The MicroRNA Landscape of Acute Beta Cell Destruction in Type 1 Diabetic Recipients of Intraportal Islet Grafts

Ongoing beta cell death in type 1 diabetes (T1D) can be detected using biomarkers selectively discharged by dying beta cells into plasma. microRNA-375 (miR-375) ranks among the top biomarkers based on studies in animal models and human islet transplantation. Our objective was to identify additional microRNAs that are co-released with miR-375 proportionate to the amount of beta cell destruction. RT-PCR profiling of 733 microRNAs in a discovery cohort of T1D patients 1 h before/after islet transplantation indicated increased plasma levels of 22 microRNAs. Sub-selection for beta cell selectivity resulted in 15 microRNAs that were subjected to double-blinded multicenter analysis. This led to the identification of eight microRNAs that were consistently increased during early graft destruction: besides miR-375, these included miR-132/204/410/200a/429/125b, microRNAs with known function and enrichment in beta cells. Their potential clinical translation was investigated in a third independent cohort of 46 transplant patients by correlating post-transplant microRNA levels to C-peptide levels 2 months later. Only miR-375 and miR-132 had prognostic potential for graft outcome, and none of the newly identified microRNAs outperformed miR-375 in multiple regression. In conclusion, this study reveals multiple beta cell-enriched microRNAs that are co-released with miR-375 and can be used as complementary biomarkers of beta cell death.

Download Full-text

The microRNA Landscape of Acute Beta Cell Destruction in Type 1 Diabetic Recipients of Intraportal Islet Grafts

10.20944/preprints202105.0095.v1 ◽

2021 ◽

Author(s):

Geert Antoine Martens ◽

Geert Stange ◽

Lorenzo Piemonti ◽

Jasper Anckaert ◽

Zhidong Ling ◽

...

Keyword(s):

Cell Death ◽

Beta Cell ◽

Beta Cells ◽

Islet Transplantation ◽

Beta Cell Death ◽

Beta Cell Destruction ◽

Cell Destruction ◽

Graft Outcome ◽

Plasma Microrna

Ongoing beta cell death in type 1 diabetes (T1D) can be detected using biomarkers selectively discharged by dying beta cells into plasma. MicroRNA-375 (miR-375) ranks among top biomarkers based on studies in animal models and human islet transplantation. Our objective was to identify additional microRNAs that are co-released with miR-375 proportionate to the amount of beta cell destruction. RT-PCR profiling of 733 microRNAs in a discovery cohort of T1D patients 1 hour before/after islet transplantation indicated increased plasma levels of 22 microRNAs. Sub-selection for beta cell selectivity resulted in 15 microRNAs that were subjected to double-blinded multicenter analysis. This led to identification of 8 microRNAs that were consistently increased during early graft destruction: besides miR-375, these included miR-132/204/410/200a/429/125b, microRNAs with known function and enrichment in beta cells. Their potential clinical translation was investigated in a third independent cohort of 46 transplant patients, by correlating post-transplant microRNA levels to C-peptide levels 2 months later. Only miR-375 and miR-132 had prognostic potential for graft outcome and none of the newly identified microRNAs outperformed miR-375 in multiple regression. In conclusion, this study reveals multiple beta cell-enriched microRNAs that are co-released with miR-375 and can be used as complementary biomarkers of beta cell death.

Download Full-text

In vitro profiling of endocrine cell death using UCHL1 and GAD65 as soluble biomarkers

10.1101/076513 ◽

2016 ◽

Author(s):

Benedicte Brackeva ◽

Sarah Roels ◽

Geert Stangé ◽

Gamze Ates ◽

Olivier R. Costa ◽

...

Keyword(s):

Cell Death ◽

Beta Cell ◽

Beta Cells ◽

Islet Transplantation ◽

High Sensitivity ◽

Low Grade ◽

Variable Degree ◽

Beta Cell Death

AbstractBACKGROUNDPancreatic islet grafts are cultured in vitro prior to transplantation and this is associated to a variable degree of beta cell loss. Optimization of culture conditions is currently hampered by the lack of a specific and sensitive in vitro indicator of beta cell death.METHODSWe developed a high-sensitivity duplex bead-based immunoassay for two protein-type biomarkers of beta cell destruction, GAD65 and UCHL1, and investigated its proficiency for in vitro toxicity profiling on rodent and human beta cells, as compared to a semi-automatic and manual image-based assessment of beta cell death, and in vivo after intraportal islet transplantation.RESULTSBoth GAD65 and UCHL1 were discharged by necrotic and apoptotic beta cells proportionate to the number of dead beta cells as counted by microscopic methods. In vitro, UCHL1 was superior to GAD65, in terms of biomarker stability providing more sensitive detection of low grade beta cell death. In vivo, however, GAD65 was consistently detected after islet transplantation while UCHL1 remained undetectable.CONCLUSIONThe use of soluble biomarkers represents a fast, selective and sensitive method for beta cell toxicity profiling in vitro. UCHL1 is superior to GAD65 in vitro but not in vivo.

