Mortality-related risk factors of inpatients with diabetes and COVID-19: A multicenter retrospective study in Belgium.

BACKGROUND AND AIMS: We describe mortality-related risk factors of inpatients with diabetes and coronavirus disease 2019 (COVID-19) in Belgium. METHODS: We conducted a multicenter retrospective study from March to May, 2020, in 8 Belgian centers. Data on admission of patients with diabetes and COVID-19 were collected. Survivors were compared to non-survivors to identify prognostic risk factors for in-hospital death using multivariate analysis in both the total population and in the subgroup of patients admitted in the intensive care unit (ICU). RESULTS: The study included 375 patients. The mortality rate was 26.4% (99/375) in the total population and 40% (27/67) in the ICU. Multivariate analysis identified older age (HR 1.05 [CI 1.03-1.07], P<0.0001) and male gender (HR 2.01 [1.31-3.07], P=0.0013) as main independent risk factors for in-hospital death in the total population. Metformin (HR 0.51 [0.34-0.78], P=0.0018) and renin-angiotensin-aldosterone system blockers (HR 0.56 [0.36-0.86], P=0.0088) use before admission were independent protective factors. In the ICU, chronic kidney disease (CKD) was identified as an independent risk factor for death (HR 4.96 [2.14-11.5], P<0.001). CONCLUSION: In-hospital mortality due to the first wave of COVID-19 pandemic in Belgium was high in patients with diabetes. We found that advanced age and male gender were independent risk factors for in-hospital death. We also showed that metformin use before admission was associated with a significant reduction of COVID-19-related in-hospital mortality. Finally, we showed that CKD is a COVID-19-related mortality risk factor in patients with diabetes admitted in the ICU.

A machine learning-based classification of adult-onset diabetes identifies patients at risk of liver-related complications.

Background & aims: Diabetes mellitus is a major risk factor for fatty liver disease development and progression. A novel machine learning method identified five clusters of patients with diabetes, with different characteristics and risk of diabetic complications using six clinical and biological variables. We evaluated whether this new classification could identify individuals with an increased risk of liver-related complications. Methods: We used a prospective cohort of patients with a diagnosis of type 1 or type 2 diabetes without evidence of advanced fibrosis at baseline recruited between 2000 and 2020. We assessed the risk of each diabetic cluster of developing liver-related complications (i.e. ascites, encephalopathy, variceal haemorrhage, hepatocellular carcinoma), using competing risk analyses. Results: We included 1,068 patients, of whom 162 (15.2%) were determined to be in the severe autoimmune diabetes subgroup, 266 (24.9%) had severe insulin-deficient diabetes, 95 (8.9%) had severe insulin-resistant diabetes (SIRD), 359 (33.6%) had mild obesity-related diabetes, and 186 (17.4%) were in the mild age-related diabetes subgroup. In multivariable analysis, patients in the SIRD cluster and those with excessive alcohol consumption at baseline had the highest risk for liver-related events. The SIRD cluster, excessive alcohol consumption, and hypertension were independently associated with clinically significant fibrosis, evaluated by liver biopsy or transient elastography. Using a simplified classification, patients assigned to the severe and mild insulin-resistant groups had a three- and twofold greater risk, respectively, of developing significant fibrosis compared with those in the insulin-deficient group. Conclusions: A novel clustering classification adequately stratifies the risk of liver-related events in a population with diabetes. Our results also underline the impact of the severity of insulin resistance and alcohol consumption as key prognostic risk factors for liver-related complications. Impact and implications: Diabetes represents a major risk factor for NAFLD development and progression. This study examined the ability of a novel machine-learning approach to identify at-risk diabetes subtypes for liver-related complications. Our results suggest that patients that had severe insulin resistance had the highest risk of liver-related outcomes and fibrosis progression. Moreover, excessive alcohol consumption at the diagnosis of diabetes was the strongest risk factor for developing liver-related events.

Comparison Between Continuous Versus Flash Glucose Monitoring in Children, Adolescents, and Young Adults with Type 1 Diabetes: An 8-Week Prospective Randomized Trial.

