Baseline plasma proinsulin response to glucose for predicting therapeutic response to otelixizumab in recent-onset type 1 diabetes

Abstract: Aims: In recent-onset type 1 diabetes, clamp-derived C-peptide predicts good response to anti-CD3. Elevated proinsulin and proinsulin/C-peptide ratio (PI/CP) suggest increased metabolic/inflammatory beta cell burden. We reanalyzed trial data to compare the ability of baseline acutely glucose-stimulated proinsulin, C-peptide and PI/CP to predict functional outcome.Methods: Eighty recent-onset type 1 diabetes patients participated in the placebo-controlled otelixizumab (GSK; NCT00627146) trial. Hyperglycemic clamps were performed at baseline, 6, 12 and 18 months, involving 3 h of induced euglycemia, followed by acutely raising and maintaining glycemia to >= 10 mmol/l for 140 min. Plasma proinsulin, C-peptide and PI/CP were determined after acute (minute 0 at 10 mmol/l; PI0, CP0, PI/CP0) and sustained glucose stimulation (AUC between minutes 60-140). Outcome was assessed as change in AUC(60-140) C-peptide from baseline.Results: In multiple linear regression, higher baseline (>= median [P50]) PI0 independently predicted preservation of beta cell function in response to anti-CD3 and interacted significantly with IAA. During follow-up, anti-CD3 tempered a further increase in PI/CP0, but not in PI0. CP0 outperformed PI0 and PI/CP0 for post-treatment monitoring.Conclusions: In recent-onset type 1 diabetes, elevated acutely glucose-stimulated proinsulin may complement or replace acutely or sustainedly stimulated C-peptide release for identifying good responders to anti-CD3, but not as outcome measure

Serum Cytokines as Biomarkers in Islet Cell Transplantation for Type 1 Diabetes

BACKGROUND: Islet cell transplantation holds a potential cure for type 1 diabetes, but many islet recipients do not reach long-lasting insulin independence. In this exploratory study, we investigated whether serum cytokines, chemokines and adipokines are associated with the clinical outcome of islet transplantation. METHODS: Thirteen islet transplant patients were selected on basis of good graft function (reaching insulin independence) or insufficient engraftment (insulin requiring) from our cohort receiving standardized grafts and immune suppressive therapy. Patients reaching insulin independence were divided in those with continued (>12 months) versus transient (<6 months) insulin independence. A panel of 94 proteins including cytokines and adipokines was measured in sera taken before and at one year after transplantation using a validated multiplex immunoassay platform. RESULTS: Ninety serum proteins were detectable in concentrations varying markedly among patients at either time point. Thirteen markers changed after transplantation, while another seven markers changed in a clinical subpopulation. All other markers remained unaffected after transplantation under generalized immunosuppression. Patterns of cytokines could distinguish good graft function from insufficient function including IFN-α, LIF, SCF and IL-1RII before and after transplantation, by IL-16, CCL3, BDNF and M-CSF only before and by IL-22, IL-33, KIM-1, S100A12 and sCD14 after transplantation. Three other proteins (Leptin, Cathepsin L and S100A12) associated with loss of temporary graft function before or after transplantation. CONCLUSIONS: Distinct cytokine signatures could be identified in serum that predict or associate with clinical outcome. These serum markers may help guiding patient selection and choice of immunotherapy, or act as novel drug targets in islet transplantation

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

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.status: publishe

SLC30A8 polymorphism and BMI complement HLA-A*24 as risk factors for poor graft function in islet allograft recipients

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.status: publishe

Hyperglycemic clamp and oral glucose tolerance test for 3-year prediction of clinical onset in persistently autoantibody-positive offspring and siblings of type 1 diabetic patients

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 (AUC(5-10min); min 5-10) was determined in all relatives and second-phase release (AUC(120-150min); min 120-150) in those aged 12-39 years (n = 62). Results: Overall, the predictive ability of AUC(5-10min) 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 AUC(5-10min) 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, AUC(5-10min) (P = .001) was the strongest independent predictor and interacted significantly with all tested OGTT-derived parameters. AUC(5-10min) below percentile 10 of controls was associated with 50-70% progression to T1D regardless of age. Similar results were obtained for AUC(120-150min). 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

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

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.SCOPUS: ar.jSCOPUS: ar.jinfo:eu-repo/semantics/publishe