-
J Oberholzer,
P Giulianotti,
K K Danielson,
M Spaggiari,
L Bejarano-Pineda,
F Bianco,
I Tzvetanov,
S Ayloo,
H Jeon,
R Garcia-Roca,
J Thielke,
I Tang,
S Akkina,
B Becker,
K Kinzer,
A Patel,
E Benedetti
American Journal of Transplantation 03/2013; 13(3):721-8. · 6.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Islet transplantation is a promising therapy for T1DM. Key factors influencing islet yield have been identified with conflicting results. In this study, we analyzed 276 isolations to identify variables for islet yield, and additionally, islet size and size distribution. Pearson correlation analyses demonstrated that BMI had a positive correlation with pancreas size, actual islet count (AIC), and islet equivalent (IEq)/g (all p ≤ 0.009), while CIT had a negative correlation with AIC and IEq/g (all p ≤ 0.003). In mixed linear regression, BMI also had a positive correlation with islet size but only for shorter digestion times ( ≤15 min); there was no association between BMI and islet size for longer digestion times ( > 15 min). CIT was not associated with islet size. Donor age, sex, and preservation solutions were shown to have no correlation with islet yields or size distribution. Pancreas size had positive correlation withAIC and negative association with IEQ/g; it also had positive association with islet size but only for females, not males. Overdigestion was positively associated with islet counts, however there was also a greater proportion of smaller islets when digestion rate >74% (p =0.005). Of the three collagenases analyzed, Sigma V had the lowest digestion rate (mean=65%), approximately 5 or 10% lower than Roche Liberase HI (p = 0.04) and Serva NB1 (p = 0.0003), respectively; however Sigma V group showed better islet size preservation. Yet, the enzymes resulted in similar IEq/g digested tissue. 70.2% of the isolated islets were smaller than 150 μm and contributed only 20.4% to total IEq, while 7.4% of islets were larger than 250 μm, but contributed 42.4% to total IEq. In summary, BMI, pancreas size, and CIT are useful variables for predicting islet yield, but selection of enzyme and balancing digestion time and rate are also important.
Cell Transplantation 01/2013; · 5.13 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Antibody-mediated rejection (AMR) typically occurs early after transplantation in approximately 5%-7% of recipients. The literature reports suggest that 12%-37% of kidney transplant recipients with acute AMR do not respond to treatment and eventually lose their grafts. The proteasome inhibitor bortezomib is currently approved by the Food and Drug Administration for the treatment of multiple myeloma. It has been demonstrated both in vitro and in vivo to possess apoptotic properties against mature plasma cells. Herein we have described a series of 3 patients with positive cross-matches who developed early AMR after kidney transplantation. Bortezomib rescue treatment was administered after the patients failed to respond to plasmapheresis/intravenous immunoglobulin and splenectomy. All 3 patients responded with full, durable recovery of renal function. In conclusion, bortezomib is useful to treat refractory AMR after kidney transplantation.
Transplantation Proceedings 12/2012; 44(10):2971-5. · 1.00 Impact Factor
-
Molecular Metabolism. 09/2012;
-
[show abstract]
[hide abstract]
ABSTRACT: AIMS/HYPOTHESIS: Diabetes is characterised by loss and dysfunction of the beta cell. A major goal of diabetes therapy is to promote the formation of new beta cells. Polymorphisms of T cell factor 7-like 2 (TCF7L2) are associated with type 2 diabetes, negatively regulating beta cell survival and function. Here, we provide evidence for a role of TCF7L2 in beta cell proliferation and regeneration. METHODS: Pancreatic sections from three mouse models (high-fat diet, exendin-4 and streptozotocin-treated mice) and from healthy individuals and patients with type 2 diabetes were used to investigate the association of beta cell regeneration and TCF7L2 levels. To analyse a direct effect of TCF7L2 on duct cell to beta cell conversion, TCF7L2 was overexpressed in isolated exocrine cells. RESULTS: TCF7L2 levels correlated with beta cell compensation during high-fat diet feeding. TCF7L2 was increased together with pancreatic duct cell proliferation and differentiation. Small islet-like cell clusters (ICCs) that contained TCF7L2 originated in the vicinity of the ductal epithelium. In human isolated exocrine tissue, TCF7L2 overexpression induced proliferation of pancreatic duct cells and ICC formation next to duct cells, an effect dependent on the JAK2/STAT3 pathway. CONCLUSIONS/INTERPRETATION: The present study demonstrates that TCF7L2 overexpression fosters beta cell regeneration. Our findings imply correlation of TCF7L2 levels and new beta cell formation.
