[Show abstract][Hide abstract] ABSTRACT: Background: In long-standing type 1 diabetes (T1D), loss of endogenous insulin secretion and glucose dysregulation can lead to severe hypoglycemia and associated complications. Here, we report the serial consistency and the correlation between different scores that characterize glucose dysregulation using self-monitoring of blood glucose (SMBG), in a cohort of T1D individuals being evaluated for transplant eligibility in Clinical Islet Transplantation Consortium trials. Subjects and Methods: In total, 152 C-peptide-negative T1D subjects with at least one severe hypoglycemia episode in the prior year documented SMBG at enrollment and every 6 months until deemed ineligible or transplanted. SMBG was used to calculate the HYPO score, Lability Index (LI), and mean amplitude of glycemic excursion (MAGE). Additionally, a blinded continuous glucose monitoring system (CGMS) was worn for 72 h at enrollment and every 12 months. Results: In this cohort, LI was the most consistent (intraclass correlation coefficient=0.70) over time, followed by the HYPO score (0.51), with MAGE being the least consistent (0.36). Although MAGE and LI were highly correlated with each other, neither correlated with CGMS SD or glucose coefficient of variation (CV). Subjects spent a median of 97 min/day at <54 mg/dL using CGMS. The HYPO score correlated with CGMS time below 54 mg/dL and glucose CV. Conclusions: The HYPO score and LI are more consistent than MAGE in patients with established T1D experiencing severe hypoglycemic events and may be especially useful both for identifying subjects experiencing the greatest difficulty in maintaining glycemic control and for longitudinal assessment of novel interventions.
[Show abstract][Hide abstract] ABSTRACT: The Collaborative Islet Transplant Registry (CITR) collects data on clinical islet isolations and transplants. This retrospective report analyzed 1017 islet isolation procedures performed for 537 recipients of allogeneic clinical islet transplantation in 1999–2010. This study describes changes in donor and islet isolation variables by era and factors associated with quantity and quality of final islet products. Donor body weight and BMI increased significantly over the period (p < 0.001). Islet yield measures have improved with time including islet equivalent (IEQ)/particle ratio and IEQs infused. The average dose of islets infused significantly increased in the era of 2007–2010 when compared to 1999–2002 (445.4 ± 156.8 vs. 421.3 ± 155.4 ×103 IEQ; p < 0.05). Islet purity and total number of β cells significantly improved over the study period (p < 0.01 and <0.05, respectively). Otherwise, the quality of clinical islets has remained consistently very high through this period, and differs substantially from nonclinical islets. In multivariate analysis of all recipient, donor and islet factors, and medical management factors, the only islet product characteristic that correlated with clinical outcomes was total IEQs infused. This analysis shows improvements in both quantity and some quality criteria of clinical islets produced over 1999–2010, and these parallel improvements in clinical outcomes over the same period.
American Journal of Transplantation 10/2014; 14(11). DOI:10.1111/ajt.12872 · 6.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives: The effects of glucocorticoid during culture on human islet cells have been controversial. Exendin-4 (EX) enhances the insulin secretion and significantly improves clinical outcomes in islet cell transplantation. In this study, we examined the effects of glucocorticoids and EX on human islet cells during pretransplant culture. Methods: Methylprednisolone (MP) and/or EX were added to the standard culture medium for clinical islet cell transplantation. Islets were cultured for 24 hours with 3 different conditions (control, no additives; MP alone; and MP + EX). β-Cell fractional viability, cellular composition, multiple cytokine/chemokine production, multiple phosphorylation proteins, and glucose-induced insulin secretion were evaluated. Results: Viable β-cell survival in MP and MP + EX group was significantly higher than in the control group. Exendin-4 prevented MP-induced reduction of insulin secretion. Methylprednisolone supplementation to the culture medium decreased cytokine and chemokine production. Moreover, extracellular signal-regulated kinase 1/2 phosphorylation was significantly increased by MP and MP + EX. Conclusions: Glucocorticoid supplementation into culture media significantly decreased the cytokine/chemokine production and increased the extracellular signal-regulated kinase 1/2 phosphorylation, resulting in the improvement of human β-cell survival. In addition, EX maintained the insulin secretion suppressed by MP. The supplementation of MP and EX together could be a useful strategy to create suitable human islets for transplantation.
