Estimation of Early Graft Function Using the BETA-2 Score Following Clinical Islet Transplantation.

Little is known about how early islet graft function evolves in the clinical setting. The BETA-2 score is a validated index of islet function that can be calculated from a single blood sample and lends itself to frequent monitoring of graft function. In this study, we characterized early graft function by calculating weekly BETA-2 score in recipients who achieved insulin independence after single transplant (group 1, n = 8) compared to recipients who required a second transplant before achieving insulin independence (group 2, n = 7). We also determined whether graft function 1-week post-transplant was associated with insulin independence in individuals who received initial transplant between 2000-2017 (n = 125). Our results show that graft function increased rapidly reaching a plateau 4-6 weeks post-transplant. The BETA-2 score was higher in group 1 compared to group 2 as early as 1-week post-transplant (15 + 3 vs. 9 + 2, p = 0.001). In an unselected cohort, BETA-2 at 1-week post-transplant was associated with graft survival as defined by insulin independence during median follow up of 12 months (range 2-119 months) with greater survival among those with BETA-2 score >10 (p < 0.001, log-rank test). These findings suggest that primary graft function is established within 4-6 weeks post-transplant and graft function at 1-week post-transplant predicts long-term transplant outcomes.

Pancreatic islet transplantation in type 1 diabetes: 20-year experience from a single-centre cohort in Canada.

BACKGROUND: Islet transplantation offers an effective treatment for selected people with type 1 diabetes and intractable hypoglycaemia. Long-term experience, however, remains limited. We report outcomes from a single-centre cohort up to 20 years after islet transplantation. METHODS: This cohort study included patients older than 18 years with type 1 diabetes undergoing allogeneic islet transplantation between March 11, 1999, and Oct 1, 2019, at the University of Alberta Hospital (Edmonton, AB, Canada). Patients who underwent islet-after-kidney transplantation and islet transplantation alone or islet transplantation before whole-pancreas transplantation (follow-up was censored at the time of whole-pancreas transplantation) were included. Patient survival, graft survival (fasting plasma C-peptide >0·1 nmol/L), insulin independence, glycaemic control, and adverse events are reported. To identify factors associated with prolonged graft survival, recipients with sustained graft survival (≥90% of patient follow-up duration) were compared with those who had non-sustained graft survival (<90% of follow-up duration). Multivariate binary logistic regression analyses were done to determine predictors of sustained graft survival. FINDINGS: Between March 11, 1999, and Oct 1, 2019, 255 patients underwent islet transplantation and were included in the analyses (149 [58%] were female and 218 [85%] were White). Over a median follow-up of 7·4 years (IQR 4·4-12·2), 230 (90%) patients survived. Median graft survival was 5·9 years (IQR 3·0-9·5), and graft failure occurred in 91 (36%) patients. 178 (70%) recipients had sustained graft survival, and 77 (30%) had non-sustained graft survival. At baseline, compared with patients with non-sustained graft survival, those with sustained graft survival had longer median type 1 diabetes duration (33·5 years [IQR 24·3-41·7] vs 26·2 years [17·0-35·5]; p=0·0003), median older age (49·4 years [43·5-56·1] vs 44·2 years [35·4-54·2]; p=0·0011), and lower median insulin requirements (0·53 units/kg per day [0·45-0·67] vs 0·59 units/kg per day [0·48-0·70]; p=0·032), but median HbA1c concentrations were similar (8·2% [7·5-9·0] vs 8·5% [7·8-9·2]; p=0·23). 201 (79%) recipients had insulin independence, with a Kaplan-Meier estimate of 61% (95% CI 54-67) at 1 year, 32% (25-39) at 5 years, 20% (14-27) at 10 years, 11% (6-18) at 15 years, and 8% (2-17) at 20 years. Patients with sustained graft survival had significantly higher rates of insulin independence (160 [90%] of 178 vs 41 [53%] of 77; p<0·0001) and sustained improvements in glycaemic control mixed-main-effects model group effect, p<0·0001) compared with those with non-sustained graft survival. Multivariate analyses identified the combined use of anakinra plus etanercept (adjusted odds ratio 7·5 [95% CI 2·7-21·0], p<0·0001) and the BETA-2 score of 15 or higher (4·1 [1·5-11·4], p=0·0066) as factors associated with sustained graft survival. In recipients with sustained graft survival, the incidence of procedural complications was lower (23 [5%] of 443 infusions vs 17 [10%] of 167 infusions; p=0·027), whereas the incidence of cancer was higher (29 of [16%] of 178 vs four [5%] of 77; p=0·015) than in those with non-sustained graft survival; most were skin cancers (22 [67%] of 33). End-stage renal disease and severe infections were similar between groups. INTERPRETATION: We present the largest single-centre cohort study of long-term outcomes following islet transplantation. Although some limitations with our study remain, such as the retrospective component, a relatively small sample size, and the absence of non-transplant controls, we found that the combined use of anakinra plus etanercept and the BETA-2 score were associated with improved outcomes, and therefore these factors could inform clinical practice. FUNDING: None.

