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islet,beta-cell,diabetes,stem cell

Nicola L Beer, Anna L Gloyn
Type 2 diabetes (T2D) is a disease of pandemic proportions, one defined by a complex aetiological mix of genetic, epigenetic, environmental, and lifestyle risk factors. Whilst the last decade of T2D genetic research has identified more than 100 loci showing strong statistical association with disease susceptibility, our inability to capitalise upon these signals reflects, in part, a lack of appropriate human cell models for study. This review discusses the impact of two complementary, state-of-the-art technologies on T2D genetic research: the generation of stem cell-derived, endocrine pancreas-lineage cells and the editing of their genomes...
2016: F1000Research
Muhammad Waseem, Irfan Khan, Hana'a Iqbal, Sana Eijaz, Shumaila Usman, Nazia Ahmed, Gulzar Alam, Asmat Salim
Insulin replacement is the current therapeutic option for type-1 diabetes. However, exogenous insulin cannot precisely represent the normal pattern of insulin secretion. Another therapeutic strategy is transplantation of pancreatic islets, but this is limited by immune rejection, intrinsic complications, and lack of donor availability. Stem cell therapy that results in the regeneration of insulin-producing cells represents an attractive choice. However, with advancing age, stem cells also undergo senescence, which leads to changes in the function of various cellular processes that result in a decrease in the regeneration potential of these aging stem cells...
October 2016: Cellular Reprogramming
James D Johnson
The production of fully functional insulin-secreting cells to treat diabetes is a major goal of regenerative medicine. In this article, I review progress towards this goal over the last 15 years from the perspective of a beta cell biologist. I describe the current state-of-the-art, and speculate on the general approaches that will be required to identify and achieve our ultimate goal of producing functional beta cells. The need for deeper phenotyping of heterogeneous cultures of stem cell derived islet-like cells in parallel with a better understanding of the heterogeneity of the target cell type(s) is emphasised...
October 2016: Diabetologia
Shabari Sarang, Chandra Viswanathan
BACKGROUND AND OBJECTIVES: Type 1 Diabetes Mellitus (T1DM) is an autoimmune disorder resulting out of T cell mediated destruction of pancreatic beta cells. Immunomodulatory properties of mesenchymal stem cells may help to regenerate beta cells and/or prevent further destruction of remnant, unaffected beta cells in diabetes. We have assessed the ability of umbilical cord derived MSCs (UCMSCs) to differentiate into functional islet cells in vitro. METHODS AND RESULTS: We have isolated UCMSCs and allowed sequential exposure of various inducing agents and growth factors...
May 30, 2016: International Journal of Stem Cells
Bernard Okere, Laura Lucaccioni, Massimo Dominici, Lorenzo Iughetti
The current treatment approach for type 1 diabetes is based on daily insulin injections, combined with blood glucose monitoring. However, administration of exogenous insulin fails to mimic the physiological activity of the islet, therefore diabetes often progresses with the development of serious complications such as kidney failure, retinopathy and vascular disease. Whole pancreas transplantation is associated with risks of major invasive surgery along with side effects of immunosuppressive therapy to avoid organ rejection...
2016: Italian Journal of Pediatrics
Joao Paulo Monteiro Carvalho Mori Cunha, Conny Gysemans, Pieter Gillard, Chantal Mathieu
Beta-cell replacement by human islets or whole pancreas offers a life-saving therapeutic remedy for patients suffering from type 1 diabetes, providing considerable advantages with respect to diminishing total daily insulin dose and lowering frequencies of debilitating hypoglycemic reactions as well as preventing chronic micro- and macrovascular complications. Although remarkable progress has been made in this area, several hurdles remain, hampering its wide-spread applicability. Such hurdles include a limiting supply of islets, the necessity of several donors to achieve enough islet mass for insulin independence, and graft failure because of metabolic pressure, continued autoimmunity, alloimmunity, high concentrations of immunosuppressive drugs as well as oxidative stress caused by hypoxia or inflammation...
June 28, 2016: Current Diabetes Reviews
Lucien Marchand, Audrey Jalabert, Emmanuelle Meugnier, Kathleen Van den Hende, Nicole Fabien, Marc Nicolino, Anne-Marie Madec, Charles Thivolet, Sophie Rome
Background. The use of miRNAs as biomarkers for Type 1 Diabetes (T1D) risk is attractive as T1D is usually diagnosed in front of acute symptoms. As miR-375 is highly expressed in the endocrine pancreas, we postulated that its circulating level might reflect beta cell alterations and might be altered in the blood of T1D patients recently diagnosed. Methods. Sera were obtained from 22 T1D children at onset of the disease, before subcutaneous insulin treatment, and from 10 nondiabetic pediatric controls. MiR-375 seric level was quantified by stem-loop RT-PCR-based assay...