[Show abstract][Hide abstract] ABSTRACT: Our objective is to evaluate if there is an association between liver fat accumulation after islet transplantation (ITx) and graft survival. A cohort study was conducted in 34 subjects with type 1 diabetes postallogeneic ITx. Liver fat content was evaluated by magnetic resonance imaging
(MRI) (change in liver signal intensity on in-phase and opposed-phase images). Kaplan‐Meier curves and Cox regression analysis were performed with islet dysfunction duration as the dependent variable and fat liver content as an independent one. Values of p
[Show abstract][Hide abstract] ABSTRACT: We evaluated whether 1,5-anhydroglucitol (1,5-AG) (GlycoMark®), a test for measuring postprandial glucose and glucose variability, could be a tool for assessing short-term glycemic control in islet cell transplant (ICT) subjects. Data of 21 subjects, with type 1 DM and
allogenic islet transplantation, who had concomitant fructosamine, HbA1c, 1,5-AG (n = 85 samples), and capillary glucose self-monitoring measurements (n = 2,979) were analyzed retrospectively at different time points after ICT. A significant negative
association was observed between 1,5-AG and HbA1c (p = 0.02), but not with fructosamine. When HbA1c was divided in quartiles as 6.2, a decrease of an estimated 0.70 ± 0.30 µg/ml in 1,5-AG was associated
with each quartile of increase in HbA1c (p
[Show abstract][Hide abstract] ABSTRACT: Allogeneic islet transplantation (IT) provokes changes in metabolic responses and nutritional behaviors. The durability of these changes needs to be described as well as their impact on the recipients' lifestyle. The goal of this study was to investigate how islet transplantation influenced diet, exercise habits, and body composition during 10 years after IT. A retrospective study performed in 33 (14 males, 19 females) IT recipients used dietary, physical activity open- ended questionnaire and anthropometric measurements. Data were collected before transplantation, every 3 months up to the 18th and every 6 months thereafter. Data were grouped by gender and eras: pre-IT; 0-3 years; 4-6 years, and 7-10 years after IT. Reduction in body mass index (BMI) from pre-IT to 0-3 years was noted: 23.68 ± 2,18 kg/m(2) to 22.07 ± 2.94 kg/m(2) (P < .05). Increased values were observed from 0-3 years to 4-6 years in: waist circumference (WC) (76.68 ± 7.22 to 79.44 ± 7.58 cm), BMI (23,68 ± 2,18 to 22,75 ± 3,11 kg/m(2)) and weight (64.69 ± 11.98 to 67.43 ± 14 kg): (P < .03). WC increased continuously up to 7-10 years (86.33 ± 9.45 cm; P < .05). There was an average of 5.3 ± 5.6 h/wk of exercise during follow-up. From pre-IT to 0-3 years there was a 19% reduction in protein consumption (P < .05) and a 39% increase in calories from saturated fats (P < .05). A trend to reduce carbohydrates intake noted from pre-IT to 0-3 years was progressively inverted from then throughout 7-10 years (not significant). IT was associated with a significantly decreased BMI early on that it was not sustained. The subsequent weight gain and WC increase could be the result of chronic immunosuppressive therapy and/or voluntary change in eating habits. The increased consumption of carbohydrates could be related to an adaptation of a lifestyle or/and reintroduction of insulin after graft dysfunction. Active lifestyle might be result of the intensive clinical care after IT, concomitant awareness of the importance of routine physical exercise on blood glucose control, and diabetes management. Continuous follow-up of IT recipients is needed to better understand these changes and for comparison with subjects with type 1 diabetes mellitus.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the effect of lysofylline (LSF) induction therapy on immune responses in the early post-transplant period after islet infusion, we followed 13 islet transplant recipients for changes in levels of peri-transplant cytokines, whole blood lymphocyte phenotype and gene expression. All recipients received thymoglobulin, sirolimus, tacrolimus and enbrel, and 5/13 also received LSF treatments. Total lymphocytes, T and T cell subsets decreased to lower levels than B and NK cells after transplant. Recovery of lymphocytes and T cells was similar between control and LSF groups. B and NK cells recovered faster than T cells in both groups, but LSF group had higher B cell levels compared to controls. Levels of CD4+/CD25bright/Foxp3+ cells were higher in LSF group compared to controls. LSF group had lower levels of granzyme B (GB) and perforin in both T and NK cells. Serum cytokines in LSF group had a trend towards lower levels of TNF-α and IL1-β and higher levels of IFN-γ, IL-6 and IL-10. Expression of the cytotoxic lymphocyte (CL) genes GB, perforin, and fas ligand and TNF-α gene was lower in LSF group compare to controls. For the one patient in the control group with complete loss of graft function (undetectable c-peptide), expression of CL, IL-4, IL-6, IL-10, TNF-α, IFN-γ, TGF-β, and Foxp3 genes was increased. Overall, the data suggest trends towards reduced immunoreactivity in the LSF treated group.