Comparison of metabolic responses to the mixed meal tolerance test vs the oral glucose tolerance test after successful clinical islet transplantation.

Following islet transplantation, mixed meal tolerance tests (MMTs) are routinely utilized to assess graft function, but how the 90-minute MMTT glucose value relates to a 120-minute glucose concentration of ≥11.1 mmol/L used to diagnose diabetes following a standardized 75 g-OGTT, is not known. We examined this relationship further. Thirteen subjects with Type 1 diabetes and stable transplant grafts, not on exogenous insulin with HbA1c < 7% (53 mmol/mol), were studied on 17 occasions with paired OGTTs and MMTTs. Receiver operating characteristic (ROC) curves were constructed to derive the 90-minute MMTT glucose threshold associated with a 120-minute glucose concentration following a 75 g-OGTT (OGTT120 ) ≥11.1 mmol/L and their diagnostic accuracy. Studies with OGTT120 ≥11.1 mmol/L (n = 5) had diminished C-peptide: glucose, greater integrated glucose and diminished insulin: glucose area under the curve (AUC) ratios (0-120 minutes) and disposition indices; all P < .05, contrasting with MMTTs where no difference in the 90-minute glucose concentrations, C-peptide:glucose, integrated glucose, C-peptide and C-peptide: glucose AUCs (0-90 minutes) was seen; all P > .05. A 90-minute MMTT glucose concentration ≥8.0 mmol/L demonstrated a sensitivity and specificity of ≥80% for the diagnosis of OGTT120 ≥11.1 mmol/L; area under ROC curve (mean ± SEM) 73 ± 13%. A 90-minute MMTT glucose ≥8.0 mmol/L, identifies islet transplant recipients who may require closer monitoring for graft dysfunction.

Single-donor islet transplantation and long-term insulin independence in select patients with type 1 diabetes mellitus.

BACKGROUND: Islet transplantation is a recognized treatment option for select patients with type I diabetes mellitus. However, islet infusions from multiple donors are often required to achieve insulin independence. Ideally, insulin independence would be achieved routinely with only a single donor. Identification of factors associated with insulin independence after single-donor islet transplantation may help to select recipient-donor combinations with the highest probability of success. METHODS: Subjects undergoing islet transplantation at a single center (Edmonton, Canada) between March 1999 and August 2013 were included. Recipient, donor, and transplant characteristics were collected and compared between recipients who became insulin independent after one islet transplantation and those who did not. RESULTS: Thirty-one patients achieved insulin independence after a single-donor islet transplantation, and 149 did not. Long-term insulin-free survival was not different between the groups. Factors significantly associated with single-donor success included recipient age, insulin requirement at baseline, donor weight, donor body mass index, islet transplant mass, and peritransplant heparin and insulin administration. On multivariate analysis, pretransplantation daily insulin requirements, the use of peritransplantation heparin and insulin infusions, and islet transplant mass remained significant. CONCLUSION: We have identified clinically relevant differences defining the achievement of insulin independence after single-donor transplantation. Based on these differences, a preoperative insulin requirement of less than 0.6 U/kg per day and receiving more than 5,646 islet equivalents (IEQ)/kg have a sensitivity of 84% and 71% and specificity of 50% and 50%, respectively, for insulin independence after single-donor islet transplantation. With ideal patient selection, this finding could potentially increase single-donor transplantation success and may be especially relevant for presensitized subjects or those who may subsequently require renal replacement.

Successful treatment of brittle diabetes following total pancreatectomy by islet allotransplantation: a case report.