2016: Journal of Diabetes Research
Krishna Prasadan, Chiyo Shiota, Xiao Xiangwei, David Ricks, Joseph Fusco, George Gittes
The insulin-secreting beta cells in the endocrine pancreas regulate blood glucose levels, and loss of functional beta cells leads to insulin deficiency, hyperglycemia (high blood glucose) and diabetes mellitus. Current treatment strategies for type-1 (autoimmune) diabetes are islet transplantation, which has significant risks and limitations, or normalization of blood glucose with insulin injections, which is clearly not ideal. The type-1 patients can lack insulin counter-regulatory mechanism; therefore, hypoglycemia is a potential risk...
October 2016: Cellular and Molecular Life Sciences: CMLS
Sofie De Groef, Willem Staels, Naomi Van Gassen, Marie Lemper, Yixing Yuchi, Mozhdeh Sojoodi, Leen Bussche, Yves Heremans, Gunter Leuckx, Nico De Leu, Mark Van de Casteele, Luc Baeyens, Harry Heimberg
The generation of beta(-like) cells to compensate for their absolute or relative shortage in type 1 and type 2 diabetes is an obvious therapeutic strategy. Patients first received grafts of donor islet cells over 25 years ago, but this procedure has not become routine in clinical practice because of a donor cell shortage and (auto)immune problems. Transplantation of differentiated embryonic and induced pluripotent stem cells may overcome some but not all the current limitations. Reprogramming exocrine cells towards functional beta(-like) cells would offer an alternative abundant and autologous source of beta(-like) cells...
September 2016: Diabetologia
Klearchos K Papas, Efstathios S Avgoustiniatos, Thomas M Suszynski
Beta-cell replacement therapy is a promising approach for the treatment of diabetes but is currently limited by the human islet availability and by the need for systemic immunosuppression. Tissue engineering approaches that will enable the utilization of islets or β-cells from alternative sources (such as porcine islets or human stem cell derived beta cells) and minimize or eliminate the need for immunosuppression have the potential to address these critical limitations. However, tissue engineering approaches are critically hindered by the device size (similar to the size of a large flat screen television) required for efficacy in humans...
March 2016: Panminerva Medica
Arturo J Vegas, Omid Veiseh, Mads Gürtler, Jeffrey R Millman, Felicia W Pagliuca, Andrew R Bader, Joshua C Doloff, Jie Li, Michael Chen, Karsten Olejnik, Hok Hei Tam, Siddharth Jhunjhunwala, Erin Langan, Stephanie Aresta-Dasilva, Srujan Gandham, James J McGarrigle, Matthew A Bochenek, Jennifer Hollister-Lock, Jose Oberholzer, Dale L Greiner, Gordon C Weir, Douglas A Melton, Robert Langer, Daniel G Anderson
The transplantation of glucose-responsive, insulin-producing cells offers the potential for restoring glycemic control in individuals with diabetes. Pancreas transplantation and the infusion of cadaveric islets are currently implemented clinically, but these approaches are limited by the adverse effects of immunosuppressive therapy over the lifetime of the recipient and the limited supply of donor tissue. The latter concern may be addressed by recently described glucose-responsive mature beta cells that are derived from human embryonic stem cells (referred to as SC-β cells), which may represent an unlimited source of human cells for pancreas replacement therapy...
March 2016: Nature Medicine
Diego Balboa, Timo Otonkoski
Although similar, mouse and human pancreatic development and beta cell physiology have significant differences. For this reason, mouse models present shortcomings that can obscure the understanding of human diabetes pathology. Progress in the field of human pluripotent stem cell (hPSC) differentiation now makes it possible to derive unlimited numbers of human beta cells in vitro. This constitutes an invaluable approach to gain insight into human beta cell development and physiology and to generate improved disease models...
December 2015: Best Practice & Research. Clinical Endocrinology & Metabolism
Fang Xiao, Liang Ma, Min Zhao, Richard A Smith, Guocai Huang, Peter M Jones, Shanta Persaud, Attilio Pingitore, Anthony Dorling, Robert Lechler, Giovanna Lombardi
BACKGROUND AND PURPOSE: A major obstacle to islet cell transplantation is the early loss of transplanted islets resulting from the instant blood-mediated inflammation reaction (IBMIR). The activation of complement pathways plays a central role in IBMIR. The aim of this study was to test the inhibitory effect of "painting" human islets with APT070, a membrane-localizing C3 convertase inhibitor, on inflammation evoked by exposure to human serum in vitro and by transplantation in vivo in a humanized diabetic mouse model...
