Human islet function following 20 years of cryogenic biobanking

Fox, Jocelyn E. Manning; Lyon, James; Dai, Xiao-Qing; Wright, Robert C.; Hayward, Julie A.; Bunt, Martijn van de; Kin, Tatsuya; Shapiro, A. M. James; McCarthy, Mark I.; Gloyn, Anna L.; Ungrin, Mark; Lakey, Jonathan R.T.; Kneteman, N. M.; Warnock, Garth L.; Korbutt, Gregory S.; Rajotte, R. V.; MacDonald, Patrick E.

doi:10.1007/s00125-015-3598-4

Cited by 39 publications

(25 citation statements)

References 40 publications

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“…Tissue. Pancreatic islets and pancreas sections were obtained from human cadaveric donors by the Nordic Network for Clinical Islet Transplantation Uppsala 64 (ethical approval by Uppsala Regional Ethics Board) or the ADI Isletcore at the University of Alberta 65 (ethical approval by Alberta Human Research Ethics Board, Pro00001754), with written donor and family consent for use in research. Work with human tissue complied with all relevant ethical regulations for use of human tissue in research and the study was approved by the Uppsala Regional Ethics Board (2006/348).…”

Section: Methodsmentioning

confidence: 99%

Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes

et al. 2020

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Glucagon is released from pancreatic α-cells to activate pathways that raise blood glucose. Its secretion is regulated by α-cell-intrinsic glucose sensing and paracrine control through insulin and somatostatin. To understand the inadequately high glucagon levels that contribute to hyperglycemia in type-2 diabetes (T2D), we analyzed granule behavior, exocytosis and membrane excitability in α-cells of 68 non-diabetic and 21 T2D human donors. We report that exocytosis is moderately reduced in α-cells of T2D donors, without changes in voltagedependent ion currents or granule trafficking. Dispersed α-cells have a non-physiological V-shaped dose response to glucose, with maximal exocytosis at hyperglycemia. Within intact islets, hyperglycemia instead inhibits α-cell exocytosis, but not in T2D or when paracrine inhibition by insulin or somatostatin is blocked. Surface expression of somatostatin-receptor-2 is reduced in T2D, suggesting a mechanism for the observed somatostatin resistance. Thus, elevated glucagon in human T2D may reflect α-cell insensitivity to paracrine inhibition at hyperglycemia.

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Section: Methodsmentioning

confidence: 99%

Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes

et al. 2020

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“…recurrence of severe hypoglycemias, intractable glucose variability, diabetes-related complications), due to the complexity of cell isolation protocols and islet viability after cryopreservation. Although Manning Fox and colleagues recently showed that human islets cryopreserved for 20 years maintained correct purity, functional intracellular Ca 2+ influx and glucose-stimulated insulin secretion (GSIS), these stored cells had decreased levels of insulin content and lower abilities to reverse diabetes in a mouse model as compared with fresh islets [Manning Fox et al 2015].…”

Section: Pancreas and Islet Transplantationmentioning

confidence: 99%

β-cell replacement sources for type 1 diabetes: a focus on pancreatic ductal cells

Corritore

Lee

Sokal

et al. 2016

Therapeutic Advances in Endocrinology

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Thorough research on the capacity of human islet transplantation to cure type 1 diabetes led to the achievement of 3-to 5-year-long insulin independence in nearly half of transplanted patients. Yet, translation of this technique to clinical routine is limited by organ shortage and the need for long-term immunosuppression, restricting its use to adults with unstable disease. The production of new bona fide β cells in vitro was thus investigated and finally achieved with human pluripotent stem cells (PSCs). Besides ethical concerns about the use of human embryos, studies are now evaluating the possibility of circumventing the spontaneous tumor formation associated with transplantation of PSCs. These issues fueled the search for cell candidates for β-cell engineering with safe profiles for clinical translation. In vivo studies revealed the regeneration capacity of the exocrine pancreas after injury that depends at least partially on facultative progenitors in the ductal compartment. These stimulated subpopulations of pancreatic ductal cells (PDCs) underwent β-cell transdifferentiation through reactivation of embryonic signaling pathways. In vitro models for expansion and differentiation of purified PDCs toward insulin-producing cells were described using cocktails of growth factors, extracellular-matrix proteins and transcription factor overexpression. In this review, we will describe the latest findings in pancreatic β-cell mass regeneration due to adult ductal progenitor cells. We will further describe recent advances in human PDC transdifferentiation to insulin-producing cells with potential for clinical translational studies.

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“…Interestingly, there is a relationship between abnormal imprinting genes and growth and development of various diseases. Recent studies show that there is a certain correlation between Kcnq1 gene changes and type 2 diabetes [14], and it is speculated that it is possible that Kcnq1 gene encodes the voltage-gated potassium ion channels and insulin secretion of islet-like cells [2].…”

Section: Discussionmentioning

confidence: 99%

Expression of Imprinted Genes Kcnq1 and Cdkn1c During the Course of Differentiation from Mouse Embryonic Stem Cells into Islet-like Cells in vitro

Liu

Peng

et al. 2017

Exp Clin Endocrinol Diabetes

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To study the effects of inducement on the expression of mouse embryonic stem cells SF1-G imprinted genes, Kcnq1 and Cdkn1c during the course of differentiation into islet-like cells in vitro. Mouse embryonic fibroblasts (MEFs) were isolated from pregnant mice embryos and fibroblast feeder cells were prepared by treating 3-5th generations MEFs with Mitomycin C. Moreover, mouse embryonic stem cells were induced to differentiate into islet-like cells directly. RT-PCR and Immunofluorescence staining were used to test the expression of islet cell-specific markers. Cells were collected at various stages throughout the differentiation process and the imprinted genes Kcnq1 and Cdkn1c were tested by reverse transcription-polymerase chain reaction fragment length polymorphism (RT-PCR/RFLP). In the present study, we found that cells appear islet cell-specific gene expression. Furthermore, immunofluorescence shows us that the islet cell-specific hormone protein can be measured at stage, which confirms that the embryonic stem cells can be successfully induced into islet-like cells in vitro. RT-PCR/RFLP analysis showsthat imprinted genes Kcnq1 and Cdkn1c are biallelic expression in the differentiated cells, suggestive of loss of imprinting (LOI), while these genes demonstrate maternal monoallelic expression in the undifferentiated cells' continued subculture; this marks the maintenance of imprinting (MOI). Our data indicate that mouse embryonic stem cells are induced into islet-like cells in vitro. The gene imprinting status of Kcnq1 and Cdkn1c may be changed in differentiated cells during the induction in vitro.

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Human islet function following 20 years of cryogenic biobanking

Cited by 39 publications

References 40 publications

Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes

Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes

β-cell replacement sources for type 1 diabetes: a focus on pancreatic ductal cells

Expression of Imprinted Genes Kcnq1 and Cdkn1c During the Course of Differentiation from Mouse Embryonic Stem Cells into Islet-like Cells in vitro

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