Diabetologia 09/2012; · 6.81 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Living donor kidney transplantation remains the best option for presensitized recipients to avoid excessive time on the waiting list. However, the possibility for a positive crossmatch with a potential living donor is high. A desensitization protocol may be required to avoid antibody-mediated rejection (AMR). Current protocols are not always effective to prevent AMR and in some cases fail to convert subjects to a negative crossmatch before transplantation. From March 2006 to January 2011, the 11 presensitized patients who displayed AMR after living donor kidney transplantation underwent splenectomy as a rescue procedure due to failure of standard rejection treatments. Splenectomy was considered to be effective in six recipients who normalized their renal function without the need for other immunomodulating therapy. Our analysis suggested that splenectomy can be successfully performed alone or in association with other treatments like bortezomib or rituximab to overcome severe AMR.
Transplantation Proceedings 06/2012; 44(5):1254-8. · 1.00 Impact Factor
-
P. Y. Benhamou, J. Oberholzer,
C. Toso,
L. Kessler,
A. Penfornis,
F. Bayle,
C. Thivolet,
X. Martin,
F. Ris,
L. Badet,
C. Colin,
P. Morel,
on behalf of the GRAGIL
[show abstract]
[hide abstract]
ABSTRACT: Aims/hypothesis. Improvements in islet transplantation require clinical series large enough to implement controlled new strategies. The goal
of this study was to demonstrate the feasibility of a multicentre network for islet transplantation in Type I (insulin-dependent)
diabetic patients. Methods. The five centres (Besançon, Geneva, Grenoble, Lyon, Strasbourg) of the GRAGIL network allow pancreas procurement, recipient
recruitment, transplantation procedure and follow-up. Islet isolation is, however, performed in one single laboratory (Geneva).
Pancreata were procured in each of the five centres and transported to Geneva with an ischaemia time of less than 8 hours.
Islets were isolated using a standard automated method. If the islet number was too low for a graft ( < 6000 Islet-equivalent
/kg), islets were cultured up to 12 days until another isolation was possible. Islets were transplanted by percutaneous transhepatic
intraportal injection. Immunosuppression consisted of cyclosporine, mycophenolate mofetil, steroids and an anti-interleukin
2 receptor antibody. Results. From March 1999 to June 2000, 56 pancreata procurements were performed with an average yield of 234 500 islet-equivalent,
with 32 preparations over 200 000 islet-equivalent. Ten C-peptide negative Type I diabetic patients (5 men and 5 women, median
age 44 years, median diabetes duration 29 years) with an established kidney graft ( > 6 months) received 9030 ± 1090 islet-equivalent/kg
with a median purity of 63 %. The number of pancreata required for each graft was 1 (n = 5) or 2 (n = 5). At the completion
of a 12 month follow-up, we observed 0 % primary nonfunction, 50 % graft survival and 20 % insulin-independence. Conclusions/interpretation. This study demonstrates the interest and the feasibility of a multicentre collaboration in human islet transplantation. [Diabetologia
(2001) 44: 859–864]
Diabetologia 04/2012; 44(7):859-864. · 6.81 Impact Factor
-
I Goehring,
N S Sauter,
G Catchpole,
A Assmann,
L Shu,
K S Zien,
M Moehlig,
A F H Pfeiffer, J Oberholzer,
L Willmitzer,
J Spranger,
K Maedler
[show abstract]
[hide abstract]
ABSTRACT: Chronic hyperglycaemia promotes the progressive failure of pancreatic beta cells in patients with type 2 diabetes mellitus, a clinically highly relevant phenomenon known as glucotoxicity. The intracellular metabolic consequences of a chronically high availability of glucose in beta cells are, as yet, poorly understood in its full complexity.
An unbiased metabolite profiling analysis (GC-time-of-flight-MS) was used to identify the time course of core metabolite patterns in rat beta cell line INS-1E during exposure to high glucose concentrations and its relation to insulin expression.
