Thipaporn Tharavanij

Long-term insulin independence and improvement in insulin secretion after supplemental islet infusion under exenatide and etanercept.

Background. Progressive graft dysfunction (GDF) and loss of insulin independence (II) have been invariably observed in islet transplant recipients under the “Edmonton protocol.” To reestablish II, we performed supplemental islet infusions (SI) in recipients of allogeneic islet transplant alone, displaying GDF. To improve the engraftment and long-term graft function of SI, exenatide (EXN) and etanercept treatment at islet infusion, and long-term EXN treatment were tested in a non-randomized pilot clinical trial. Methods. Patients with GDF received SI under Edmonton-like immunosuppression with daclizumab induction, either without interventions (SI-control; n=5) or with EXN and etanercept treatment (SI-EXN; n=4). Clinical and metabolic profiles were assessed during 18-month follow-up. Results. Long-term II (18 months) was observed in 100% of SI-EXN and in 20% of SI-control (P=0.04). SI-EXN subjects demonstrated restoration of function better than that seen after initial islet infusions. Comparison of SI-EXN and SI-control groups demonstrated better responses in SI-EXN subjects at 3 months post-SI. During the 18 months of follow-up, function was sustained in the SI-EXN subjects better than in SI-controls. Acute effects of EXN during mixed meal tolerance test and intravenous glucose tolerance test results in improved first and second phase insulin release in response to intravenous glucose tolerance test and suppressed postprandial hyperglucagonemia after mixed meal tolerance test. Conclusion. These results suggest that the combination of EXN and etanercept improve engraftment and long-term islet survival and function in subjects undergoing SI. This data, however, must be interpreted with some caution because of small sample size, lack of randomization, and sequential comparison with historical controls.

Restoration of Hypoglycemia Awareness After Islet Transplantation

OBJECTIVE—To determine the impact of islet transplantation (ITx) on hypoglycemia awareness in patients with unstable type 1 diabetes and its relation to islet function. RESEARCH DESIGN AND METHODS—A total of 31 ITx recipients were studied. Hypoglycemia unawareness was assessed using the Clarke hypoglycemic score (0 = no hypoglycemia; ≥4 = hypoglycemia unawareness). Subjects were grouped based on graft function: off-insulin (n = 8), graft dysfunction (on-insulin and stimulated C-peptide ≥0.3 ng/ml, n = 13), and graft failure (stimulated C-peptide <0.3 ng/ml, n = 10, evaluated 11.5 ± 14.5 months after graft failure). RESULTS—The hypoglycemia score improved after ITx when compared with baseline values (before vs. after: 5.29 ± 1.51 vs. 1.35 ± 1.92, P < 0.001). This result was sustained even after patient stratification based on islet function (pre vs. post off-insulin: 5.63 ± 2.00 vs. no hypoglycemia reported; graft dysfunction: 5.31 ± 1.49 vs. 1.15 ± 1.63, P < 0.001; and graft failure: 5.00 ± 1.16 vs. 2.70 ± 2.26, P = 0.014). CONCLUSIONS—The improved metabolic control achieved with ITx can restore hypoglycemia awareness in patients with type 1 diabetes, persisting even after islet graft failure.

Improved long-term health-related quality of life after islet transplantation.

Background. Health related quality of life (HRQoL) is one of the most important outcomes to measure effectiveness of an intervention, especially for islet transplantation in which benefits should outweigh risks of long-term immunosuppression. This study aimed to evaluate long-term effects of islet transplantation and to outline possible influential factors. Methods. Forty islet transplant recipients who completed 344 Health Status Questionnaires (HSQ 2.0) and 384 Diabetes Quality of Life Questionnaires (DQoL) between 2000 and 2007 were retrospectively reviewed. Assessments were analyzed in pretransplantation period, then every 3 months after the first infusion for 18 months and every 6 months thereafter. The mean follow-up posttransplantation was 40.8±21.9 months (9–72 months). Results. Sustained improvement in DQoL-impact score was observed at all time-points posttransplantation. Similarly, worry and satisfaction scales were significantly better than pretransplant evaluation for most time-points. Four of eight HSQ 2.0 scales demonstrated a significant improvement at some time-points. Longitudinal analysis, after adjustments for potential confounding factors, showed significantly sustained improvement in impact scale up to 72 months. Longer diabetes duration, higher insulin dosage, and occurrence of adverse events had negative effects on HRQoL. Single islet infusion or islet after kidney transplant recipients showed the lowest values in HSQ 2.0. In contrast, subjects on exenatide therapy had significantly higher HSQ 2.0 scores. Conclusions. Islet transplantation is associated with long-term improvement in HRQoL. Exenatide usage had a positive effect whereas single islet infusion, islet after kidney transplantation, longer diabetes duration, higher insulin dosage, and adverse events had a negative impact on HRQoL scores.

Long-term metabolic and hormonal effects of exenatide on islet transplant recipients with allograft dysfunction.

