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04659330.

VC-02 combination product (PEC-Direct) is a clinical-stage regenerative medicine therapy being developed for patients with type 1 diabetes and hypoglycemia unawareness intended to restore homeostatic glycemic control. It is comprised of stem cell-derived pancreatic progenitors (PEC-01) loaded into a macroencapsulation device that facilitates the in-growth of blood vessels into the device lumen, supporting the maturation and differentiation of the graft into hormone-positive islet cells comprising glucose-responsive beta cells. Initial data from one patient (2021, Keymeulen) demonstrated clinically-relevant levels of stimulated C-peptide and corresponding improvements in glycemic control within six months after subcutaneous implantation. These improvements now include a time-in-range consistently >90% and a persistent HbA1C Presentation: Saturday, June 11, 2022 12:45 p.m. - 1:00 p.m.

Aims/hypothesis We examined whether the non-HLA susceptibility locus ERBB3/IKZF4 influences progression of type 1 diabetes stage specifically according to sex. Methods SNPs of ERBB3 (rs2292239 T/G) and IKZF4 (rs1701704 G/T) were screened by allelic discrimination quantitative PCR assay in first-degree relatives of type 1 diabetes patients who had developed at least one circulating autoantibody. The effect of ERBB3/IKZF4 genotypes and sex, on the progression of single autoantibody positivity to multiple autoantibody positivity and from multiple autoantibody positivity to diabetes, was studied by Kaplan–Meier analysis and multivariate Cox regression. Results In the cohort of autoantibody-positive first-degree relatives, the risk allele frequencies for ERBB3 rs2292239 (T) and IKZF4 rs1701704 (G) were increased. There was a significant male excess at the stage of multiple autoantibody positivity (p = 0.021). In Kaplan–Meier survival analysis, progression from single to multiple antibody positivity was delayed in female participants with genotype ERBB3 GG (p = 0.018, vs ERBB3 TG+TT) or IKZF4 TT (p = 0.023, vs IKZF4 GT+GG), but not in male participants. In multivariate Cox regression models, the interaction effects between female sex and ERBB3 GG (p = 0.012; HR = 0.305 [95% CI 0.120, 0.773]) or between female sex and IKZF4 TT (p = 0.011; HR = 0.329 [95% CI 0.140, 0.777]) emerged as potential determinants of delayed progression to multiple autoantibodies. The progression from multiple autoantibody positivity to type 1 diabetes appeared not to be influenced by ERBB3/IKZF4. Conclusions/interpretation In siblings and offspring of type 1 diabetes patients, polymorphism in region ERBB3/IKZF4 may affect disease progression at the level of epitope spreading in female individuals. Our findings suggest that interaction between sex and ERBB3/IKZF4 may contribute to the post-pubertal male excess in type 1 diabetes. Graphical abstract

Aims This paper describes the pharmacological findings from a study where otelixizumab, an anti-CD3ɛ mAb, was dosed in new onset Type 1 diabetes mellitus (NOT1DM) patients. This is the first time that the full dose-response of an anti-CD3ɛ mAb has been investigated in the clinic. The data have been validated using a previously developed pharmacokinetic/pharmacodynamic (PK/PD) model of otelixizumab to simulate the interplay between drug administration, CD3ɛ target engagement and downmodulation. Methods Patients were randomized to control or active treatment with otelixizumab (1:4), administered via infusion over 6 days, in a dose-ascending study consisted of three cohorts (n = 10 per cohort) at doses of 9, 18 or 27 mg respectively. The study allowed quantification of otelixizumab PK, CD3ɛ target engagement and its pharmacodynamic effect (CD3e/TCR modulation on circulating T lymphocytes). Results Otelixizumab concentrations increased and averaged to 364.09 (54.3), 1625.55 (72.5) and 2781.35 (28.0) ng ml-1 (Geom.mean, %CV) at the 9, 18 and 27 mg dose respectively. CD3ɛ target engagement was found to be rapid (within the first 30 min), leading to a receptor occupancy of ~60% within 6 h of dosing in all three doses. A dose-response relationship was observed with the two highest doses achieving a ~90% target engagement and consequential CD3ɛ/TCR downmodulation by Day 6. Conclusions Data from this study revealed maximum target engagement and CD3ɛ/TCR modulation is achieved at doses of 18, 27 mg of otelixizumab. These findings can be useful in guiding dose selection in clinical trials with anti-CD3ɛ mAbs.