We report here that pentose phosphate pathway (PPP) metabolites accumulate remarkably during chronic but not acute glucose treatment, indicating altered processing of glucose through the pentose phosphate pathway. Subsequent functional studies in INS-1E cells and human islets revealed that a disturbance in this pathway contributes to decreases in insulin gene expression and a lack of glucose-stimulated insulin secretion. These effects were found to depend on the activation of extracellular-regulated-kinase (ERK1/2). Long-term inhibition of 6-phosphogluconic acid dehydrogenase resulted in accumulation of PPP metabolites, induced ERK1/2 activation independently of high glucose and impaired beta cell function. In turn, inhibition of ERK1/2 overstimulation during chronic glucose exposure partly inhibited metabolite accumulation and restored beta cell function.
Based on unbiased metabolite analyses, the data presented here provide novel targets, namely the inhibition of PPP metabolite accumulation towards the therapeutic goal to preserve and potentially improve beta cell function in diabetes.
Diabetologia 07/2011; 54(10):2584-94. · 6.81 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A review of the clinical presentation, diagnosis, treatment and outcomes of 30 solid organ transplant recipients (SOTRs) with histoplasmosis or blastomycosis from 3 Midwestern academic medical centers.
The endemic fungal pathogens, Histoplasma capsulatum and Blastomyces dermatitidis, may cause severe infection in SOTRs. In this report, we describe the clinical presentation, diagnosis, treatment, and outcomes of these endemic fungal infections (EFIs) among SOTRs at 3 academic transplant centers.
A retrospective review was conducted of SOTRs with histoplasmosis or blastomycosis from 3 Midwestern medical centers in the United States. Data collected included demographics, immunosuppression, clinical presentation, method of diagnosis, antifungal treatment, response to therapy, and patient and graft survival.
Between 1996 and 2008, 30 transplant recipients with histoplasmosis or blastomycosis were identified, giving a cumulative incidence of infection of 0.50% (30/5989); 73% of the study patients were renal transplant recipients, and the median time to disease onset after transplantation was 10.5 months. The lungs were the most common site of infection (83%), and 60% had disseminated disease. Urine antigen testing was positive in all patients in whom it was performed (23/23). Initial antifungal therapy consisted of amphotericin B in 70%, and 87% received azoles, typically itraconazole (83%). Two patients developed relapsed infection and 7 patients had graft failure after EFI. Overall mortality was 30%, with an attributable mortality of 13%.
As in several previous single-center studies, the incidence of post-transplant histoplasmosis and blastomycosis was <1%, but often resulted in disseminated infection. In this cohort, EFI was associated with a high rate of allograft loss and overall mortality.
Transplant Infectious Disease 07/2011; 14(1):17-23. · 2.22 Impact Factor
-
American Journal of Transplantation 08/2010; 10(8):1725-6. · 6.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Kidney transplantation in morbidly obese patients can be technically demanding. Furthermore, morbidly obese patients experience a high rate of wound infections and related complications, which mostly result from the longer length and extent of the incision. These complications can be avoided through minimally invasive surgery; however, conventional laparoscopic instruments are unsuitable for the safe performance of a kidney transplant in morbidly obese patients. Herein, we report the first minimally invasive, total robotic kidney transplant in a morbidly obese patient. A left, deceased donor kidney was transplanted into a 29-year-old woman with a body mass index (BMI) of 41 kg/m(2) who had been on hemodialysis for 5 years. The operation was performed intraabdominally using the DaVinci Robotic Surgical System with 4 trocars and a 7 cm midline incision. The operative time was 223 min, and the blood loss was less than 50 cc. The kidney had immediate graft function. No perioperative complications were observed, and the patient was discharged on postoperative day 5 with normal kidney function. Minimally invasive access and robotic technology facilitated the safe performance of a successful kidney transplant in a morbidly obese patient.
American Journal of Transplantation 06/2010; 10(6):1478-82. · 6.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In obesity, beta cells activate compensatory mechanisms to adapt to the higher insulin demand. Interleukin-1 receptor antagonist (IL-1Ra) prevents obesity-induced hyperglycaemia and is a potent target for the treatment of diabetes, but the mechanisms of its secretion and regulation in obesity are unknown. In the present study, we hypothesise the regulation of IL-1Ra secretion by purinergic P2X(7) receptors in islets.
Production and regulation of P2X(7) were studied in pancreatic sections from lean and obese diabetic patients, non-diabetic controls and in isolated islets. IL-1Ra, IL-1beta and insulin secretion, glucose tolerance and beta cell mass were studied in P2x7 (also known as P2Rx7)-knockout mice.