CONTEXT: Allotransplantation of islets can successfully treat subjects with type 1 diabetes complicated by severe hypoglycemia and erratic glycemic control. Insulin independence is often lost over time due to several factors, including recurrent autoimmunity. Brittle diabetes (frequent hypoglycemia and labile glycemic control) is common after pancreatectomy. This is ameliorated by auto-islet transplantation in pancreatectomized patients who have better glycemic control, even without insulin independence. CASE REPORT: We herein report a case where islet allotransplantation was carried out in a patient who had undergone total pancreatectomy. Following two islet infusions, he became insulin independent with excellent glycemic control and remains so currently, more than four years after his second islet infusion. Side effects from immunosuppressive therapy were minimal. DISCUSSION: Islet allotransplantation can be considered in selected individuals post-pancreatectomy. The absence of autoimmunity may be advantageous for long term graft function relative to islet allotransplantation in type 1 diabetic recipients.

Clinical islet isolation outcomes with a highly purified neutral protease for pancreas dissociation.

BACKGROUND: Pancreas dissociation is a critical initial component of the islet isolation procedure and introduces high variability based on factors including the enzyme type, specificity and potency. Product refinement and alterations to the application strategies have improved isolation outcomes over time; however, islet utilization from donor organs remains low. In this study we evaluate a low endotoxin-high activity grade neutral protease in clinical islet isolation. MATERIALS AND METHODS: The use of a non-collagenolytic enzyme, either thermolysin or high active neutral protease, was randomized in clinical islet isolations to evaluate efficacy. Additionally a retrospective comparison to neutral protease NB was conducted. RESULTS: The thermolysin group had lower trapped islet population and increased purity and post-culture islet mass in comparison to high active grade neutral protease. Comparison of neutral protease NB GMP grade to high active neutral protease displayed no measurable difference in islet mass or viability and transplantation outcomes at 1 mo post-transplant were favorable for both groups. CONCLUSIONS: High activity neutral protease can generate clinical grade islets and may prove beneficial to islet function and viability based on a reduced endotoxin load but dosing of neutral protease requires ongoing optimization.

Long-term follow-up of hepatic ultrasound findings in subjects with magnetic resonance imaging defined hepatic steatosis following clinical islet transplantation: a case-control study.

Hepatic steatosis is one complication patients may experience following clinical islet transplantation (CIT), yet the cause and consequences of this are poorly understood. The purpose of this case-control study was to examine the relationship between hepatic steatosis, metabolic parameters and graft function in an Albertan cohort of CIT recipients. Hepatic steatosis was detected by magnetic resonance imaging (MRI) in n = 10 cases age-matched with n=10 MRI-negative controls. Progression/regression of steatosis was determined by ultrasound (US) in cases. Hepatic steatosis first appeared 2.8 ± 2.2 (mean ± SD) years post-CIT, and lasted approximately 4.6 ± 2.0 years. In five cases steatosis resolved, with recurrence in two cases during the follow-up period (8.5 ± 3.2 years). No evidence of CIT causing deleterious effects on long-term liver function or graft outcome was observed.

Comparison of human islet isolation outcomes using a new mammalian tissue-free enzyme versus collagenase NB-1.

BACKGROUND: After the discontinuation of the manufacturing Liberase HI because of a small potential for prion disease transmission, Roche Diagnostics (Indianapolis, IN) developed a new enzyme product (Liberase MTF [mammalian tissue free]), which is similar to Liberase HI with the exception that no mammalian tissue is used in the manufacture of the collagenase component. We report our experience using the MTF enzyme in clinical islet isolations compared with Serva NB-1 with modified enzyme delivery method. METHODS: Islets were isolated from 41 pancreata using MTF enzyme (n=17) or NB-1 enzyme (n=24). NB-1 enzymes were delivered using a modified (nonsimultaneous) enzyme delivery method whereas isolations using MTF used the standard method of simultaneous collagenase and thermolysin perfusion. Islets were purified on a COBE 2991 Cell Blood Processor and subsequently cultured. RESULTS: The average islet mass after purification was 392+/-36 x 10 islet equivalent (IE) for MTF versus 371+/-40 x 10 IE for Serva NB-1 (P=0.63). Post-IE/cm of tissue was 110+/-9 x 10 IE/cm and 91+/-11 x 10 IE/cm for MTF and NB-1, respectively (P=0.07). The isolation success rate (>400,000 IE) for MTF was 53% compared with 33% for Serva (P=0.33). CONCLUSION: We conclude that MTF may be successfully used for high-yield human islet isolation and clinical transplantation and provides similar quality islets to those derived using NB-1.