Patients with T1D exhibit a major loss in beta cell mass, associated with low or undetectable circulating markers of beta cell function. C-peptide serves as a biomarker used to assess the residual mass of functional insulin-producing pancreatic beta cells present in patients with T1D on insulin replacement therapies; this measurement is not confounded by exogenous insulin. Novel cell replacement therapies to address T1D, including VC-02 (PEC-Direct), have demonstrated the ability to control disease state and mitigate diabetes-related complications due to the absence of insulin and glycemic variability. In the current VC02-101 study, T1D patients were required to be C-peptide negative (during a mixed meal tolerance test) upon enrollment. Study participants received subcutaneous implanted VC-02 combination product containing pancreatic precursor cells (PEC-01 cells) derived from ViaCyte’s proprietary CyT49 pluripotent stem cell line. When effectively engrafted, these cells are capable of producing circulating C-peptide, as previously shown in rodent models, and now for the first time at clinically relevant levels in patients. Preliminary data for one patient implanted with the most current device configuration are presented through 6 months study duration. Stimulated C-peptide Cmax concentrations increased from 0.1 ng/mL (baseline) to 0.5 ng/mL (week 26), and AUC0-4hr increased from 0.225 to 1.775 ng x hr/mL. These results are corroborated by histology evidencing successful engraftment and cell survival. This effect was accompanied by an increase in time-in-range from 56 to 86% and reduction in HbA1C by 0.5%. Together, these data provide clinical proof-of-concept that further optimization of this therapy can result in a functional cure for T1D. Disclosure B. Keymeulen: None. D. Jacobs-tulleneers-thevissen: None. E. J. Kroon: Employee; Self; Viacyte, Inc. M. S. Jaiman: Employee; Self; Viacyte, Inc., Stock/Shareholder; Self; Viacyte, Inc. M. Daniels: Employee; Self; Viacyte, Inc. R. Wang: Employee; Self; Viacyte, Inc. D. Pipeleers: Board Member; Self; Beta-Cell NV. K. D’amour: Employee; Self; Viacyte, Inc. H. L. Foyt: Employee; Self; Viacyte, Inc., Stock/Shareholder; Self; Viacyte, Inc. Funding European Commission, Horizon 2020 (681070); California Institute of Regenerative Medicine (CLIN2-09672); JDRF (2011)

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.

Ongoing beta cell death in type 1 diabetes (T1D) can be detected using biomarkers selectively discharged by dying beta cells into plasma. microRNA-375 (miR-375) ranks among the top biomarkers based on studies in animal models and human islet transplantation. Our objective was to identify additional microRNAs that are co-released with miR-375 proportionate to the amount of beta cell destruction. RT-PCR profiling of 733 microRNAs in a discovery cohort of T1D patients 1 h before/after islet transplantation indicated increased plasma levels of 22 microRNAs. Sub-selection for beta cell selectivity resulted in 15 microRNAs that were subjected to double-blinded multicenter analysis. This led to the identification of eight microRNAs that were consistently increased during early graft destruction: besides miR-375, these included miR-132/204/410/200a/429/125b, microRNAs with known function and enrichment in beta cells. Their potential clinical translation was investigated in a third independent cohort of 46 transplant patients by correlating post-transplant microRNA levels to C-peptide levels 2 months later. Only miR-375 and miR-132 had prognostic potential for graft outcome, and none of the newly identified microRNAs outperformed miR-375 in multiple regression. In conclusion, this study reveals multiple beta cell-enriched microRNAs that are co-released with miR-375 and can be used as complementary biomarkers of beta cell death.