P2X(7) levels were elevated in beta cells of obese patients, but downregulated in patients with type 2 diabetes mellitus. Elevated glucose and non-esterified fatty acids rapidly activated P2X(7) and IL-1Ra secretion in human islets, and this was inhibited by P2X(7) blockade. In line with our results in vitro, P2x7-knockout mice had a lower capacity to secrete IL-1Ra. They exhibited severe and rapid hyperglycaemia, glucose intolerance and impaired beta cell function in response to a high-fat/high-sucrose diet, were unable to compensate by increasing their beta cell mass in response to the diet and showed increased beta cell apoptosis.
Our study shows a tight correlation of P2X(7) activation, IL-1Ra secretion and regulation of beta cell mass and function. The increase in P2X(7) production is one mechanism that may explain how beta cells compensate by adapting to the higher insulin demand. Disturbances within that system may result in the progression of diabetes.
Diabetologia 05/2009; 52(8):1579-88. · 6.81 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Results of islet of Langerhans transplantation have markedly improved in recent years, but most patients still lose insulin independence in the long-term. We report herein the longest (over 11 years) case of insulin independence after allogeneic islet transplantation. The subject had a 27-year history of type 1 diabetes and received a single islet-after-kidney graft of 8800 islet equivalents (IEQ)/kg, pooled from 2 donors. Insulin was discontinued by 3 months posttransplant and the patient has remained off insulin ever since. Yearly follow-up studies have revealed normal metabolic control, including normal oral glucose tolerance test (OGTT). Reasons for success may involve choice of immunosuppression, low metabolic demand and low immune responsiveness as suggested by an excellent HLA matching and a high count of circulating regulatory T cells. This observation is so far an exceptional case, but clearly demonstrates the validity of the concept that long-term insulin independence after allogeneic islet transplantation is an achievable target.
American Journal of Transplantation 01/2009; 9(2):419-23. · 6.39 Impact Factor
-
A Gangemi,
P Salehi,
B Hatipoglu,
J Martellotto,
B Barbaro,
J B Kuechle,
M Qi,
Y Wang,
P Pallan,
C Owens,
J Bui,
D West,
B Kaplan,
E Benedetti, J Oberholzer
[show abstract]
[hide abstract]
ABSTRACT: This prospective phase 1/2 trial investigated the safety and reproducibility of allogeneic islet transplantation (Tx) in type I diabetic (T1DM) patients and tested a strategy to achieve insulin-independence with lower islet mass. Ten C-peptide negative T1DM subjects with hypoglycemic unawareness received 1-3 intraportal allogeneic islet Tx and were followed for 15 months. Four subjects (Group 1) received the Edmonton immunosuppression regimen (daclizumab, sirolimus, tacrolimus). Six subjects (Group 2) received the University of Illinois protocol (etanercept, exenatide and the Edmonton regimen). All subjects became insulin- independent. Group 1 received a mean total number of islets (EIN) of 1460 080 +/- 418 330 in 2 (n = 2) or 3 (n = 2) Tx, whereas Group 2 became insulin- independent after 1 Tx (537 495 +/- 190 968 EIN, p = 0.028). All Group 1 subjects remained insulin free through the follow-up. Two Group 2 subjects resumed insulin: one after immunosuppression reduction during an infectious complication, the other with exenatide intolerance. HbA1c reached normal range in both groups (6.5 +/- 0.6 at baseline to 5.6 +/- 0.5 after 2-3 Tx in Group 1 vs. 7.8 +/- 1.1 to 5.8 +/- 0.3 after 1 Tx in Group 2). HYPO scores markedly decreased in both groups. Combined treatment of etanercept and exenatide improves islet graft function and facilitates achievement of insulin-independence with less islets.
American Journal of Transplantation 07/2008; 8(6):1250-61. · 6.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We previously used an integrative genetics approach to demonstrate that 5-lipoxygenase (5-LO) deficiency in mice (Alox5 (-/-)) protects against atherosclerosis despite increasing lipid levels and fat mass. In the present study, we sought to further examine the role of 5-LO in adiposity and pancreatic function.
Alox5 (-/-) and wild-type (WT) mice were characterised with respect to adiposity and glucose/insulin metabolism using in vivo and in vitro approaches. The role of ALOX5 in pancreatic function in human islets was assessed through short interfering RNA (siRNA) knockdown experiments.