Supplemental islet infusions restore insulin independence after graft dysfunction in islet transplant recipients.

BACKGROUND: The ability of supplemental islet infusions (SII) to restore insulin independence in islet transplant recipients with graft dysfunction has been attributed to the coadministration of exenatide. However, improving islet transplant outcomes could explain the success of SII. We aimed to determine the effect on islet graft function and insulin independence of SII using these new protocols, without the use of exenatide. METHODS: Seventeen islet transplant recipients underwent SIIs after developing graft dysfunction requiring insulin use. For induction therapy, four subjects received daclizumab induction therapy, whereas 13 subjects received thymoglobulin and etanercept. Maintenance immunosuppression consisted of sirolimus+tacrolimus or tacrolimus+cellcept. RESULTS: SII was performed 49.3+/-4.8 months (mean+/-SEM) after the preceding islet transplant. Subjects received significantly lower islet mass with their SII compared with initial transplant(s) (6076+/-492 vs. 9071+/-796 IEQ/kg; P=0.003). Fifteen of the 17 subjects (88.2%) became insulin independent 2.4+/-0.5 months after SII. Insulin-independent duration after SII exceeded that of the initial transplant(s) (24.8+/-2.2 vs. 14.2+/-2.6 months by Kaplan-Meier analysis, P=0.009). Subjects show improved glycemic control after SII (HbA1c 7.0%+/-0.2% pre-SII vs. 6.1%+/-0.2% post-SII, P=0.005) and did not become immunosensitized. CONCLUSION: Using current protocols, SII in the absence of exenatide results in impressive insulin-independence rates and the durability of insulin independence seems to be promising. However, a beneficial effect of exenatide should not be discounted until tested in randomized controlled studies.

Insulin-heparin infusions peritransplant substantially improve single-donor clinical islet transplant success.

BACKGROUND: Successful islet transplantation can result in insulin independence in many patients with type 1 diabetes mellitus, but it often requires more than one islet infusion. The ability to achieve insulin independence with a single donor is an important goal in clinical islet transplantation due to the limited organ supply. METHODS: We examined factors that may be associated with insulin independence after islet transplantation with islets from a single donor, using univariate and multivariate analysis. RESULTS: Thirteen of 85 (15.3%) achieved insulin independence after single-donor islet transplantation. Using multivariate analysis, only the use of insulin and heparin infusions peritransplant was a significant factor associated with insulin independence, with an adjusted odds ratio of 8.6 (95% confidence interval 2.0-37.0). Patients who had received insulin and heparin infusions peritransplant had greater indices of islet engraftment and a greater reduction in insulin use (80.1% + or - 4.3% vs. 54.2% + or - 2.8%, P<0.001) even if insulin independence was not achieved. CONCLUSIONS: Peritransplant intensive insulin and heparin enhances islet transplantation outcomes likely related in part to mitigation of the effects of the instant blood-mediated inflammatory reaction, combined with islet rest and avoidance of inflammation. It would be important to further investigate the effects of peritransplant insulin and heparin infusions on islet engraftment.

Histologic graft assessment after clinical islet transplantation.

BACKGROUND: An accurate monitoring would help understanding the fate of islet grafts after transplantation. METHODS: This work assessed the feasibility of needle biopsy monitoring after intraportal islet transplantation (n=16), and islet graft morphology was studied with the addition of autopsy samples (n=2). Pancreas autopsy samples from two nondiabetic individuals were used as control. RESULTS: Islet tissue was found in five needle samples (31%). Sampling success was related to size (100% sampling for the four biopsies of 1.8 cm in length or higher, P

Nonsimultaneous administration of pancreas dissociation enzymes during islet isolation.