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

Autoantibodies against islet cell antigens are routinely used to identify subjects at increased risk of symptomatic type 1 diabetes, but their relation to the intra-islet pathogenetic process that leads to positivity for these markers is poorly understood. We screened 556 non-diabetic organ donors (3 months to 24 years) for five different autoantibodies and found positivity in 27 subjects, 25 single- and two double autoantibody-positive donors. Histopathological screening of pancreatic tissue samples showed lesion characteristic for recent-onset type 1 diabetes in the two organ donors with a high-risk profile, due to their positivity for multiple autoantibodies and HLA-inferred risk. Inflammatory infiltrates (insulitis) were found in a small fraction of islets (

Objective: In recent years, a growing number of people with type 1 diabetes have access to real-time continuous glucose monitoring (rtCGM). Long-term benefits of rtCGM are unclear due to lack of large studies of long duration. We evaluated whether real-world rtCGM-use up to 24 months offered benefits, in particular to those living with impaired awareness of hypoglycemia (IAH). Research Design and Methods: This 24-month, prospective, observational, cohort study followed 441 adults with insulin pumps receiving full reimbursement for rtCGM. Forty-two percent had IAH. Primary endpoint was evolution of HbA1c, with secondary endpoints change in acute hypoglycemia complications, diabetes-related work absenteeism, and quality of life (QOL) scores. Additionally, we evaluated if people could achieve glycemic consensus targets during follow-up. Results: After 24 months, HbA1c remained significantly lower compared to baseline (7.64% [60 mmol/mol] vs 7.37% [57 mmol/mol], p1c Conclusion: Use of rtCGM led to sustained improvements in hypoglycemia-related glucose control over 24 months. Lower fear of hypoglycemia, less acute hypoglycemia-related events and diabetes-related days off work were observed, particularly in those with IAH.

The clinical benefit of islet allo- and autotransplantation is limited by a massive loss of implanted cells immediately postimplantation. Episodes of more subtle beta cell loss occur during the natural history of type 1 diabetes and at later time points posttransplantation. Our understanding of the disease and the development of innovative therapies to preserve or restore a sufficient beta-cell mass would benefit from noninvasive measures to detect and quantify episodes of beta-cell destruction. This can be assessed indirectly by monitoring changes in functional beta-cell mass, most precisely and accurately by hyperglycemic clamp test. Non-secreted beta cell-selective proteins, unmethylated gene regions, and microRNAs (miRs) have been validated as circulating markers of ongoing beta-cell damage. In the context of islet transplantation, 65 kDa-glutamate decarboxylase and miR-375 have been most closely associated with beta-cell loss and subsequent graft function.

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. ispartof: TRANSPLANTATION vol:104 issue:10 pages:E295-E302 ispartof: location:United States status: published

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 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.

β-cell replacement therapy, available currently as pancreas or islet transplantation, has developed without a clear definition of graft functional and clinical outcomes. The International Pancreas and Islet Transplant Association and European Pancreas and Islet Transplantation Association held a workshop to develop consensus for an International Pancreas and Islet Transplant Association and European Pancreas and Islet Transplant Association Statement on the definition of function and failure of current and future forms of β-cell replacement therapy. There was consensus that β-cell replacement therapy could be considered as a treatment for β-cell failure, regardless of etiology and without requiring undetectable C-peptide, accompanied by glycemic instability with either problematic hypoglycemia or hyperglycemia. Glycemic control should be assessed at a minimum by glycated hemoglobin (HbA(1c)) and the occurrence of severe hypoglycemia. Optimal β-cell graft function is defined by near-normal glycemic control (HbA(1c) ≤6.5% [48 mmol/mol]) without severe hypoglycemia or requirement for insulin or other antihyperglycemic therapy, and with an increase over pretransplant measurement of C-peptide. Good β-cell graft function requires HbA(1c) less than 7.0% (53 mmol/mol) without severe hypoglycemia and with a significant (>50%) reduction in insulin requirements and restoration of clinically significant C-peptide production. Marginal β-cell graft function is defined by failure to achieve HbA(1c) less than 7.0% (53 mmol/mol), the occur-rence of any severe hypoglycemia, or less than 50% reduction in insulin requirements when there is restoration of clinically significant C-peptide production documented by improvement in hypoglycemia awareness/severity, or glycemic variability/lability. A failed β-cell graft is defined by the absence of any evidence for clinically significant C-peptide production. Optimal and good function are considered successful clinical outcomes.