Beginning at 12 weeks of age, Alox5 (-/-) mice had significantly increased fat mass, plasma leptin levels and fasting glucose levels, but lower fasting insulin levels (p<0.05). Although Alox5 (-/-) mice did not exhibit insulin resistance, they had impaired insulin secretion in response to a bolus glucose injection. Histological analyses revealed that Alox5 (-/-) mice had increased islet area, beta cell nuclear size, and numbers of beta cells/mm(2) islet (p<0.05), indicative of both hyperplasia and hypertrophy. Basal and stimulated insulin secretion in isolated Alox5 (-/-) islets were significantly lower than in WT islets (p<0.05) and accompanied by a three- to fivefold decrease in the expression of the genes encoding insulin and pancreatic duodenal homeobox 1 (Pdx1). Direct perturbation of ALOX5 in isolated human islets with siRNA decreased insulin and PDX1 gene expression by 50% and insulin secretion by threefold (p<0.05).
These results provide strong evidence for pleiotropic metabolic effects of 5-LO on adiposity and pancreatic function and may have important implications for therapeutic strategies targeting this pathway for the treatment of cardiovascular disease.
Diabetologia 06/2008; 51(6):978-88. · 6.81 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Cytomegalovirus (CMV) infection is a major complication following solid organ transplantation resulting in significant morbidity and mortality. The guidelines published in 2004 have recommendations for therapy; however, the frequency of resistant CMV infection is increasing and therapy is not clearly defined. There are a few alternatives to ganciclovir such as foscarnet, cidofovir, and leflunomide; however, their use is limited by adverse effects. This report summarizes the successful use of high-dose ganciclovir for the treatment of a resistant CMV caused by UL97 mutation.
Transplant Infectious Disease 05/2008; 10(2):129-32. · 2.22 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Positive cross-match (PXM) renal transplantation has been utilized to address the issue of the increasing demand for transplantation with the shortage of suitable organs. Our primary objective was to analyze the outcomes of African American (AA) PXM renal transplant recipients utilizing AA negative cross-match (NXM) renal transplant recipients as a comparator group. This was a retrospective study consisting of all PXM patients who underwent a desensitization protocol and all AA NXM transplant recipients at the University of Illinois at Chicago from July 2001 to March 2007. We found that AA PXM recipients had significantly lower estimated glomerular filtration rate (eGFR) at 1 year than AA NXM (46.2 vs. 60.6, p = 0.007). AA PXM who experienced acute rejection within the first year were more likely to have an eGFR less than 30 mL/min/1.73 m(2) at 1 year compared to their NXM counterparts (45.5% vs. 12.5%, p = 0.034). Positive cross-match renal transplantation in AA seems to be associated with a high degree of AR and severe renal compromise at 1 year. Larger studies are needed to determine if protocols that are associated with good short-term outcomes in non-AA need to be modified for the AA population.
American Journal of Transplantation 03/2008; 8(2):348-54. · 6.39 Impact Factor
-
S Horgan,
C Galvani,
M V Gorodner,
G R Jacobsen,
F Moser,
A Manzelli, J Oberholzer,
M P Fisichella,
D Bogetti,
G Testa,
H N Sankary,
E Benedetti
[show abstract]
[hide abstract]
ABSTRACT: The number of living-related donor kidney transplantations have increased since the advent of minimally invasive surgery. Robotic technology has emerged as a promising alternative to laparoscopic techniques. The authors reviewed their institution experience with robotic hand-assisted donor nephrectomies (RHADNs).
Between August 2000 and April 2006, 273 robotically assisted left donor nephrectomies were performed using a hand-assisted technique. Prospectively collected information for 214 patients regarding complications, hospital stay, blood loss, warm ischemia time, operative time, and outcomes is presented.
The cohort of donors included 110 men and 104 women with a mean age of 36 years (range, 18-61 years). These donors included 86 African Americans, 46 Caucasians, 74 Hispanics, and 8 of other races. Left renal artery anomalies were found in 61 patients (29%). Four patients underwent conversion to open surgery. The hospital stay was 2.3 days (range, 1-8 days), the blood loss 82 ml (range, 10-1,500 ml), and the mean warm ischemia time 98 s (range, 50-200 s). The operative time was 201 min (range, 100-320 min) for the first 74 cases, 129 min (range, 65-240 min) for the second 70 cases, and 103 min for the last 70 cases (p < 0.001), for an overall average of 150 min. Complications decreased significantly after the first 74 cases. The 1-year patient survival rate was 100%, and the 1-year graft survival rate was 98%. The average recipient creatinine at 6 months was 1.4 mg/dl.