BACKGROUND: Successful islet isolation relies heavily on enzyme products. Among them, Liberase was used in islet transplantation programs until the islet community was notified of the use of a bovine brain component during the manufacturing process. To minimize potential risk of prion disease transmission, many islet isolation facilities switched to Serva enzyme, which is considered to pose less risk. However, this conversion significantly affected the field in transplant activity. Here, we report our successful conversion from Liberase to Serva collagenase with the use of a modified digestion protocol. METHODS: We compared the quality of Serva versus Liberase enzyme using chromatography and collagenase activity assay. On the basis of the findings, we developed a pancreas digestion protocol optimized for Serva enzyme, where only collagenase was injected into the pancreas through the duct, and then neutral protease was added to the circulating system during the digestion phase. RESULTS: Class I collagenase activity of Serva was remarkably reduced compared with Liberase. Chromatography of Serva demonstrated suspected degradation of class I collagenase. When the modified protocol was applied to donor pancreata more than 35 years of age, we recovered 3119+/-147 islet equivalent/g pancreas with a success rate of 51% (35/68), whereas the standard method yielded only 1809+/-266 islet equivalent/g pancreas (P=0.02) with a success rate of 11% (1/9). This beneficial effect of the modified method was, however, diminished when applied to younger donor pancreata. CONCLUSIONS: Our study brings new insight into the role of collagenase and noncollagenolytic protease on pancreas dissociation.

Islets isolated from donors with elevated HbA1c can be successfully transplanted.

Clinical islet transplantation is limited by the availability of donor organs. We report two cases where islets were isolated from donors with elevated HbA1c (6.3% and 7.9%). Islet isolation yield was adequate in both cases (521,350 and 497,472 islet equivalents, respectively). Islet graft analyses revealed a decreased proportion of beta cells (21.6%) and an increase in alpha cells (51.0%) in the donor with the higher HbA1c, although graft characteristics of the other donor were similar to donors with normal HbA1c. Both islet preparations were transplanted into type 1 diabetes recipients with brittle diabetes. One recipient has remained insulin independent for 4 years to date with good glycemic control. The other recipient who received islets from the donor with the higher HbA1c had a 56% reduction in insulin requirement after transplant. Pancreases from donors with mild hyperglycemia may be a source of islets that could be considered for clinical islet transplantation.

Long-term graft function after allogeneic islet transplantation.

Islet transplants are emerging as a viable option for the treatment of type 1 diabetes mellitus. From 1989 to 1995 we conducted a series of simultaneous islet-kidney transplants in six uremic type 1 diabetic patients. We report two of these patients who have shown persistent islet graft function over many years. Two female patients with duration of diabetes of 27 and 37 years underwent simultaneous islet-kidney transplant under steroid- and cyclosporine-based immunosuppression. Freshly isolated islets were supplemented with cryopreserved islets from our low-temperature bank of frozen islets. A total islet mass of 9,866 and 15,061 islet equivalents/kg body weight, respectively, was transplanted into the liver through portal vein. Reasonable blood glucose control has been achieved for up to 6 years posttransplant in one patient, but there was minimum clinical benefit from the islet graft at 10 years. In contrast, sustained insulin secretion with nearly normal HbA1c at 13 years follow-up was observed in another patient, providing hope for improving long-term graft outcomes for islet transplant recipient.

Long-Term Graft Function after Allogeneic Islet Transplantation.

Islet transplants are emerging as a viable option for the treatment of type 1 diabetes mellitus. From 1989 to 1995 we conducted a series of simultaneous islet-kidney transplants in six uremic type 1 diabetic patients. We report two of these patients who have shown persistent islet graft function over many years. Two female patients with duration of diabetes of 27 and 37 years underwent simultaneous islet-kidney transplant under steroid- and cyclosporine-based immunosuppression. Freshly isolated islets were supplemented with cryopreserved islets from our low-temperature bank of frozen islets. A total islet mass of 9,866 and 15,061 islet equivalents/kg body weight, respectively, was transplanted into the liver through portal vein. Reasonable blood glucose control has been achieved for up to 6 years posttransplant in one patient, but there was minimum clinical benefit from the islet graft at 10 years. In contrast, sustained insulin secretion with nearly normal HbA1c at 13 years follow-up was observed in another patient, providing hope for improving long-term graft outcomes for islet transplant recipient.

Islet isolation and transplantation outcomes of pancreas preserved with University of Wisconsin solution versus two-layer method using preoxygenated perfluorocarbon.