The initial success of islet transplantation (ITx) is followed by graft dysfunction (GDF) and insulin reintroduction. Exenatide, a GLP-1 agonist, increases insulin and decreases glucagon secretion and has potential for β-cell regeneration. To improve functional islet mass, exenatide treatment was given to ITx recipients with GDF. The objective of this study was to assess metabolic and hormonal effects of exenatide in GDF. In this prospective, single-arm, nonrandomized study, 11 type 1 diabetes recipients of ITx with GDF had HbA1c, weight, insulin requirements, and 5-h mixed meal tolerance test (MMTT; with/without exenatide given before test) at baseline, 3, 6, and 12 months after initiating exenatide treatment. Baseline MMTT showed postprandial hyperglycemia and hyperglucagonemia. Daily exenatide treatment resulted in improved glucose, increased amylin/insulin ratio, and decreased proinsulin/insulin ratio as assessed by MMTT. Glucagon responses remained unchanged. Exenatide administration 1 h before MMTT showed decreased glucagon and glucose at 0 min and attenuation in their postprandial rise. Time-to-peak glucose was delayed, followed by insulin, proinsulin, amylin, and C-peptide, indicating glucose-driven insulin secretion. Five subjects completed 12-month follow-up. Glucose and glucagon suppression responses after MMTT with exenatide were no longer observed. Retrospective 3-month analysis of these subjects revealed higher and sustained glucagon levels that did not suppress as profoundly with exenatide administration, associated with higher glucose levels and increased C-peptide responses. In conclusion, Exenatide suppresses the abnormal postprandial hyperglucagonemia and hyperglycemia observed in GDF. Changes in amylin and proinsulin secretion may reflect more efficient insulin processing. Different degrees of responsiveness to exenatide were identified. These may help guide the clinical management of ITx recipients.

Retinol-binding protein 4 is not associated with insulin resistance in pregnancy.

Retinol-binding protein 4 (RBP4) is an adipokine proposed to be specifically associated with insulin resistance (IR). We examined whether serum levels of RBP4 were associated with IR in pregnancy. One hundred seventy-two women with gestational diabetes mellitus (GDM) and 361 pregnant Thai women who did not have GDM but had a positive 50-g glucose challenge test result (plasma glucose level was ≥7.2 mmol/L after 1 hour) were enrolled. We measured fasting serum levels of RBP4 and assessed IR at a 100-g oral glucose tolerance test. We found a higher degree of IR in the GDM group compared with the non-GDM group, but serum RBP4 levels between the 2 groups were not different. Retinol-binding protein 4 levels were associated with serum triglyceride levels but were not associated with the degree of IR assessed by homeostasis model assessment or quantitative insulin sensitivity check index. Our results suggest that serum RBP4 levels in pregnancy are not associated with IR.

Lipotoxicity and Decreased Islet Graft Survival

OBJECTIVE To evaluate if baseline serum lipids are associated with islet graft survival in type 1 diabetes islet transplant (ITx) recipients. RESEARCH DESIGN AND METHODS Baseline fasting lipid profile was collected from 44 ITx recipients. Comparisons were performed between subjects below and above the median values of each lipid fraction. Differences in outcomes were compared by Kaplan-Meier curves and Cox regression analysis. RESULTS Subjects with baseline fasting plasma triglycerides and VLDL cholesterol above the median had shorter islet graft survival (triglycerides: 39.7 ± 6.1 vs. 61.3 ± 6.6 months, P = 0.029, and VLDL: 41.5 ± 5.7 vs. 62.8 ± 7.3 months, P = 0.032). Total, LDL, and HDL cholesterol did not influence islet function. Triglycerides (odds ratio 2.97 [95% CI 1.03–8.52], P = 0.044) maintained its association with graft failure after adjustments for confounders. CONCLUSIONS Higher baseline triglycerides are associated with earlier decline in islet graft function. Prospective clinical trials should address whether it is directly caused by lipotoxicity and if strategies focusing on lowering serum lipids may prolong islet graft survival.

Nutritional status and behavior in subjects with type 1 diabetes, before and after islet transplantation.

Background. To investigate whether changes of nutritional status and behavior are associated with islet transplantation (ITx) and to assess their possible mechanisms. Methods. In this observational study, 52 subjects with type 1 diabetes, 30 of whom received ITx, underwent nutritional assessments. The study consisted of questionnaires complemented by a dietary intake recording, anthropometric measurements, and body composition analysis. Laboratory tests were also reviewed as part of the follow up. Results. After ITx, significant reductions in body weight (3.7 kg; P<0.0001), body mass index (1.39 kg/m2; P<0.0001), waist circumference (3.96 cm; P=0.006), and fat weight (3.28 kg; P<0.01) were observed. The average consumption of carbohydrate and protein were also lower than pretransplant, together with some micronutrients (vitamins B12 and B6, zinc, and phosphorus). Insulin administration and changes in A1C were not associated with a significant change in anthropometric measurements. Subjects on exenatide after ITx showed significantly lower weight and body mass index than those not taking exenatide. Conclusions. ITx is associated with modifications in nutritional behavior and status. Drugs and health conditions are likely to be at least in part responsible for these changes, but a voluntary modification of eating habits by the patients also plays a role. Strict monitoring of nutritional parameters, counseling by experts in nutrition, and multivitamin/mineral supplement after ITx could be of benefit to the patients.