Specific changes in operative technique over time have improved patient safety and diminished complications with RHADN. Currently, RHADN can be performed expeditiously with a minimal rate of complications and conversion to open procedure by a surgical team with appropriate training and experience.
Surgical Endoscopy 10/2007; 21(9):1512-7. · 4.01 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Impaired surgical site healing occurs in 20% to 50% of sirolimus (SRL)-treated renal transplant (RT) recipients, with most patients having received concomitant corticosteroids. We determined the incidence of surgical site complications among RT recipients receiving SRL with mycophenolate mofetil (MMF), with most patients on a steroid-avoidance protocol. SRL/MMF patients with complications within 3 months of transplantation were compared with 1) SRL/MMF patients without them and 2) matched RT recipients receiving tacrolimus (FK)/MMF. Between January 2002 and March 2005, 44 of 300 (15%) RT recipients received SRL within 6 weeks of transplantation. Fourteen (31.8%) developed lymphocele, bladder leak, wound dehiscence, cellulitis, or an abscess. Obesity (BMI > or =30 kg/m2) was significantly associated with problems: the mean BMI of SRL cases with complications was 29.9 kg/m2 vs 25.4 kg/m2 for SRL patients without them (P = .047). Seventy-one percent of obese SRL patients experienced complications compared with 24.3% (P = .025) of non-obese SRL patients. Surgical treatment was required in 29% of patients. Rates of maintenance steroid use were similar in SRL complicated cases compared with SRL patients without them. The FK control group showed a lower rate of complications (14.3%; P = .163) despite similar BMI, rejection rates, and chronic steroid use as the SRL group. Obesity and graft rejection were independent predictors of complications. Thus, among a group of predominantly steroid-free recipients on SRL, the rates of wound complications were similar to those seen previously, but the highest risk for them was observed in obese recipients and in those with acute rejection episodes. Wound complications were associated with significant morbidity.
Transplantation Proceedings 12/2006; 38(10):3520-3. · 1.00 Impact Factor
-
J G Avila,
Y Wang,
B Barbaro,
A Gangemi,
M Qi,
J Kuechle,
N Doubleday,
M Doubleday,
T Churchill,
P Salehi,
J Shapiro,
L H Philipson,
E Benedetti,
J R T Lakey, J Oberholzer
[show abstract]
[hide abstract]
ABSTRACT: During isolation, islets are exposed to warm ischemia. In this study, intraductal administration of oxygenated polymerized, stroma-free hemoglobin-pyridoxalated (Poly SFH-P) was performed to improve O2 delivery. Rat pancreata subjected to 30-min warm ischemia were perfused intraductally with collagenase in oxygenated Poly SFH-P/RPMI or RPMI (control). PO2 was increased by Poly SFH-P (381.7 +/- 35.3 mmHg vs. 202.3 +/- 28.2, p = 0.01) and pH maintained within physiological range (7.4-7.2 vs. 7.1-6.6, p = 0.009). Islet viability (77% +/- 4.6 vs. 63% +/- 4.7, p = 0.04) was improved and apoptosis lower with Poly SFH-P (caspase-3: 34,714 +/- 2167 vs. 45,985 +/- 1382, respectively, p = 0.01). Poly SFH-P improved islet responsiveness to glucose as determined by increased intracellular Ca2+ levels and improved insulin secretion (SI 5.4 +/- 0.1 vs. 3.1 +/- 0.2, p = 0.03). Mitochondrial integrity was improved in Poly SFH-P-treated islets, which showed higher percentage change in membrane potential after glucose stimulation (14.7% +/- 1.8 vs. 9.8 +/- 1.4, respectively, p < 0.05). O2 delivery by Poly SFH-P did not increase oxidative stress (GSH 7.1 +/- 2.9 nm/mg protein for Poly SFH-P vs. 6.8 +/- 2.4 control, p = 0.9) or oxidative injury (MDA 1.8 +/- 0.9 nmol/mg protein vs. 6.2 +/- 2.4, p = 0.19). Time to reach normoglycemia in transplanted diabetic nude mice was shorter (1.8 +/- 0.4 vs. 7 +/- 2.5 days, p = 0.02), and glucose tolerance improved in the Poly SFH-P group (AUC 8106 +/- 590 vs. 10,863 +/- 946, p = 0.03). Oxygenated Poly SFH-P improves islet isolation and transplantation outcomes by preserving mitochondrial integrity.
American Journal of Transplantation 12/2006; 6(12):2861-70. · 6.39 Impact Factor