INTRODUCTION: To assess the impact of real-time continuous glucose monitoring (RT-CGM) instead of first-generation flash glucose monitoring (FGM) on hypoglycaemia in children and adolescents with type 1 diabetes. METHODS: In this randomized controlled interventional study, young individuals with type 1 diabetes used RT-CGM or FGM for 8 weeks. We evaluated changes in time below range (TBR), severe hypoglycaemia (SH), HbA1c, glycaemic variability, and impaired awareness of hypoglycaemia with RT-CGM (intervention group) in comparison with FGM. RESULTS: We randomly assigned 37 participants to either the intervention group (n = 19) or the control group (n = 18). At 8 weeks, we did not find a decrease in TBR in either group, but there was a significant reduction in SH in the intervention group. For participants with TBR ≥ 5% at baseline, we observed significant reductions in 24-h TBR, wake TBR, sleep TBR, and glucose variability at 8 weeks in the intervention group. CONCLUSIONS: The use of RT-CGM versus FGM decreased SH in young individuals with type 1 diabetes, and TBR and glucose variability in patients with a higher TBR at baseline. The patient's history should be taken into account when advising on the method of blood glucose monitoring, as RT-CGM could be more effective in younger patients at high risk for SH. TRIAL REGISTRATION: ClinicalTrials.gov NCT04249102.

Durable metabolic improvements 2 years after duodenal mucosal resurfacing (DMR) in patients with type 2 diabetes (REVITA-1 Study).

AIMS: Duodenal mucosal resurfacing (DMR) is an endoscopic procedure developed to improve metabolic parameters and restore insulin sensitivity in patients with diabetes. Here we report long-term DMR safety and efficacy from the REVITA-1 study. MATERIALS AND METHODS: REVITA-1 was a prospective, single-arm, open-label, multicenter study of DMR feasibility, safety, and efficacy in patients with type 2 diabetes (hemoglobin A1c [HbA1c] of 7.5-10.0% (58-86 mmol/mol)) on oral medication. Safety and glycemic (HbA1c), hepatic (alanine aminotransferase [ALT]), and cardiovascular (HDL, triglyceride [TG]/HDL ratio) efficacy parameters were assessed (P values presented for LS mean change). RESULTS: Mean ± SD HbA1c levels reduced from 8.5 ± 0.7% (69.1 ± 7.1 mmol/mol) at baseline (N = 34) to 7.5 ± 0.8% (58.9 ± 8.8 mmol/mol) at 6 months (P < 0.001); and this reduction was sustained through 24 months post-DMR (7.5 ± 1.1% [59.0 ± 12.3 mmol/mol], P < 0.001) while in greater than 50% of patients, glucose-lowering therapy was reduced or unchanged. ALT decreased from 38.1 ± 21.1 U/L at baseline to 32.5 ± 22.1 U/L at 24 months (P = 0.048). HDL and TG/HDL improved during 24-months of follow-up. No device- or procedure-related serious adverse events, unanticipated device effects, or hypoglycemic events were noted between 12 and 24 months post-DMR. CONCLUSIONS: DMR is associated with durable improvements in insulin sensitivity and multiple downstream metabolic parameters through 24 months post-treatment in type 2 diabetes. Clinical trial reg. no. NCT02413567, clinicaltrials.gov.

Relationship Between Time in Range, Glycemic Variability, HbA1c, and Complications in Adults With Type 1 Diabetes Mellitus.

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.

Use of Culture to Reach Metabolically Adequate Beta-cell Dose by Combining Donor Islet Cell Isolates for Transplantation in Type 1 Diabetes Patients.

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.

Endoscopic duodenal mucosal resurfacing for the treatment of type 2 diabetes mellitus: one year results from the first international, open-label, prospective, multicentre study.

