Pieter Gillard

Correlation between beta cell mass and glycemic control in type 1 diabetic recipients of islet cell graft.

Islet grafts can induce insulin independence in type 1 diabetic patients, but their function is variable with only 10% insulin indepence after 5 years. We investigated whether cultured grafts with defined β cell number help standardize metabolic outcome. Nonuremic C-peptide-negative patients received an intraportal graft with 0.5–5.0 × 106 β cells per kilogram of body weight (kgBW) under antithymocyte globulin and mycophenolate mofetil plus tacrolimus. Metabolic outcome at posttransplant (PT) month 2 was used to decide on a second graft under maintenance mycophenolate mofetil/tacrolimus. Graft function was defined by C-peptide >0.5 ng/ml and reduced insulin needs, metabolic control by reductions in HbA1c, glycemia coefficient of variation, and hypoglycemia. At PT month 2, graft function was present in 16 of 17 recipients of >2 × 106 β cells per kgBW versus 0 of 5 with lower number. The nine patients with C-peptide >1 ng/ml and glycemia coefficient of variation of <25% did not receive a second graft; five of them were insulin-independent until PT month 12. The 12 others received a second implant; it achieved insulin-independence at PT month 12 when the first and second graft contained >2 × 106 β cells per kgBW. Of the 20 recipients of at least one graft with >2 × 106 β cells per kgBW, 17 maintained graft function and metabolic control up to PT month 12. At PT month 12, β cell function in insulin-independent patients ranged around 25% of age-matched control values. Thus, 1-year metabolic control can be reproducibly achieved and standardized by cultured islet cell grafts with defined β cell number.

Differences in Baseline Lymphocyte Counts and Autoreactivity Are Associated With Differences in Outcome of Islet Cell Transplantation in Type 1 Diabetic Patients

OBJECTIVE The metabolic outcome of islet cell transplants in type 1 diabetic patients is variable. This retrospective analysis examines whether differences in recipient characteristics at the time of transplantation are correlated with inadequate graft function. RESEARCH DESIGN AND METHODS Thirty nonuremic C-peptide–negative type 1 diabetic patients had received an intraportal islet cell graft of comparable size under an ATG-tacrolimus–mycophenolate mofetil regimen. Baseline patient characteristics were compared with outcome parameters during the first 6 posttransplant months (i.e., plasma C-peptide, glycemic variability, and gain of insulin independence). Correlations in univariate analysis were further examined in a multivariate model. RESULTS Patients that did not become insulin independent exhibited significantly higher counts of B-cells as well as a T-cell autoreactivity against insulinoma-associated protein 2 (IA2) and/or GAD. In one of them, a liver biopsy during posttransplant year 2 showed B-cell accumulations near insulin-positive β-cell aggregates. Higher baseline total lymphocytes and T-cell autoreactivity were also correlated with lower plasma C-peptide levels and higher glycemic variability. CONCLUSIONS Higher total and B-cell counts and presence of T-cell autoreactivity at baseline are independently associated with lower graft function in type 1 diabetic patients receiving intraportal islet cells under ATG-tacrolimus–mycophenolate mofetil therapy. Prospective studies are needed to assess whether control of these characteristics can help increase the function of islet cell grafts during the first year posttransplantation.

Feasibility, Safety, and Efficacy of Percutaneous Transhepatic Injection of β-Cell Grafts

PURPOSE To evaluate the safety, feasibility, and clinical efficacy of percutaneous transhepatic injection of β-cell grafts in patients with type 1 diabetes mellitus. MATERIALS AND METHODS Between December 2001 and November 2003, 15 patients with C-peptide–negative type 1 diabetes underwent 31 percutaneous injections for intraportal implantation of β-cell grafts. Grafts consisted of cultured β-cell preparations as previously described. In 13 cases, the transplant procedure was done under sedation, whereas in 18 cases, general anesthesia was given. In all procedures, percutaneous access to the right portal vein occurred under ultrasound (US) guidance with use of a microbore puncture needle. The subsequent catheterization of the main portal vein was performed under fluoroscopic and angiographic control with use of a microbore delivery catheter and guide wire. Clinical, biochemical, and radiologic evaluation was performed before and after the procedure. RESULTS In all cases, it was possible to access the portal vein (median number of needle passes, 1; range, 1–6). The volume of cultured β-cell grafts injected for each transplantation averaged 0.58 mL (range, 0.26–1.60 mL) and the mean recorded procedure time (from puncture to catheter withdrawal) was 19 minutes (range, 10–80 min). Three patients presented with transient abdominal pain immediately after the procedure; postprocedural duplex US of the liver revealed a patent portal vein and end branches in all cases and a minor perihepatic fluid collection in another three patients. From the end of week 1 to week 3, a mean 3.8-fold increase in liver aminotransferase levels was measured in all recipients after the first implantation session. A similar increase was seen in only one patient after a second transplantation session. At 6 months after transplantation, 13 of 15 patients (86%) had a functioning graft with plasma C-peptide levels greater than 0.5 ng/mL. CONCLUSIONS The combined US, fluoroscopic, and angiographic monitoring of percutaneous transhepatic injection with use of a microbore delivery catheter is a safe and reproducible radiologic procedure for transplantation of -cell grafts in diabetic patients. Increased posttransplantation C-peptide levels, which demonstrate acceptable graft function, can be obtained.