Device‐encapsulated human stem cell‐derived pancreatic endoderm (PE) can generate functional β‐cell implants in the subcutis of mice, which has led to the start of clinical studies in type 1 diabetes. Assessment of the formed functional β‐cell mass (FBM) and its correlation with in vivo metabolic markers can guide clinical translation. We recently reported ex vivo characteristics of device‐encapsulated human embryonic stem cell‐derived (hES)‐PE implants in mice that had established a metabolically adequate FBM during 50‐week follow‐up. Cell suspensions from retrieved implants indicated a correlation with the number of formed β cells and their maturation to a functional state comparable to human pancreatic β cells. Variability in metabolic outcome was attributed to differences in number of PE‐generated β cells. This variability hinders studies on processes involved in FBM‐formation. This study reports modifications that reduce variability. It is undertaken with device‐encapsulated human induced pluripotent stem cell‐derived‐PE subcutaneously implanted in mice. Cell mass of each cell type was determined on intact tissue inside the device to obtain more precise data than following isolation and dispersion. Implants in a preformed pouch generated a glucose‐controlling β‐cell mass within 20 weeks in over 60% of recipients versus less than 20% in the absence of a pouch, whether the same or threefold higher cell dose had been inserted. In situ analysis of implants indicated a role for pancreatic progenitor cell expansion and endocrine differentiation in achieving the size of β‐ and α‐cell mass that correlated with in vivo markers of metabolic control. stem cells translational medicine 2019;8:1296&1305, Device‐encapsulated human induced pluripotent stem cell‐derived pancreatic endoderm can generate a glucose‐controlling β‐cell mass in immune‐compromised mice. For a dose of 5 × 106 cells, this involves pancreatic progenitor cell differentiation as well as a cell mass increase following an initial cell loss. Measurement of these processes inside the device allows selection of conditions that help achieve metabolic control.

INTRODUCTION: With the development of new neuroimaging tools it has become possible to assess neurochemical alterations in patients experiencing chronic pain and to determine how these factors change during pharmacological treatment. The goal of this study was to examine the exact neurochemical mechanism underlying pregabalin treatment, utilizing magnetic resonance spectroscopy (1H-MRS), in a population of patients with painful diabetic polyneuropathy (PDN), with the overall aim to ultimately objectify the clinical effect of pregabalin. METHODS: A double blind, randomized, placebo-controlled study was conducted. A total of 27 patients with PDN were enrolled in the study, of whom 13 received placebo treatment (control group) and 14 received pregabalin (intervention group). Pregabalin treatment consisted of stepwise dose escalation over the study period from 75 mg daily ultimately to 600 mg daily. 1H-MRS was performed at 3T on four regions of interest in the brain: the rostral anterior cingulate cortex (rACC),left and right thalamus and prefrontal cortex. The absolute concentrations of N-acetyl aspartate, glutamate, glutamine, gamma-amino-butyric-acid (GABA), glucose (Glc) and myo-inositol (mINS) were determined using LCModel. RESULTS: The concentration of most neurometabolites in the placebo and pregabalin group did not significantly differ over time, with only a small significant difference in Glc level in the left thalamus (p = 0.049). Comparison of the effects of the different doses revealed significant differences for mINS in the rACC (baseline 2.42 ± 1.21 vs. 450 mg 1.58 ± 0.94; p = 0.022) and dorsolateral prefrontal cortex (75 mg 2.38 ± 0.89 vs. 450 mg 1.59 ± 0.85; p = 0.042) and also for GABA in the rACC (75 mg 0.53 ± 0.51 vs. 225 mg 0.28 ± 0.19; p = 0.014). CONCLUSION: No differences were found in metabolite concentrations between the placebo (control) and intervention groups, but some differences, although small, were found between the different doses. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT01180608). FUNDING: Lyrica Independent Investigator Research Award (LIIRA) 2010 (Pfizer) funded the study.