BACKGROUND: The duodenum has become a metabolic treatment target through bariatric surgery learnings and the specific observation that bypassing, excluding or altering duodenal nutrient exposure elicits favourable metabolic changes. Duodenal mucosal resurfacing (DMR) is a novel endoscopic procedure that has been shown to improve glycaemic control in people with type 2 diabetes mellitus (T2D) irrespective of body mass index (BMI) changes. DMR involves catheter-based circumferential mucosal lifting followed by hydrothermal ablation of duodenal mucosa. This multicentre study evaluates safety and feasibility of DMR and its effect on glycaemia at 24 weeks and 12 months. METHODS: International multicentre, open-label study. Patients (BMI 24-40) with T2D (HbA1c 59-86 mmol/mol (7.5%-10.0%)) on stable oral glucose-lowering medication underwent DMR. Glucose-lowering medication was kept stable for at least 24 weeks post DMR. During follow-up, HbA1c, fasting plasma glucose (FPG), weight, hepatic transaminases, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), adverse events (AEs) and treatment satisfaction were determined and analysed using repeated measures analysis of variance with Bonferroni correction. RESULTS: Forty-six patients were included of whom 37 (80%) underwent complete DMR and 36 were finally analysed; in remaining patients, mainly technical issues were observed. Twenty-four patients had at least one AE (52%) related to DMR. Of these, 81% were mild. One SAE and no unanticipated AEs were reported. Twenty-four weeks post DMR (n=36), HbA1c (-10±2 mmol/mol (-0.9%±0.2%), p<0.001), FPG (-1.7±0.5 mmol/L, p<0.001) and HOMA-IR improved (-2.9±1.1, p<0.001), weight was modestly reduced (-2.5±0.6 kg, p<0.001) and hepatic transaminase levels decreased. Effects were sustained at 12 months. Change in HbA1c did not correlate with modest weight loss. Diabetes treatment satisfaction scores improved significantly. CONCLUSIONS: In this multicentre study, DMR was found to be a feasible and safe endoscopic procedure that elicited durable glycaemic improvement in suboptimally controlled T2D patients using oral glucose-lowering medication irrespective of weight loss. Effects on the liver are examined further. TRIAL REGISTRATION NUMBER: NCT02413567.

Flash Glucose Monitoring Accepted in Daily Life of Children and Adolescents with Type 1 Diabetes and Reduction of Severe Hypoglycemia in Real-Life Use.

Background: Flash glucose monitoring (FGM) is covered by the Belgian public health insurance for type 1 diabetes since 2016. The objective of this study was to describe the use of FGM and diabetes outcomes in type 1 diabetic children and adolescents 1 year after reimbursement. Methods: All patients had the choice to convert to FGM or to continue with self-monitoring of blood glucose (SMBG). Clinical data were collected at baseline, at the next visit, and after 12 months; glucose profiles at next visit and after 12 months. Regression analyses were performed to identify predictors of FGM acceptance and changes in metabolic control. Results: A total of 334 subjects were included, of whom 278 (83.2%) switched to FGM. They were younger (13.6 vs. 15.2 years; P = 0.012) and performed more SMBG testing at baseline than patients who did not switch (4.3 vs. 4.1 tests daily; P = 0.008). At the end of follow-up, the rate of severe hypoglycemia decreased by 53% in the group of FGM users (P = 0.012) while it remained stable in SMBG users. Median glycated hemoglobin did not change significantly in both groups. Among subjects who switched to FGM, 15.8% reverted to SMBG after a median use of 5.3 months. Adverse events, diabetes duration, and FGM utilization were independent predictors of the risk for reverting. FGM-related adverse events were associated with a fivefold increased risk to revert to SMBG (hazard ratio = 5.12; P < 0.0001). Conclusions: FGM is relatively well accepted and decreases the risk of severe hypoglycemic events in our pediatric population. FGM is more often discontinued in patients experiencing adverse events and with longer diabetes duration.

Effect of Continuous Glucose Monitoring on Glycemic Control, Acute Admissions, and Quality of Life: A Real-World Study.

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.

Age and Early Graft Function Relate With Risk-Benefit Ratio of Allogenic Islet Transplantation Under Antithymocyte Globulin-Mycophenolate Mofetil-Tacrolimus Immune Suppression.

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

Glucose Complexity Estimates Insulin Resistance in Either Nondiabetic Individuals or in Type 1 Diabetes.

Glucose entropy was inversely correlated with insulin resistance in a series of non-diabetic individuals with low glucose variability. In long-standing type 1 diabetes, the inverse correlation between glucose entropy and insulin resistance is preserved, as lower glucose entropy is associated with higher BMI.