BACKGROUND: Previous small clinical trials indicate that the two-layer method (TLM) for pancreas preservation improves islet isolation outcome. However, the effect of TLM has not been evaluated in large-scale study. In addition, a direct benefit of TLM on islet transplantation outcome has not been addressed in the setting of any randomized controlled trials. METHODS: Between April 2003 and October 2005, human pancreata from brain-dead donors were preserved by TLM using preoxygenated perfluorocarbon (n = 75) or in University of Wisconsin (UW) solution (n = 91) prior to islet isolation. Islet isolation and transplantation outcomes were compared between the two groups. RESULTS: We did not find any significant differences in adenosine triphosphate content in pancreatic tissue after preservation, pre and postpurification islet yields, in vitro insulin secretory function, or utilization ratio of transplantation between the two groups. Transplanted mass and functional viability of islet isolated from TLM-preserved pancreas were similar to those from UW-preserved pancreas. Patients receiving the TLM-islet or the UW-islet showed a marked decrease in insulin requirement after transplantation. However, no significant difference was observed in a decrease in insulin requirement between patients receiving the TLM-islet and the UW-islet. CONCLUSIONS: No beneficial effect of TLM on islet isolation and transplantation outcomes was observed. Our findings bring into question the true merit of routine use of TLM prior to islet isolation.

Islet graft assessment in the Edmonton Protocol: implications for predicting long-term clinical outcome.

The success of the Edmonton Protocol for islet transplantation has provided new hope in the treatment of type 1 diabetes. This study reports on the assessment of 83 human islet grafts transplanted using the Edmonton Protocol since 1999. Cellular composition, as assessed by immunohistochemistry, showed a lower islet purity (approximately 40%) than has been reported in previous studies using dithizone staining to quantitate islet equivalents. Furthermore, grafts were found to contain substantial populations of exocrine and ductal tissue. Total cellular insulin transplanted was 8,097.6 +/- 3,164.4 microg/patient, and was significantly lower in bottom gradient layer grafts than top gradient layer or whole/combined grafts (P < 0.0005). A static incubation test for islet function gave a stimulation index of 3-4, although this measure did not correlate with posttransplant metabolic outcome. Furthermore, we confirmed a previously reported trend in which donor age affects islet yield and purity. It is important to note that a significant positive correlation was observed between the number of islet progenitor (ductal-epithelial) cells transplanted and long-term metabolic success as assessed an by intravenous glucose tolerance test at approximately 2 years posttransplant. In summary, careful assessment of islet graft composition is needed in a clinical transplantation program to accurately estimate islet purity and assess the contribution of other cell types present, such as islet progenitor cells.

Short-term intensive insulin therapy in newly diagnosed type 2 diabetes.

OBJECTIVE: Type 2 diabetes is associated with defects in insulin secretion and insulin action. Hyperglycemia may aggravate these defects, a feature known as glucose toxicity. Previous studies have shown that acute correction of hyperglycemia in subjects with long-standing type 2 diabetes gives only short-term improvement in glycemic control after discontinuation of insulin. The current study attempts to identify any characteristics of patients with newly diagnosed type 2 diabetes (fasting glucose >11.0 mmol/l) who would have a long-term benefit, in terms of glycemic control, from a brief course of insulin therapy. RESEARCH DESIGN AND METHODS: A total of 16 subjects (52 +/- 2 years old [range 36-64], BMI 30.8 +/- 1.9 kg/m2) with newly diagnosed type 2 diabetes had a 2-3 week course of intensive insulin therapy that was then discontinued. RESULTS: Fasting glucose fell from 13.3 +/- 0.7 to 7.0 +/- 0.4 mmol/l, and this improvement was maintained at the 1-year follow-up (6.7 +/- 0.3 mmol/l). The insulin area under the curve for the posttreatment oral glucose tolerance test also improved (8,251 +/- 1,880 before therapy, 18,404 +/- 4,040 directly after insulin therapy, and 42,368 +/- 8,517 pmol.min at the 1-year follow-up). At 1 year, seven of the subjects maintained good glycemic control on diet therapy alone, eight required oral hypoglycemic agent (OHA) therapy, and one required insulin therapy. The distinguishing features of those who did not require OHA or insulin therapy were that they required less insulin during the active insulin therapy phase (0.37 +/- 0.05 vs. 0.73 +/- 0.07 units.kg(-1).day(-1)) and were able to attain a lower fasting serum glucose at the end of the period of insulin therapy (5.9 +/- 0.3 vs. 7.7 +/- 0.4 mmol/l). CONCLUSIONS: These results demonstrate that in newly diagnosed type 2 diabetes with elevated fasting glucose levels, a 2- to 3-week course of intensive insulin therapy can successfully lay a foundation for prolonged good glycemic control. The ease with which normoglycemia is achieved on insulin may predict those patients who can later succeed in controlling glucose levels with attention to diet alone.