Alginate (Alg)-encapsulated porcine islet cell grafts are developed to overcome limitations of human islet transplantation. They can generate functional implants in animals when prepared from fetal, perinatal, and adult pancreases. Implants have not yet been examined for efficacy to establish sustained, metabolically adequate functional β-cell mass (FBM) in comparison with human islet cells. This study in immune-compromised mice demonstrates that subcutaneous implants of Alg-encapsulated porcine prenatal islet cells with 4 × 105 β-cells form, over 10 weeks, a FBM that results in glucose-induced plasma C-peptide >2 ng/mL and metabolic control over the following 10 weeks, with higher efficiency than nonencapsulated, while failing in peritoneum. This intracapsular FBM formation involves β-cell replication, increasing number fourfold, and maturation toward human adult β-cells. Subcutaneous Alg-encapsulated human islet cells with similar β-cell number establish implants with plasma C-peptide >2 ng/mL for the first 10 weeks, with nonencapsulated cells failing; their β-cells do not replicate but progressively die (>70%), explaining C-peptide decline and insufficient metabolic control. An Alg matrix thus helps establish β-cell functions in subcutis. It allows formation of sustained metabolically adequate FBM by immature porcine β-cells with proliferative activity but not by human adult islet cells. These findings define conditions for evaluating its immune-protecting properties.

CONTEXT: Randomized controlled trials evaluating real-time continuous glucose monitoring (RT-CGM) patients with type 1 diabetes (T1D) show improved glycemic control, but limited data are available on real-world use. OBJECTIVE: To assess impact of RT-CGM in real-world settings on glycemic control, hospital admissions, work absenteeism, and quality of life (QOL). DESIGN: Prospective, observational, multicenter, cohort study. PARTICIPANTS: A total of 515 adults with T1D on continuous subcutaneous insulin infusion (CSII) therapy starting in the Belgian RT-CGM reimbursement program. INTERVENTION: Initiation of RT-CGM reimbursement. MAIN OUTCOME MEASURE: Hemoglobin A1c (HbA1c) evolution from baseline to 12 months. RESULTS: Between September 1, 2014, and December 31, 2016, 515 adults entered the reimbursement system. Over this period, 417 (81%) patients used RT-CGM for at least 12 months. Baseline HbA1c was 7.7 ± 0.9% (61 ± 9.8 mmol/mol) and decreased to 7.4 ± 0.8% (57 ± 8.7 mmol/mol) at 12 months (P < 0.0001). Subjects who started RT-CGM because of insufficient glycemic control showed stronger decrease in HbA1c at 4, 8, and 12 months compared with patients who started because of hypoglycemia or pregnancy. In the year preceding reimbursement, 16% of patients were hospitalized for severe hypoglycemia or ketoacidosis in contrast to 4% (P < 0.0005) the following year, with decrease in admission days from 54 to 18 per 100 patient years (P < 0.0005). In the same period, work absenteeism decreased and QOL improved significantly, with strong decline in fear of hypoglycemia. CONCLUSION: Sensor-augmented pump therapy in patients with T1D followed in specialized centers improves HbA1c, fear of hypoglycemia, and QOL, whereas work absenteeism and admissions for acute diabetes complications decreased. TRIAL REGISTRATION: ClinicalTrials.gov NCT02601729.

AIM: Several biomarkers have been proposed to detect pancreatic β cell destruction in vivo but so far have not been compared for sensitivity and significance. METHODS: We used islet transplantation as a model to compare plasma concentrations of miR-375, 65-kDa subunit of glutamate decarboxylase (GAD65), and unmethylated insulin DNA, measured at subpicomolar sensitivity, and study their discharge kinetics, power for outcome prediction, and detection of graft loss during follow-up. RESULTS: At 60 minutes after transplantation, GAD65 and miR-375 consistently showed near-equimolar and correlated increases proportional to the number of implanted β cells. GAD65 and miR-375 showed comparable power to predict poor graft outcome at 2 months, with areas under the curve of 0.833 and 0.771, respectively (P = 0.53). Using receiver operating characteristic analysis, we defined likelihood ratios (LRs) for rationally selected result intervals. In GADA-negative recipients (n = 28), GAD65 12.2 pmol/L (LR = ∞) predicted good and poor outcomes, respectively. miR-375 could be used in all recipients irrespective of GAD65 autoantibody status (n = 46), with levels 7.6 pmol/L (LR = 9.53) as dual thresholds. The posttransplant surge of unmethylated insulin DNA was inconsistent and unrelated to outcome. Combined measurement of these three biomarkers was also tested as liquid biopsy for β cell death during 2-month follow-up; incidental surges of GAD65, miR-375, and (un)methylated insulin DNA, alone or combined, were confidently detected but could not be related to outcome. CONCLUSIONS: GAD65 and miR-375 performed equally well in quantifying early graft destruction and predicting graft outcome, outperforming unmethylated insulin DNA.