Poincaré plot quantification for assessing glucose variability from continuous glucose monitoring systems and a new risk marker for hypoglycemia: application to type 1 diabetes patients switching to continuous subcutaneous insulin infusion.

BACKGROUND: The Poincaré plot (PCP) is a valuable tool for describing glucose variability (GV) from continuous glucose monitoring (CGM) but remains only visual and qualitative. The aim of this work was to validate metrics for the geometry of the PCP in type 1 diabetes and to apply them to the study of a series of patients switching to continuous subcutaneous insulin infusion (CSII). PATIENTS AND METHODS: We reviewed the CGM profiles of 44 patients with type 1 diabetes. A subgroup (n=13) used CGM before and after 6 months on CSII. Additionally, we prospectively collected seven recordings from healthy controls. The new PCP metrics were correlated with hypoglycemia and classical GV indices and were compared between groups. RESULTS: SDs related to the PCP fitting ellipse (SD1, SD2) and area and shape of the fitting ellipse (SFE) were all higher in diabetes patients than in the controls and decreased significantly on CSII. SD1 represented short-term GV and was equivalent to continuous overlapping net glycemic action (CONGA). SD2 represented long-term GV and correlated with the SD of glucose levels (r ≥ 0.98), mean of daily differences (r ≥ 0.91), and mean amplitude of glycemic excursions (r ≥ 0.88). SFE correlated positively with CONGA at 1 h but not with the other indices and was inversely correlated with hypoglycemic episodes (Spearman's ρ=-0.42), independently of the coefficient of variation and the Low Blood Glucose Index in a multivariate analysis (partial r=-0.34). CONCLUSIONS: PCP metrics are correlated with known GV indices and may be used for the study of CGM recording series in type 1 diabetes. SFE is a new risk marker for hypoglycemia.

Glucose variability assessed by low blood glucose index is predictive of hypoglycemic events in patients with type 1 diabetes switched to pump therapy.

OBJECTIVE: To determine whether subgroups of type 1 diabetic patients with different glucose variability indices respond differently to continuous subcutaneous insulin infusion (CSII) in terms of reduced hypoglycemic events. RESEARCH DESIGN AND METHODS: We studied 50 adults with long-standing type 1 diabetes switched to CSII because of persistently high A1C or frequent hypoglycemia despite well-managed intensive basal-bolus therapy. We compared A1C, hypoglycemic events, and glucose variability from self-monitoring of blood glucose profiles at baseline and after 6 months of CSII. Regression analysis was performed to identify predictors of response. RESULTS: In multivariate analysis, baseline low blood glucose index (LBGI) was the best independent predictor of hypoglycemia outcome on CSII (R(2) = 0.195, P = 0.0013). An ROC curve analysis demonstrated a sensitivity of 70.8% (95% CI 48.9-87.4) and specificity of 73.1% (52.2-88.4) by using the LBGI cutoff of 3.34 as predictor of reduction of hypoglycemia on CSII. By grouping patients by LBGI tertiles, we found a 23.3% reduction in hypoglycemic events (<60 mg/dL [3.3 mmol/L]) in the third tertile (range 4.18-9.34) without change in A1C (P < 0.05). Conversely, the first tertile (range 0.62-2.05) demonstrated the greatest A1C reduction, -0.99% (P = 0.00001), but with increasing hypoglycemia. CONCLUSIONS: Baseline LBGI predicts the outcome of type 1 diabetic patients who switch to CSII in terms of hypoglycemia.

Switching to biphasic insulin aspart 30/50/70 from biphasic human insulin 30/50 in patients with type 2 diabetes in normal clinical practice: observational study results.

