Eba Hathout

Dynamic Production of Hypoxia‐Inducible Factor‐1α in Early Transplanted Islets

More than half of transplanted β‐cells undergo apoptotic cell death triggered by nonimmunological factors within a few days after transplantation. To investigate the dynamic hypoxic responses in early transplanted islets, syngeneic islets were transplanted under the kidney capsule of balb/c mice. Hypoxia‐inducible factor‐1α (HIF‐1α) was strongly expressed at post‐transplant day (POD) 1, increased on POD 3, and gradually diminished on POD 14. Insulin secretion decreased on POD 3 in association with a significant increase of HIF‐1α‐related β‐cell death, which can be suppressed by short‐term hyperbaric oxygen therapy. On POD 7, apoptosis was not further activated by continually produced HIF‐1α. In contrast, improvement of nerve growth factor and duodenal homeobox factor‐1 (PDx‐1) production resulted in islet graft recovery and remodeling. In addition, significant activation of vascular endothelial growth factor in islet grafts on POD 7 correlated with development of massive newly formed microvessels, whose maturation is advanced on POD 14 with gradual diminution of HIF‐1α. We conclude that (1) transplanted islets strongly express HIF‐1α in association with β‐cell death and decreased insulin production until adequate revascularization is established and (2) early suppression of HIF‐1α results in less β‐cell death thereby minimizing early graft failure.

Air pollution and type 1 diabetes in children

Background: Over the past decade, there has been a worldwide largely unexplained increase in the incidence of type 1 diabetes in young children. This study explores the quantitative role of exposure to specific air pollutants in the development of type 1 diabetes in children.

Bone marrow cell cotransplantation with islets improves their vascularization and function.

Background. To test the angiogenesis-promoting effects of bone marrow cells when cotransplanted with islets. Methods. Streptozotocin-induced diabetic BALB/c mice were transplanted syngeneically under the kidney capsule: (1) 200 islets, (2) 1 to 5×106 bone marrow cells, or (3) 200 islets and 1 to 5×106 bone marrow cells. All mice were evaluated for blood glucose, serum insulin, and glucose tolerance up to postoperative day (POD) 28, and a subset was monitored for 3 months after transplantation. Histologic assessment was performed at PODs 3, 7, 14, 28, and 84 for the detection of von Willebrand factor (vWF), vascular endothelial growth factor (VEGF), insulin, cluster of differentiation-34, and pancreatic duodenal homeobox-1 (PDX-1) protein. Results. Blood glucose was the lowest and serum insulin was the highest in the islet+bone marrow group at POD 7. Blood glucose was significantly lower in the islet+bone marrow group relative to the islet only group after 63 days of transplantation (P<0.05). Significantly more new periislet vessels were detected in the islet+bone marrow group compared with the islet group (P<0.05). Vascular endothelial growth factor staining was more prominent in bone marrow than in islets (P<0.05). Pancreatic duodenal homeobox-1-positive areas were identified in bone marrow cells with an increase in staining over time. However, there were no normoglycemic mice and no insulin-positive cells in the bone marrow alone group. Conclusions. Cotransplantation of bone marrow cells with islets is associated with enhanced islet graft vascularization and function.

In vitro and in vivo improvement of islet survival following treatment with nerve growth factor.

Background. Nerve growth factor (NGF) has been reported to play an important regulatory role in pancreatic beta-cell function. However, the usefulness of NGF in a transplantation setting is unknown. Methods. A marginal number of islet cells (260 islet equivalents/recipient) cultured for 24 hr with NGF (500 ng/ml) was syngeneically transplanted under the kidney capsule of streptozotocin-induced diabetic Balb/c mice. Fluorescence microscopy was used to evaluate islet viability. Islet function was evaluated in vitro and in vivo by static assay and glucose tolerance test, respectively. Results. In vitro, improved viability and survival were found in murine islets cultured in serum-free medium for 96 hr with 500 ng/ml NGF (P<0.05). NGF-treated islets had more insulin secretion than islets cultured without NGF in response to 2.8 mmol/L glucose (P<0.05), and 20 mmol/L glucose conditions. In vivo, 67% of recipients with a submarginal number of islets cultured in NGF attained normoglycemia for more than 120 days, whereas transplanted islets without NGF treatment survived a maximum of 13 days in control mice. At posttransplant day 4, recipients of NGF-cultured islets showed significant improvement of glucose tolerance. On immunohistochemistry, the kidney capsules containing NGF-cultured islets displayed higher insulin content, and more dilated neoplastic microvessels than control renal capsules. The number of apoptotic cells using TUNEL staining decreased by nearly 50% in NGF-cultured islet grafts in comparison to control islet grafts. Conclusions. The above data suggest potential advantages of NGF for islet survival following transplantation. This neurotrophic approach may prove beneficial in human islet transplantation.

Effect of therapy with insulin glargine (lantus) on glycemic control in toddlers, children, and adolescents with diabetes.