Comparative evaluation of simple indices of graft function after islet transplantation.

Background. Several simple measures of graft function after islet transplantation have been proposed but a comparative evaluation is lacking. Here, we compared the performance of five indices of &bgr;-cell function: &bgr;-score, transplant estimated function (TEF), homeostasis model assessment (HOMA) 2-B%, C-peptide/glucose ratio, and Secretory Units of Islets in Transplantation (SUIT). Methods. Two cohorts of transplanted patients were analyzed. Cohort 1 consisted of 14 recipients with type 1 diabetes of islet transplantation whereas cohort 2 consisted of 21 recipients with type 1 diabetes of cultured islet cell graft. The five surrogate indices were compared against the first- and second-phase insulin response to arginine in cohort 1, and against the C-peptide response to a hyperglycemic clamp in cohort 2. Results. We found that the performances of the five surrogate indices were close one to each other in cohort 1. The correlation coefficients ranged 0.62 to 0.67 and 0.62 to 0.68 against the first- and second-phase insulin response to arginine, respectively. In cohort 2, we found that the &bgr;-score, TEF, C-peptide/glucose ratio, and SUIT were reasonably well correlated with the clamp response (correlation coefficients were in the range 0.71–0.81), whereas HOMA2-B% showed a modest performance (r=0.54). HOMA2-B% could not be evaluated in one patient whose fasting glucose concentration level was below the lower bound indicated by the HOMA calculator (3 mmol/L). SUIT could not be evaluated in three patients whose fasting glucose concentration was below the glucose threshold of the SUIT formula (3.43 mmol/L). Conclusion. In summary, no single index ouperformed the others. Nevertheless, when the benefit to cost ratio is considered, TEF stands out for its good performance at a very low cost.

Screening for insulinoma antigen 2 and zinc transporter 8 autoantibodies: a cost‐effective and age‐independent strategy to identify rapid progressors to clinical onset among relatives of type 1 diabetic patients

In first‐degree relatives of type 1 diabetic patients, we investigated whether diabetes risk assessment solely based on insulinoma antigen 2 (IA‐2) and zinc transporter 8 (ZnT8) antibody status (IA‐2A, respectively, ZnT8A) is as effective as screening for three or four autoantibodies [antibodies against insulin (IAA), glutamate decarboxylase 65 kDa (GAD) glutamate decarboxylase autoantibodies (GADA) and IA‐2A with or without ZnT8A] in identifying children, adolescents and adults who progress rapidly to diabetes (within 5 years). Antibodies were determined by radiobinding assays during follow‐up of 6444 siblings and offspring aged 0–39 years at inclusion and recruited consecutively by the Belgian Diabetes Registry. We identified 394 persistently IAA+, GADA+, IA‐2A+ and/or ZnT8A+ relatives (6·1%). After a median follow‐up time of 52 months, 132 relatives developed type 1 diabetes. In each age category tested (0–9, 10–19 and 20–39 years) progression to diabetes was significantly quicker in the presence of IA‐2A and/or ZnT8A than in their joint absence (P < 0·001). Progression rate was age‐independent in IA‐2A+ and/or ZnT8A+ relatives but decreased with age if only GADA and/or IAA were present (P = 0·008). In the age group mainly considered for immune interventions until now (10–39 years), screening for IA‐2A and ZnT8A alone identified 78% of the rapid progressors (versus 75% if positive for ≥ 2 antibodies among IAA, GADA, IA‐2A and ZnT8A or versus 62% without testing for ZnT8A). Screening for IA‐2A and ZnT8A alone allows identification of the majority of rapidly progressing prediabetic siblings and offspring regardless of age and is more cost‐effective to select participants for intervention trials than conventional screening.

Insulin analogues in type 1 diabetes mellitus: getting better all the time

The treatment of type 1 diabetes mellitus consists of external replacement of the functions of β cells in an attempt to achieve blood levels of glucose as close to the normal range as possible. This approach means that glucose sensing needs to be replaced and levels of insulin need to mimic physiological insulin-action profiles, including basal coverage and changes around meals. Training and educating patients are crucial for the achievement of good glycaemic control, but having insulin preparations with action profiles that provide stable basal insulin coverage and appropriate mealtime insulin peaks helps people with type 1 diabetes mellitus to live active lives without sacrificing tight glycaemic control. Insulin analogues enable patients to achieve this goal, as some have fast action profiles, and some have very slow action profiles, which gives people with type 1 diabetes mellitus the tools to achieve dynamic insulin-action profiles that enable tight glycaemic control with a risk of hypoglycaemia that is lower than that with human short-acting and long-acting insulins. This Review discusses the established and novel insulin analogues that are used to treat patients with type 1 diabetes mellitus and provides insights into the future development of insulin analogues.