OBJECTIVE: To investigate the safety and efficacy of switching to biphasic insulin aspart (BIAsp) 30, 50 or 70 in patients with type 2 diabetes previously treated with biphasic human insulin (BHI) 30/50 (with or without oral glucose-lowering drugs) in routine clinical practice. METHODS: This was a 26-week, prospective, observational study conducted in Belgium and Luxembourg. Data were collected at baseline before patients switched and at 12 and 26 weeks after starting BIAsp 30, 50 or 70. Safety endpoints were incidence and rate of hypoglycemia (major, minor, nocturnal), adverse events and body-weight changes. Efficacy assessments included HbA(1c) and 7-point self-measured plasma glucose (PG) profiles. Changes from baseline were analyzed using paired t-tests. RESULTS: Of 592 patients analyzed, 72% switched to twice-daily BIAsp and 20% to three-times daily BIAsp. Upon switching, 27% of patients received intensified treatment (i.e., more daily doses than with their previous BHI). At all three data-collection points, approximately two-thirds of patients were taking BIAsp 30 and approximately one-third were taking BIAsp 50; very few patients took BIAsp 70. Mean total daily insulin dose increased significantly from baseline (51.2 U) to 26 weeks (54.3 U) and mean time of intake before meals changed from 17 minutes for BHI to ∼3 minutes with BIAsp. Incidence of hypoglycemia did not change during the study (baseline: 30.7%, week 26: 29.2%). HbA(1c) improved significantly from baseline (7.9 %) to weeks 12 and 26 (7.6% and 7.5%, respectively; p < 0.001). Mean PG profiles also showed significant improvements. As this is an observational study, some limitations should be considered such as the absence of a control group and a possible bias of increased medical attention. CONCLUSIONS: Patients with long-standing type 2 diabetes can switch safely from BHI to BIAsp therapy, even if they receive intensified treatment, and they have no problems changing the timing of their insulin injections.

Transient Epstein-Barr virus reactivation in CD3 monoclonal antibody-treated patients.

Here we report a unique situation in which an early and synchronized Epstein-Barr virus (EBV) reactivation was induced by a 6-day course of treatment with a humanized CD3-specific monoclonal antibody in patients with recent onset of type 1 diabetes. The virologic and immunologic analysis demonstrated that this reactivation was transient, self-limited, and isolated, associated with the rapid advent of an EBV-specific T-cell response. The anti-CD3 antibody administration induced short-lasting immunosuppression and minor yet clear-cut signs of T-cell activation that preceded viral reactivation. Early posttransplant monitoring of renal and islet allograft recipients showed that no comparable phenomenon was observed after the administration of full-dose immunosuppressive therapy. This EBV reactivation remains of no apparent clinical concern over the long term and should not preclude further development of therapeutic anti-CD3 antibodies. This phenomenon may also direct new research avenues to understand the still ill-defined nature of stimuli triggering EBV reactivation in vivo.

Comparison of sirolimus alone with sirolimus plus tacrolimus in type 1 diabetic recipients of cultured islet cell grafts.

BACKGROUND: One year survival of islet cell grafts has been reproducibly achieved under combination immune therapy including tacrolimus (TAC). However, the use of TAC causes beta-cell and renal toxicity. Because sirolimus (SIR) monotherapy was successful in kidney transplantation under antithymocyte globulin (ATG), we undertook a pilot study comparing SIR monotherapy with SIR-TAC combination therapy. METHODS: Nonuremic type 1 diabetics received a cultured beta-cell graft under ATG and were randomly assigned to SIR or SIR-TAC-maintenance therapy; a second graft was implanted during posttransplantation month 3 without ATG. The planned number of patients per group (n=10) was reduced to five in view of the observed side effects. RESULTS: At posttransplant month 6, three SIR-patients had lost graft function and two presented marginal function; among SIR-TAC-patients, there were two early graft failures but three became insulin-independent. These three patients maintained metabolically relevant function (C-peptide >1 ng/ml and coefficient of variation fasting glycemia <25%) for more than 2 years but low-dose insulin therapy was needed from 8, 18, and 26 months posttransplant; this was still the case in two of them after reducing and stopping TAC dose. In both groups, incapacitating adverse events were attributed to sirolimus requiring its discontinuation in 4 of 10 patients; in the 3 patients with pretransplant microalbuminuria, macroalbuminuria developed which resolved when sirolimus was stopped. CONCLUSIONS: SIR monotherapy is not sufficient to suppress rejection after transplantation under ATG, but it can maintain survival of established beta-cell grafts. However, the risk for a SIR-induced proteinuria remains a concern.

Conversion from tacrolimus to cyclosporine A for new-onset diabetes after transplantation: a single-centre experience in renal transplanted patients and review of the literature.

