Molecular Detection of Circulating β-Cells After Islet Transplantation

Ritz-Laser, Beate; Oberholzer, José; Toso, Christian; Brulhart, Marie-Claude; Zakrzewska, Katerina; Ris, Frédéric; Bucher, Pascal Alain Robert; Morel, Philippe; Philippe, Jacques

doi:10.2337/diabetes.51.3.557

Cited by 37 publications

(21 citation statements)

References 26 publications

(44 reference statements)

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“…Circulating insulin mRNA has also been measured to detect islet cell death after transplantation(52; 53). Immediately after islet infusion, all (19) recipients of islet allografts showed an initial peak of insulin mRNA, with a mean duration of 4.2 days and amplitude of 510 copies/2.5 mL, indicating a release of the mRNA from β cells.…”

Section: Identifying β Cell Killing With Molecular Signaturesmentioning

confidence: 99%

Life and death of β cells in Type 1 diabetes: A comprehensive review

Wilcox

Rui

Hebrok

et al. 2016

Journal of Autoimmunity

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Type 1 diabetes (T1D) is an autoimmune disorder characterized by the destruction of insulin-producing pancreatic β cells. Immune modulators have achieved some success in modifying the course of disease progression in T1D. However, there are parallel declines in C-peptide levels in treated and control groups after initial responses. In this review, we discuss mechanisms of β cell death in T1D that involve necrosis and apoptosis. New technologies are being developed to enable visualization of insulitis and β cell mass involving positron emission transmission that identifies β cell ligands and magnetic resonance imaging that can identify vascular leakage. Molecular signatures that identify β cell derived insulin DNA that is released from dying cells have been described and applied to clinical settings. We also consider changes in β cells that occur during disease progression including the induction of DNA methyltransferases that may affect the function and differentiation of β cells. Our findings from newer data suggest that the model of chronic long standing β cell killing should be reconsidered. These studies indicate that the pathophysiology is accelerated in the peridiagnosis period and manifest by increased rates of β cell killing and insulin secretory impairments over a shorter period than previously thought. Finally, we consider cellular explanations to account for the ongoing loss of insulin production despite continued immune therapy that may identify potential targets for treatment. The progressive decline in β cell function raises the question as to whether β cell failure that is independent of immune attack may be involved.

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Section: Identifying β Cell Killing With Molecular Signaturesmentioning

confidence: 99%

Life and death of β cells in Type 1 diabetes: A comprehensive review

Wilcox

Rui

Hebrok

et al. 2016

Journal of Autoimmunity

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“…Success of islet transplantation greatly depends on the graft viability and function against post-transplantation challenges including inflammatory cytokines, hypoxic environment, and reactive oxygen species (ROS) at the transplantation site 3-6. Islet loss occurs mostly in the first two weeks after transplantation, and will decrease significantly due to successful revascularization thereafter 7-8.…”

Section: Introductionmentioning

confidence: 99%

XIAP Gene Expression Protects β-Cells and Human Islets from Apoptotic Cell Death

Panakanti

et al. 2010

Mol. Pharmaceutics

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Islet transplantation has the potential to treat type I diabetes, however, its clinical application is limited due to the massive apoptotic cell death and other post-transplantation challenges to islet grafts. Therefore, the objective of this study was to determine whether ex vivo transduction of rat insulin producing INS-1E cells and human islets with adenoviral vector encoding human X-linked inhibitor of apoptosis (Adv-hXIAP) can protect them from inflammatory cytokines and improve their viability and function. There was dose dependent XIAP gene expression. XIAP expression led to decrease in the activities of caspase 3/7, 8 and 9, resulting in reduced apoptotic cell death induced by a cocktail of inflammatory cytokines such as IL-1β, TNFα, and IFNγ. Prolonged normoglycemic control could be achieved by transplantation of Adv-XIAP transduced human islets under the kidney capsule of streptozotocin induced diabetic NOD-SCID mice. Immunohistological staining of the islets bearing kidney sections at day 42 after transplantation was positive for insulin. Moreover, the protective effect of XIAP was reversed by co-administration of XIAP inhibitor embelin. These results indicate that ex vivo transduction of islets with Adv-XIAP will decrease cytokine induced apoptosis and improve the outcome of islet transplantation.