Bariatric Surgery Induces Weight Loss but Does Not Improve Glycemic Control in Patients With Type 1 Diabetes

Brethauer et al. (1) report an improvement of glycemic control following bariatric surgery in patients with type 1 diabetes. However, the small sample size and limited time of follow-up of this latest and other previous reports preclude drawing firm conclusions (1–3). We collected data from 22 patients with confirmed type 1 diabetes and BMI ≥35 kg/m2 from three Belgian bariatric surgery centers. Six patients underwent sleeve gastrectomy and 16 had Roux-en-Y gastric bypass surgery. Overall, we compared BMI, glycemic control (as assessed by A1C), and daily insulin dose between pre- and postsurgery using a linear mixed model with a random patient and a fixed period effect. P values < 0.05 are considered significant. At each time point, mean ± SEM is given in Fig. 1. …

Functional β-Cell Mass and Insulin Sensitivity Is Decreased in Insulin-Independent Pancreas-Kidney Recipients

Background. To compare functional &bgr;-cell mass and insulin sensitivity in insulin-independent pancreas-kidney recipients with that in age- and body mass index-matched nondiabetic kidney recipients and normal controls. Methods. All transplant recipients were on maintenance immunosuppression with mycophenolate mofetil and tacrolimus since more than 2.7 years (2.2–3.8 years). Their C-peptide release was measured during a 170-min hyperglycemic clamp, first in absence and then in presence of glucagon. Data were compared with those after glucose stimulation alone. Insulin sensitivity under basal and stimulated conditions was calculated using homeostasis model assessment of insulin resistance and insulin sensitivity index, respectively. Results. Functional &bgr;-cell mass in pancreas-kidney recipients with systemic venous drainage was reduced, representing, respectively, 63% and 80% of that in healthy controls and kidney recipients. Pancreas-kidney recipients exhibited lower insulin sensitivity than healthy controls (homeostasis model assessment of insulin resistance was 0.8, 0.7–1.1 vs. 0.4, 0.3–0.8; P=0.02 and insulin sensitivity index was 17, 12–24 mg/kg/min per 100 &mgr;U/mL vs. 31, 20–38 mg/kg/min per 100 &mgr;U/mL; P=0.04). Conclusions. Using a hyperglycemic clamp, the functional &bgr;-cell mass in insulin-independent pancreas-kidney recipients was found to be 37% and 20% lower than in healthy controls and nondiabetic kidney recipients.

Minimal Functional β-Cell Mass in Intraportal Implants That Reduces Glycemic Variability in Type 1 Diabetic Recipients

OBJECTIVE Previous work has shown a correlation between β-cell number in cultured islet cell grafts and their ability to induce C-peptide secretion after intraportal implantation in C-peptide–negative type1 diabetic patients. In this cross-sectional study, we examined the minimal functional β-cell mass (FBM) in the implant that induces metabolic improvement. RESEARCH DESIGN AND METHODS Glucose clamps assessed FBM in 42 recipients with established implants. C-peptide release during each phase was expressed as percentage of healthy control values. Its relative magnitude during a second hyperglycemic phase was most discriminative and therefore selected as a parameter to be correlated with metabolic effects. RESULTS Recipients with functioning β-cell implants exhibited average FBM corresponding to 18% of that in normal control subjects (interquartile range 10–33%). Its relative magnitude negatively correlated with HbA1c levels (r = −0.47), daily insulin dose (r = −0.75), and coefficient of variation of fasting glycemia (CVfg) (r = −0.78, retained in multivariate analysis). A correlation between FBM and CVfg <25% appeared from the receiver operating characteristic curve (0.97 [95% CI 0.93–1.00]). All patients with FBM >37% exhibited CVfg <25% and a >50% reduction of their pretransplant CVfg; this occurred in none with FBM <5%. Implants with FBM >18% reduced CVfg from a median pretransplant value of 46 to <25%. CONCLUSIONS Glucose clamping assesses the degree of restoration in FBM achieved by islet cell implants. Values >37% of normal control subjects appear needed to reduce glycemic variability in type 1 diabetic recipients. Further studies should examine whether the test can help guide decisions on additional islet cell transplants and on adjusting or stopping immunotherapy.

Otelixizumab in the treatment of Type 1 diabetes mellitus

Anti-CD3 antibodies have been demonstrated in both animal and human studies to be able to reverse autoimmune diseases; for example Type 1 diabetes. Not only does treatment with anti-CD3 antibodies result in the removal of pathogenic T cells but evidence suggests that a state of operational tolerance can be induced through the effects on regulatory T cells. The clinical use of anti-CD3 antibodies has been hampered by their safety profile. However, the introduction of humanized, nonmitogenic, aglycosylated anti-CD3 antibodies, such as otelixizumab, and promising results reported in newly-diagnosed patients with Type 1 diabetes, have renewed the interest for these antibodies in the treatment of autoimmune diseases.