We examined whether measures of glycaemic variability (GV), assessed by continuous glucose monitoring (CGM) and self-monitoring of blood glucose (SMBG), can complement or replace measures of beta cell function and insulin action in detecting the progression of preclinical disease to type 1 diabetes. Twenty-two autoantibody-positive (autoAb+) first-degree relatives (FDRs) of patients with type 1 diabetes who were themselves at high 5-year risk (50%) for type 1 diabetes underwent CGM, a hyperglycaemic clamp test and OGTT, and were followed for up to 31 months. Clamp variables were used to estimate beta cell function (first-phase [AUC5–10 min] and second-phase [AUC120–150 min] C-peptide release) combined with insulin resistance (glucose disposal rate; M 120–150 min). Age-matched healthy volunteers (n = 20) and individuals with recent-onset type 1 diabetes (n = 9) served as control groups. In autoAb+ FDRs, M 120–150 min below the 10th percentile (P10) of controls achieved 86% diagnostic efficiency in discriminating between normoglycaemic FDRs and individuals with (impending) dysglycaemia. M 120–150 min outperformed AUC5–10 min and AUC120–150 min C-peptide below P10 of controls, which were only 59–68% effective. Among GV variables, CGM above the reference range was better at detecting (impending) dysglycaemia than elevated SMBG (77–82% vs 73% efficiency). Combined CGM measures were equally efficient as M 120–150 min (86%). Daytime GV variables were inversely correlated with clamp variables, and more strongly with M 120–150 min than with AUC5–10 min or AUC120–150 min C-peptide. CGM-derived GV and the glucose disposal rate, reflecting both insulin secretion and action, outperformed SMBG and first- or second-phase AUC C-peptide in identifying FDRs with (impending) dysglycaemia or diabetes. Our results indicate the feasibility of developing minimally invasive CGM-based criteria for close metabolic monitoring and as outcome measures in trials.

Problematic hypoglycemia, defined as two or more episodes per year of severe hypoglycemia or as one episode associated with impaired awareness of hypoglycemia, extreme glycemic lability, or major fear and maladaptive behavior, is a challenge, especially for patients with long-standing type 1 diabetes. Individualized therapy for such patients should include a composite target: optimal glucose control without problematic hypoglycemia. Therefore, we propose a tiered, four-stage algorithm based on evidence of efficacy given the limitations of educational, technological, and transplant interventions. All patients with problematic hypoglycemia should undergo structured or hypoglycemia-specific education programs (stage 1). Glycemic and hypoglycemia treatment targets should be individualized and reassessed every 3–6 months. If targets are not met, one diabetes technology—continuous subcutaneous insulin infusion or continuous glucose monitoring—should be added (stage 2). For patients with continued problematic hypoglycemia despite education (stage 1) and one diabetes technology (stage 2), sensor-augmented insulin pumps preferably with an automated low-glucose suspend feature and/or very frequent contact with a specialized hypoglycemia service can reduce hypoglycemia (stage 3). For patients whose problematic hypoglycemia persists, islet or pancreas transplant should be considered (stage 4). This algorithm provides an evidence-informed approach to resolving problematic hypoglycemia; it should be used as a guide, with individual patient circumstances directing suitability and acceptability to ensure the prudent use of technology and scarce transplant resources. Standardized reporting of hypoglycemia outcomes and inclusion of patients with problematic hypoglycemia in studies of new interventions may help to guide future therapeutic strategies.