Tacrolimus (TRL) increases the incidence of new-onset diabetes mellitus after transplantation (NODAT). Little is known about whether conversion from TRL to cyclosporine A (CsA) improves glucose metabolism in patients with NODAT. We retrospectively analysed glucose metabolism parameters in 54 TRL-treated renal transplant patients who developed NODAT. Thirty-four were converted to CsA whereas 20 patients continued TRL. After conversion, fasting plasma glucose decreased from 146 +/- 64 to 104 +/- 20 mg/dl (P < 0.0001) and HbA1c levels decreased from 6.8 +/- 0.8% to 6.0 +/- 0.6% (P < 0.0001) after 1 year of follow-up. The remission rate of NODAT reached 42% (95% confidence interval 24-59%) 1 year after conversion versus 0% in the control group (P = 0.001). Blood pressure and lipid levels were stable after conversion although the use of statins significantly increased (P < 0.01). The conversion was safe in terms of graft function and acute rejection episodes. The 1-year patient survival and graft survival rate were 100%. In conclusion, our results suggest a significant improvement of glucose metabolism after conversion to CsA in renal transplant patients with NODAT.

Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes.

BACKGROUND: Type 1 diabetes mellitus is a T-cell-mediated autoimmune disease that leads to a major loss of insulin-secreting beta cells. The further decline of beta-cell function after clinical onset might be prevented by treatment with CD3 monoclonal antibodies, as suggested by the results of a phase 1 study. To provide proof of this therapeutic principle at the metabolic level, we initiated a phase 2 placebo-controlled trial with a humanized antibody, an aglycosylated human IgG1 antibody directed against CD3 (ChAglyCD3). METHODS: In a multicenter study, 80 patients with new-onset type 1 diabetes were randomly assigned to receive placebo or ChAglyCD3 for six consecutive days. Patients were followed for 18 months, during which their daily insulin needs and residual beta-cell function were assessed according to glucose-clamp-induced C-peptide release before and after the administration of glucagon. RESULTS: At 6, 12, and 18 months, residual beta-cell function was better maintained with ChAglyCD3 than with placebo. The insulin dose increased in the placebo group but not in the ChAglyCD3 group. This effect of ChAglyCD3 was most pronounced among patients with initial residual beta-cell function at or above the 50th percentile of the 80 patients. In this subgroup, the mean insulin dose at 18 months was 0.22 IU per kilogram of body weight per day with ChAglyCD3, as compared with 0.61 IU per kilogram with placebo (P<0.001). In this subgroup, 12 of 16 patients who received ChAglyCD3 (75 percent) received minimal doses of insulin (< or =0.25 IU per kilogram per day) as compared with none of the 21 patients who received placebo. Administration of ChAglyCD3 was associated with a moderate "flu-like" syndrome and transient symptoms of Epstein-Barr viral mononucleosis. CONCLUSIONS: Short-term treatment with CD3 antibody preserves residual beta-cell function for at least 18 months in patients with recent-onset type 1 diabetes.

Islet xenograft rejection in absence of CD8+ T cells does not require either interferon-gamma or interleukin-5.

We recently demonstrated that interleukin-5 and eosinophils mediate rejection of skin allografts when CD8+ T cell-dependent and Th1-type CD4+ T cell-dependent pathways are not functional. The purpose of this study was to determine whether a similar mechanism might be operative during rejection of rat islet xenografts in mice. First, we observed that eosinophils indeed infiltrate rejected islet grafts together with CD4+ and CD8+ T cells. CD8+ T cell depletion significantly enhanced graft survival and a further prolongation of islet function was obtained in combination with interferon-gamma neutralization. However, islet rejection characterized by prominent eosinophil and macrophage infiltration still occurred in this setting. Although eosinophil infiltrates were dramatically reduced in interleukin-5 deficient mice, the ability of these animals to reject islet xenografts under CD8+ T cell depletion and interferon-gamma neutralization was similar to that of wild-type mice. We conclude that in absence of CD8+ T cells and interferon-gamma, macrophages, but not eosinophils, mediate rejection of rat-to-mouse islet xenografts.