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“…Cell losses can then be monitored through assays of these compounds in tissue and/or blood. Such method is not yet available to detect destruction of pancreatic ␤-cells during development of diabetes, but release of insulin-mRNA might qualify as a marker for a massive destruction of a ␤-cell graft (22). There is not an established method for quantifying the mass of living ␤-cells in isolated tissue fractions.…”

mentioning

confidence: 99%

Comparison of cellular and medium insulin and GABA content as markers for living β-cells

Wang¹,

Ling²,

Pipeleers³

2005

American Journal of Physiology-Endocrinology and Metabolism

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-Experimental and therapeutic use of islet cell preparations could benefit from assays that measure variations in the mass of living ␤-cells. Because processes of cell death can be followed by depletion and/or discharge of cell-specific substances, we examined whether in vitro conditions of ␤-cell death resulted in changes in tissue and medium content of insulin and of ␥-aminobutyric acid (GABA), two ␤-cell-specific compounds with different cellular localization and turnover. Exposure of rat purified ␤-cells to streptozotocin (5 mM, 120 min) or to the nitric oxide donor GEA-3162 (GEA; 50 M, 120 min) caused 80% necrosis within 24 h; at the end of this period, cellular insulin content was not significantly decreased, but cellular GABA content was reduced by 70%; when cultured at basal glucose (6 mM), the toxin-exposed cells did not discharge less insulin but released 80% less GABA in the period 8 -24 h. As in rat ␤-cell purification, GABA comigrated with insulin during human islet cell isolation. Twenty-four hours after GEA (500 M, 120 min), human islet cell preparations exhibited 90% dead cells and a 45 and 90% reduction, respectively, in tissue insulin and GABA content; in the period 9 -24 h, insulin discharge in the medium was not reduced, but GABA release was decreased by 90%. When rat ␤-cells were cultured for 24 h with nontoxic interleukin (IL)-1␤ concentrations that suppressed glucose-induced insulin release, cellular GABA content was not decreased and GABA release increased by 90% in the period 8 -24 h. These data indicate that a reduction in cellular and medium GABA levels is more sensitive than insulin as a marker for the presence of dead ␤-cells in isolated preparations. Pancreatic GABA content also rapidly decreased after streptozotocin injection and remained unaffected by 12 h of hyperglycemia. At further variance with insulin, GABA release from living ␤-cells depends little on its cellular content but increases with IL-1␤-induced alterations in ␤-cell phenotype.islet; diabetes; ␤-cell death; ␥-aminobutyric acid PROCESSES OF CELL DEATH can be associated with depletion and/or discharge of cell-specific substances. Cell losses can then be monitored through assays of these compounds in tissue and/or blood. Such method is not yet available to detect destruction of pancreatic ␤-cells during development of diabetes, but release of insulin-mRNA might qualify as a marker for a massive destruction of a ␤-cell graft (22). There is not an established method for quantifying the mass of living ␤-cells in isolated tissue fractions. This lack makes it difficult to assess the therapeutic potential of islet cell preparations and to compose grafts accordingly. Tissue insulin content and secretory activity have been used as quality control tests in islet transplantation (9, 10, 13, 21), but their significance as indexes for the living ␤-cell mass needs to be further validated. Living ␤-cells can indeed markedly vary in their insulin content and can variably degranulate during isolation and culture procedures; furthermor...

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Molecular Detection of Circulating β-Cells After Islet Transplantation

Cited by 37 publications

References 26 publications

Life and death of β cells in Type 1 diabetes: A comprehensive review

Life and death of β cells in Type 1 diabetes: A comprehensive review

XIAP Gene Expression Protects β-Cells and Human Islets from Apoptotic Cell Death

Comparison of cellular and medium insulin and GABA content as markers for living β-cells

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