Context and Objective: In preparation of future prevention trials, we aimed to identify predictors of 3-year diabetes onset among oral glucose tolerance test (OGTT)- and hyperglycemic clamp-derived metabolic markers in persistently islet autoantibody positive (autoAb+) offspring and siblings of patients with type 1 diabetes (T1D). Design: The design is a registry-based study. Setting: Functional tests were performed in a hospital setting. Participants: Persistently autoAb+ first-degree relatives of patients with T1D (n = 81; age 5–39 years). Main Outcome Measures: We assessed 3-year predictive ability of OGTT- and clamp-derived markers using receiver operating characteristics (ROC) and Cox regression analysis. Area under the curve of clamp-derived first-phase C-peptide release (AUC5–10min; min 5–10) was determined in all relatives and second-phase release (AUC120–150min; min 120–150) in those aged 12–39 years (n = 62). Results: Overall, the predictive ability of AUC5–10min was better than that of peak C-peptide, the best predictor among OGTT-derived parameters (ROC-AUC [95%CI]: 0.89 [0.80–0.98] vs 0.81 [0.70–0.93]). Fasting blood glucose (FBG) and AUC5–10min provided the best combination of markers for prediction of diabetes within 3 years; (ROC-AUC [95%CI]: 0.92 [0.84–1.00]). In multivariate Cox regression analysis, AUC5–10min (P = .001) was the strongest independent predictor and interacted significantly with all tested OGTT-derived parameters. AUC5–10min below percentile 10 of controls was associated with 50–70% progression to T1D regardless of age. Similar results were obtained for AUC120–150min. Conclusions: Clamp-derived first-phase C-peptide release can be used as an efficient and simple screening strategy in persistently autoAb+ offspring and siblings of T1D patients to predict impending diabetes.

OBJECTIVE Immune intervention trials in recent-onset type 1 diabetes would benefit from biomarkers associated with good therapeutic response. In the previously reported randomized placebo-controlled anti-CD3 study (otelixizumab; GlaxoSmithKline), we tested the hypothesis that specific diabetes autoantibodies might serve this purpose. RESEARCH DESIGN AND METHODS In the included patients (n = 40 otelixizumab, n = 40 placebo), β-cell function was assessed as area under the curve (AUC) C-peptide release during a hyperglycemic glucose clamp at baseline (median duration of insulin treatment: 6 days) and every 6 months until 18 months after randomization. (Auto)antibodies against insulin (I[A]A), GAD (GADA), IA-2 (IA-2A), and ZnT8 (ZnT8A) were determined on stored sera by liquid-phase radiobinding assay. RESULTS At baseline, only better preserved AUC C-peptide release and higher levels of IAA were associated with better preservation of β-cell function and lower insulin needs under anti-CD3 treatment. In multivariate analysis, IAA (P = 0.022) or the interaction of IAA and C-peptide (P = 0.013) independently predicted outcome together with treatment. During follow-up, good responders to anti-CD3 treatment (i.e., IAA+ participants with relatively preserved β-cell function [≥25% of healthy control subjects]) experienced a less pronounced insulin-induced rise in I(A)A and lower insulin needs. GADA, IA-2A, and ZnT8A levels were not influenced by anti-CD3 treatment, and their changes showed no relation to functional outcome. CONCLUSIONS There is important specificity of IAA among other diabetes autoantibodies to predict good therapeutic response of recent-onset type 1 diabetic patients to anti-CD3 treatment. If confirmed, future immune intervention trials in type 1 diabetes should consider both relatively preserved functional β-cell mass and presence of IAA as inclusion criteria.

We investigated the effect of HLA class I risk alleles on disease progression in various phases of subclinical islet autoimmunity in first-degree relatives of patients with type 1 diabetes.A registry-based group of siblings/offspring (aged 0-39 years) was monitored from single- to multiple-autoantibody positivity (Unlike

Background Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes. Methods The CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high cardiovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results The mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. The rate of the primary outcome was lower with canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; 95% confidence interval [CI], 0.75 to 0.97; P