Download Full-text

Endoplasmic Reticulum-Mitochondria Crosstalk and Beta-Cell Destruction in Type 1 Diabetes

Frontiers in Immunology ◽

10.3389/fimmu.2021.669492 ◽

2021 ◽

Vol 12 ◽

Author(s):

Saurabh Vig ◽

Joost M. Lambooij ◽

Arnaud Zaldumbide ◽

Bruno Guigas

Keyword(s):

Endoplasmic Reticulum ◽

Type 1 Diabetes ◽

Beta Cell ◽

Beta Cells ◽

Beta Cell Destruction ◽

Unfolded Protein ◽

Cell Destruction ◽

The Unfolded Protein Response ◽

And Function

Beta-cell destruction in type 1 diabetes (T1D) results from the combined effect of inflammation and recurrent autoimmunity. In response to inflammatory signals, beta-cells engage adaptive mechanisms where the endoplasmic reticulum (ER) and mitochondria act in concert to restore cellular homeostasis. In the recent years it has become clear that this adaptive phase may trigger the development of autoimmunity by the generation of autoantigens recognized by autoreactive CD8 T cells. The participation of the ER stress and the unfolded protein response to the increased visibility of beta-cells to the immune system has been largely described. However, the role of the other cellular organelles, and in particular the mitochondria that are central mediator for beta-cell survival and function, remains poorly investigated. In this review we will dissect the crosstalk between the ER and mitochondria in the context of T1D, highlighting the key role played by this interaction in beta-cell dysfunctions and immune activation, especially through regulation of calcium homeostasis, oxidative stress and generation of mitochondrial-derived factors.

Download Full-text

A Model for Human Islet Transplantation to Immunodeficient Streptozotocin-Induced Diabetic Mice

Cell Transplantation ◽

10.1177/0963689718801006 ◽

2018 ◽

Vol 27 (11) ◽

pp. 1684-1691 ◽

Cited By ~ 5

Author(s):

Elisabet Estil·les ◽

Noèlia Téllez ◽

Montserrat Nacher ◽

Eduard Montanya

Keyword(s):

Cell Death ◽

Beta Cell ◽

Beta Cells ◽

Islet Transplantation ◽

Cell Mass ◽

Human Islet ◽

Diabetic Mice ◽

Beta Cell Death ◽

Human Beta Cells ◽

Human Islet Transplantation

Streptozotocin (STZ) is a cytotoxic glucose analogue that causes beta cell death and is widely used to induce experimental diabetes in rodents. The sensitivity of beta cells to STZ is species-specific and human beta cells are resistant to STZ. In experimental islet transplantation to rodents, STZ-diabetes must be induced before transplantation to avoid destruction of grafted islets by STZ. In human islet transplantation, injection of STZ before transplantation is inconvenient and costly, since human islet availability depends on organ donation and frail STZ-diabetic mice must be kept for unpredictable lapses of time until a human islet preparation is available. Based on the high resistance of human beta cells to STZ, we have tested a new model for STZ-diabetes induction in which STZ is injected after human islet transplantation. Human and mouse islets were transplanted under the kidney capsule of athymic nude mice, and 10–14 days after transplantation mice were intraperitoneally injected with five consecutive daily doses of STZ or vehicle. Beta-cell death increased and beta-cell mass was reduced in mouse islet grafts after STZ injection. In contrast, in human islet grafts beta cell death and mass did not change after STZ injection. Mice transplanted with rodent islets developed hyperglycemia after STZ-injection. Mice transplanted with human islets remained normoglycemic and developed hyperglycemia when the graft was harvested. STZ had no detectable toxic effects on beta cell death, mass and function of human transplanted islets. We provide a new, more convenient and cost-saving model for human islet transplantation to STZ-diabetic recipients in which STZ is injected after islet transplantation.

Download Full-text