To determine the effect of insulin glargine on glycemic control in pediatric type 1 and 2 diabetes, a retrospective repeated-measure analysis of variance was performed of hemoglobin A1C (HbA1C), frequency of hypoglycemia and hyperglycemia, mean blood glucose, body mass index (BMI), and daily weight-adjusted insulin dosage before and after institution of glargine therapy in 72 children and adolescents with diabetes. At glargine start, age range was 1.2-19.6 years, mean age was 12.5 +/- 4.6 years, BMI was 22.48 +/- 6.3 kg/m(2), and mean HbA1C was 9.7 +/- 1.9%. Mean duration of diabetes was 3.58 years, and mean baseline insulin dose was 0.93 U/kg/day. Gender breakdown was 60% female, and the majority (83%) had type 1 diabetes. Average HbA1C decreased from 9.5% pre-glargine to 8.6% post-glargine (p < 0.001). HbA1C decrease was significant in both types of diabetes without a concomitant increase in frequency of hypoglycemia, BMI, or weight-adjusted insulin dose. Hypoglycemia decreased significantly in type 1 diabetes. Thus, glargine therapy may decrease HbA1C and frequency of hypoglycemia in toddlers, children, and adolescents with diabetes, without an increase in BMI or insulin requirements.

Post-transplant diabetes mellitus in pediatric liver transplantation

Abstract:  To determine the characteristics of pediatric liver transplant recipients who develop GI and/or PTDM, data on children undergoing their first liver transplant from the SPLIT database were analyzed (n = 1611). Recipient and donor characteristics that were evaluated included age at transplant, gender, race, primary disease, hospitalization status at transplant, BMI, recipient and donor CMV status, donor type, donor age, and primary immunosuppression. GI/PTDM was found in 214 individuals (13%) of whom 166 (78%) were diagnosed within 30 days of transplantation (early GI/PTDM). Multivariate analyses suggests that age >5 yr at transplant, hospitalization at transplant, a primary diagnosis other than BA, early steroid use, and tacrolimus use are associated with increased incidence of early GI. Routine monitoring for the development of GI and post‐transplant diabetes is indicated in the short‐ and long‐term care of children after liver transplantation.

Pediatric Post-Transplant Diabetes: Data From a Large Cohort of Pediatric Heart-Transplant Recipients

A retrospective analysis of 381 pediatric heart‐transplant recipients was performed to determine the frequency, characteristics, and risk factors for post‐transplant diabetes. The rate of post‐transplant diabetes was 1.8% with antithymocyte globulin, cyclosporine and azathioprine as primary immunosuppressive therapy. Time from transplant to diabetes was 0.25–13 years. Diabetes was characterized by reversibility, and lack of insulinopenia and autoimmunity. The post‐transplant diabetes rate in tacrolimus‐converted children (n = 45) was 8.8%. In tacrolimus‐converted children, age at transplant, mean and maximum tacrolimus blood levels, and first‐year rejection episodes were higher in the post‐transplant diabetes group, which also consistently had DR‐mismatched transplants and HLA DR3/DR4 haplotypes. Body mass index was not different between diabetic and control tacrolimus‐converted children. In conclusion, pediatric post‐transplant diabetes may be related to reversible insulin resistance. Tacrolimus levels, HLA DR mismatch, and older age at transplant may predispose to post‐transplant diabetes.

MRI assessment of ischemic liver after intraportal islet transplantation.

Background. There is a recent focus on embolization of the portal vein by transplanted islets as a major cause of early graft loss. The resultant ischemia causes necrosis or apoptosis of cells within the liver. Thus, noninvasive assessment of the liver receiving the islet transplant is important to evaluate the status islet grafts. Methods. This study used noninvasive magnetic resonance imaging (MRI) for assessment of the posttransplant ischemic liver. Syngeneic islets in streprozotocin-induced diabetic mice were used. MRI and morphological liver assessments were performed at 0, 2, and 28 days after transplantation. Histologic assessment of insulin, hypoxia induced factor 1-&agr;, and apoptosis were undertaken at similar time points. Results. Ischemic/necrotic regions in the liver were detected by MRI at 2 days but not at 28 days after transplantation and were confirmed histologically. Liver injury was quantified from high intensity areas on T2-weighted images. Insulin release peaked 2 days after transplantation. Conclusion. Onset and reversal of liver ischemia due to intraportal islet transplantation are detectable using T2-weighted MRI. These changes coincide with periods of maximum insulin release likely due to partial islet destruction. We propose that MRI, as a noninvasive monitor of graft-related ischemia, may be useful in assessment of liver and islet engraftment after intraportal islet transplantation in a clinical setting.

Role of exposure to air pollutants in the development of type 1 diabetes before and after 5 yr of age.

Abstract: Objective:  To assess the role of ambient air pollutants in type 1 diabetes in children.

Use of the GlucoWatch biographer in children and adolescents with diabetes.

Abstract: Objective:  This study was done to evaluate the accuracy and safety of measuring glucose with the GlucoWatch® biographer in children and adolescents with diabetes.