Changes in liver enzymes after clinical islet transplantation.

BACKGROUND: Clinical islet transplantation (ITx) shows insulin independence with adequate metabolic control in patients with type 1 diabetes. The aim of this study was to characterize the pattern of elevation in liver enzymes observed after ITx and to investigate any correlation between these elevations and graft characteristics or graft functional outcome. METHODS: Eighty-four consecutive ITx procedures were performed in 42 recipients. Liver function tests (LFT) were assessed during the first 40 days posttransplant. LFT elevated greater than or equal to 2.5 times above the upper limit of normal (ULN) were considered relevant. RESULTS: In 54% of the transplants, the aspartate aminotransferase (AST) increased by more than 2.5 times above ULN. A 5-fold increase in AST was observed in 27% of the procedures. The highest AST levels were observed after the first ITx. AST for all transplants peaked at 7+/-0.5 days at a value of 162+/-23 U/L (P<0.001, compared with the pretransplant values). Changes in alanine aminotransferase were similar to AST. Alkaline phosphatase increased more than 2-fold above ULN in 12% of the procedures. LFT normalized in 90% of the recipients within 4 weeks posttransplant. The remaining 10% normalized within 2 months after ITx. Graft characteristics and graft function were not significantly different when comparing LFT with greater than 5-fold versus less than 2.5-fold increase above ULN. The mean bilirubin remained within the normal range. CONCLUSIONS: After intraportal ITx, a significant increase in LFT levels was noticed in more than 50% of the procedures. These levels normalized spontaneously in 90% of the recipients within 4 weeks. No correlation between the increase in LFT and graft characteristics or graft function was found.

Successful islet transplantation: continued insulin reserve provides long-term glycemic control.

Clinical islet transplantation is gaining acceptance as a potential therapy, particularly for subjects who have labile diabetes or problems with hypoglycemic awareness. The risks of the procedure and long-term outcomes are still not fully known. We have performed 54 islet transplantation procedures on 30 subjects and have detailed follow-up in 17 consecutive Edmonton protocol-treated subjects who attained insulin independence after transplantation of adequate numbers of islets. Subjects were assessed pretransplant and followed prospectively posttransplant for immediate and long-term complications related to the procedure or immunosuppressive therapy. The 17 patients all became insulin independent after a minimum of 9,000 islets/kg were transplanted. Of 15 consecutive patients with at least 1 year of follow-up after the initial transplant, 12 (80%) were insulin independent at 1 year. In 14 subjects who have maintained demonstrable C-peptide secretion, glucose control has been stable and glycemic lability and problems with hypoglycemic reactions have been corrected. After 2 of the 54 procedures, some thrombosis was detected in the portal vein circulation. Five subjects had bleeding related to the percutaneous portal vein access procedures: three required transfusion alone, and in one subject, who had a partial thrombosis of the portal vein, an expanding intrahepatic and subscapular hemorrhage occurred while on anticoagulation, requiring transfusion and surgery. Elevated liver function test results were found in 46% of subjects but resolved in all. Complications related to the therapy have been hypercholesterolemia requiring statin therapy in 65%; a rise in creatinine in two patients, both of whom had preexisting renal disease; a rise in protein in four, all of whom had preexisting proteinuria; and antihypertensive therapy increased or started in 53%. Three of the 17 patients have required retinal laser photocoagulation. There have been no cases of posttransplant lymphoproliferative disorder or cytomegalovirus infection, and no deaths. The acute insulin response to arginine correlated better with transplanted islet mass than acute insulin response to glucose (AIR(g)) and area under the curve for insulin (AUC(i)), but the AIR(g) and AUC(i) were more closely related to glycemic control. The AUC(i) directly posttransplant was lower in those who eventually became C-peptide deficient. Our results, with a maximum follow-up of 34 months, indicate that prolonged insulin independence can be achieved after islet transplantation. There are some risks associated acutely with the procedure, and hypercholesterolemia and hypertension are treatable concerns on longer-term follow-up. All patients with persisting C-peptide secretion have had a resolution of both glycemic lability and problems with hypoglycemic reactions. Apart from the rise in serum creatinine in two subjects, no serious consequences of immunosuppressive therapy have been encountered. Islet transplantation is a reasonable option in those with severe problems with glycemic lability or hypoglycemia.