Type 2 Diabetes Mellitus Phenotype and Graft Survival After Islet Transplantation

Background. Body fat accumulation decreases insulin sensitivity. It has being associated with earlier onset of type 1 diabetes mellitus (DM) and islet graft failure. The aim of this study was to evaluate whether insulin resistance, characterized by risk factors for type 2 DM, can predict islet graft survival in type 1 DM islet transplant (ITx) recipients. Methods. Demographic, anthropometrical, and laboratory data, as well as family history of type 2 DM (first degree relatives), were collected from 44 ITx recipients. Risk factors for type 2 DM, such as positive family history of type 2 DM (n=11) and overweight (body mass index >25 kg/m2; n=14), were analyzed separately and in combination, which was designated as “type 2 DM phenotype” (n=5). Differences in outcomes (time-to-graft dysfunction and failure) were compared using Kaplan-Meier curves. Cox regression analysis was performed to control for possible confounding factors. Results. Neither positive family history of type 2 DM nor overweight at baseline could predict islet function outcomes after ITx. However, when both risk factors were grouped, the “type 2 DM phenotype” was associated with earlier islet graft failure (mean estimate graft survival 25.7±9.1 vs. 54.1±5.2 months, P=0.022). These results were sustained after adjustments for confounding variables (OR 5.20, 95% CI 1.12–24.0). Conclusions. Predisposition for type 2 DM can coexist with the type 1 DM phenotype and is associated with earlier decline in islet graft function. Prospective clinical trials should address whether it is associated with decreased insulin sensitivity and if insulin sensitizers play a role in prolonging islet graft survival.

Clinical use of fructosamine in islet transplantation.

Many islet transplant recipients have medical conditions that could interfere with the accuracy of HbA1c measurements (e.g., anemia/dapsone use). Fructosamine is less prone to have clinical interferences and reflects glucose control in a shorter period of time than HbA1c. This study aimed to validate fructosamine use in islet transplant subjects and to evaluate its effectiveness as a predictor for islet graft dysfunction. Thirty-three islet transplant recipients who had concomitant fructosamine and HbA1c data available were retrospectively analyzed. HbA1c, fructosamine, mean capillary blood glucose, and islet graft function (fasting C-peptide/glucose ratio) were assessed. There was a significant and positive association between fructosamine and HbA1c (p < 0.0001). Both variables were also positively associated with mean overall and fasting capillary glucose. Neither fructosamine nor HbA1c was shown by ROC analysis to significantly discriminate between periods with and without subsequent graft dysfunction. HbA1c >6% was predictive of this outcome 1 month in advance (OR 2.95, p = 0.003). However, although significantly associated with graft dysfunction, use of this cutoff as a predictor of dysfunction has poor sensitivity (50%) and specificity (77.6%). Fructosamine above the normal range (>270 μmol/L Quest Diagnostics) was also predictive of ensuing dysfunction (OR 2.47, p = 0.03); however, it had similarly poor sensitivity (62%) and specificity (64%). Fructosamine can be used as an alternative to HbA1c for glycemic assessment in islet transplant recipients in situations with HbA1c assay interference. Neither HbA1c nor fructosamine are good predictors of islet graft dysfunction.

Nonalbumin Proteinuria in Islet Transplant Recipients

The aim of this study was to evaluate the importance of nonalbumin-predominant proteinuria on kidney function (KF) after islet transplantation (ITx). Twenty-four-hour proteinuria and albuminuria were available in 27 recipients. KF was assessed by serum creatinine and estimated glomerular filtration rate (eGFR) was calculated by Modification of Diet in Renal Disease formula. Correlations between eGFR and albuminuria (r = −0.422, p < 0.001) were higher than with proteinuria (r = −0.223, p < 0.001; p = 0.006 for comparison between correlations). Nineteen (70%) subjects had proteinuria ≥ 300 mg/24 h during the follow-up. Subjects were divided into three groups according to urinary protein excretion patterns: no proteinuria (n = 8), nonalbumin-predominant (n = 8), and albumin-predominant (n = 11) proteinuria. Proteinuria ≥ 500 mg/24 h was observed only among patients with albumin-predominant proteinuria (64%; p = 0.002) and these patients had the lowest eGFR means post-ITx (no proteinuria: 84.2 ± 16.4 vs. nonalbumin: 69.1 ± 13.8 vs. albumin-predominant proteinuria: 65.5 ± 16.6 ml/min/1.73 m2, p = 0.044 for first vs. last group). In conclusion, high frequency of proteinuria was observed after ITx. However, it seems to be milder and have less impact on KF when albumin is not the major source of proteinuria. Prospective evaluation of proteinuria, including tubular function markers, should be performed to elucidate the mechanisms of kidney damage in this population.