Laurent Crenier

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.

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.

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 (Spearmans 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 (R2 = 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.

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.

A case of rapidly fatal systemic capillary leak syndrome in a kidney transplant recipient.

Idiopathic Systemic Capillary Leak Syndrome (SCLS) is a rare entity characterised by idiopathic increasing of capillary permeability associated with recurrent attacks of hypovolaemic shock. We report the case of a 39-year-old man with a SCLS fourteen years after a cadaveric renal transplantation. The clinical evolution was rapidly fatal despite treatment with corticoids, aminophylline and terbutaline which are the most efficient drugs known to prevent attacks.

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

Abstract 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 HbA1c 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%). HbA1c 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.

Correlates of fractures in elderly, diabetic outpatients

It is widely recognized that patients presenting diabetes are at increased risk for fractures. In a retrospective case-control study, 101 cases were selected from medical charts of outpatients older than 70 with diabetes mellitus and a fracture within the past 5 years. Glycosylated hemoglobin (HbA1c) had been measured within 4 months around the assessment. Each case was matched for sex and age with one control, diabetic patient with no fracture. HbA1c level was similar in both groups. Patients with fractures presented significantly lower BMIs than controls, and had a higher rate of declared osteoporosis and comorbidity. A small number of cases were using vitamin D supplements while more were treated with benzodiazepine, opiates and Selective serotonin reuptake inhibitors (SSRI). This study suggests that, rather than the tight control of blood glucose, other factors such as medication and comorbidity could be associated with fracture risk in elderly diabetics.

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.

Islet xenograft rejection in absence of CD8+ T cells does not require either interferon-γ 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.