2013 Clinical Immunology Society Annual Meeting; 04/2013
[Show abstract][Hide abstract] ABSTRACT: To describe trends of primary efficacy and safety outcomes of islet transplantation in type 1 diabetes recipients with severe hypoglycemia from the Collaborative Islet Transplant Registry (CITR) from 1999 to 2010.
A total of 677 islet transplant-alone or islet-after-kidney recipients with type 1 diabetes in the CITR were analyzed for five primary efficacy outcomes and overall safety to identify any differences by early (1999-2002), mid (2003-2006), or recent (2007-2010) transplant era based on annual follow-up to 5 years.
Insulin independence at 3 years after transplant improved from 27% in the early era (1999-2002, n = 214) to 37% in the mid (2003-2006, n = 255) and to 44% in the most recent era (2007-2010, n = 208; P = 0.006 for years-by-era; P = 0.01 for era alone). C-peptide ≥0.3 ng/mL, indicative of islet graft function, was retained longer in the most recent era (P < 0.001). Reduction of HbA(1c) and resolution of severe hypoglycemia exhibited enduring long-term effects. Fasting blood glucose stabilization also showed improvements in the most recent era. There were also modest reductions in the occurrence of adverse events. The islet reinfusion rate was lower: 48% by 1 year in 2007-2010 vs. 60-65% in 1999-2006 (P < 0.01). Recipients that ever achieved insulin-independence experienced longer duration of islet graft function (P < 0.001).
The CITR shows improvement in primary efficacy and safety outcomes of islet transplantation in recipients who received transplants in 2007-2010 compared with those in 1999-2006, with fewer islet infusions and adverse events per recipient.
Diabetes care 07/2012; 35(7):1436-45. DOI:10.2337/dc12-0063 · 8.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The seemingly inexorable decline in insulin independence after islet transplant alone (ITA) has raised concern about its clinical utility. We hypothesized that induction immunosuppression therapy determines durability of insulin independence. We analyzed the proportion of insulin-independent patients following final islet infusion in four groups of ITA recipients according to induction immunotherapy: University of Minnesota recipients given FcR nonbinding anti-CD3 antibody alone or T cell depleting antibodies (TCDAb) and TNF-α inhibition (TNF-α-i) (group 1; n = 29); recipients reported to the Collaborative Islet Transplant Registry (CITR) given TCDAb+TNF-α-i (group 2; n = 20); CITR recipients given TCDAb without TNF-α-i (group 3; n = 43); and CITR recipients given IL-2 receptor antibodies (IL-2RAb) alone (group 4; n = 177). Results were compared with outcomes in pancreas transplant alone (PTA) recipients reported to the Scientific Registry of Transplant Recipients (group 5; n = 677). The 5-year insulin independence rates in group 1 (50%) and group 2 (50%) were comparable to outcomes in PTA (group 5: 52%; p>0.05) but significantly higher than in group 3 (0%; p = 0.001) and group 4 (20%; p = 0.02). Induction immunosuppression was significantly associated with 5-year insulin independence (p = 0.03), regardless of maintenance immunosuppression or other factors. These findings support potential for long-term insulin independence after ITA using potent induction therapy, with anti-CD3 Ab or TCDAb+TNF-α-i.
American Journal of Transplantation 04/2012; 12(6):1576-83. DOI:10.1111/j.1600-6143.2011.03977.x · 6.19 Impact Factor