February 2016: British Journal of Pharmacology
Vivian Anastasiou, Elpiniki Ninou, Dimitra Alexopoulou, Julia Stertmann, Andreas Müller, Andreas Dahl, Michele Solimena, Stephan Speier, Ioannis Serafimidis, Anthony Gavalas
AIMS/HYPOTHESIS: Pancreatic beta cells maintain glucose homeostasis and beta cell dysfunction is a major risk factor in developing diabetes. Therefore, understanding the developmental regulatory networks that define a fully functional beta cell is important for elucidating the genetic origins of the disease. Aldehyde dehydrogenase activity has been associated with stem/progenitor cells and we have previously shown that Aldh1b1 is specifically expressed in pancreas progenitor pools. Here we address the hypothesis that Aldh1b1 may regulate the timing of the appearance and eventual functionality of beta cells...
January 2016: Diabetologia
Xiaoli Shi, Xiaokan Xiong, Zhe Dai, Haohua Deng, Li Sun, Xuemei Hu, Feng Zhou, Yancheng Xu
Nuclear orphan receptor TLX is an essential regulator of the growth of neural stem cells. However, its exact function in pancreatic islet cells is still unknown. In the present study, gene expression profiling analysis revealed that overexpression of TLX in beta cell line MIN6 causes suppression of 176 genes and upregulation of 49 genes, including a cadre of cell cycle, cell proliferation and cell death control genes, such as Btg2, Ddit3 and Gadd45a. We next examined the effects of TLX overexpression on proliferation, apoptosis and insulin secretion in MIN6 cells...
December 4, 2015: Biochemical and Biophysical Research Communications
G Basta, P Montanucci, R Calafiore
Pancreatic islet cell transplantation has represented the mainstay of cell therapy for the potential, final cure of type 1 diabetes mellitus (T1D), along the past two decades. Unfortunately, the restricted availability of cadaveric human donor pancreases coupled with heavy side effects of the recipient's general immunosuppression, have severely crippled progress of this approach into clinical trials. Only a few excellence centers, worldwide, have thus far accrued still quite marginal clinical success. In an attempt to overcome the limits of islet transplantation new technologies for use of several stem cell lineages are being under investigation, with initial experimental evidence of success...
December 2015: Minerva Endocrinologica
Mario R Ehlers, Mark R Rigby
Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to progressive destruction of pancreatic beta cells. Compared to healthy controls, a characteristic feature of patients with T1D is the presence of self-reactive T cells with a memory phenotype. These autoreactive memory T cells in both the CD4(+) and CD8(+) compartments are likely to be long-lived, strongly responsive to antigenic stimulation with less dependence on costimulation for activation and clonal expansion, and comparatively resistant to suppression by regulatory T cells (Tregs) or downregulation by immune-modulating agents...
November 2015: Current Diabetes Reports
Sofie De Groef, Gunter Leuckx, Naomi Van Gassen, Willem Staels, Ying Cai, Yixing Yuchi, Violette Coppens, Nico De Leu, Yves Heremans, Luc Baeyens, Mark Van de Casteele, Harry Heimberg
Expansion of pancreatic beta cells in vivo or ex vivo, or generation of beta cells by differentiation from an embryonic or adult stem cell, can provide new expandable sources of beta cells to alleviate the donor scarcity in human islet transplantation as therapy for diabetes. Although recent advances have been made towards this aim, mechanisms that regulate beta cell expansion and differentiation from a stem/progenitor cell remain to be characterized. Here, we describe a protocol for an injury model in the adult mouse pancreas that can function as a tool to study mechanisms of tissue remodeling and beta cell proliferation and differentiation...
2015: Journal of Visualized Experiments: JoVE
Sergiu Şuşman, Dan Rus-Ciucă, Olga Soriţău, Răzvan Ciortea, Mihai Gîrlovanu, Dan Mihu, Carmen Mihaela Mihu
OBJECTIVES: The apparition of sugar diabetes is produced by the decrease of the number and capacity of beta cells to secrete insulin. Cell mass recovery through cell therapy might be one of the solutions for treating this disease. The use of various cell sources of different differentiation grades has been tried over the last years. Decoding the molecular mechanisms of the pancreatic morphogenesis is essential for obtaining cells having a phenotype, which would be very similar to the mature cells located in the pancreatic endocrine component...
2015: Romanian Journal of Morphology and Embryology, Revue Roumaine de Morphologie et Embryologie
David Martin, Yung-Hae Kim, Dror Sever, Chai-An Mao, Jacques-Antoine Haefliger, Anne Grapin-Botton
To contribute to devise successful beta-cell differentiation strategies for the cure of Type 1 diabetes we sought to uncover barriers that restrict endocrine fate acquisition by studying the role of the transcriptional repressor REST in the developing pancreas. Rest expression is prevented in neurons and in endocrine cells, which is necessary for their normal function. During development, REST represses a subset of genes in the neuronal differentiation program and Rest is down-regulated as neurons differentiate...
September 15, 2015: Developmental Biology
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