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      Therapies for Type 1 Diabetes: Current Scenario and Future Perspectives

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          Abstract

          Type 1 diabetes (T1D) is caused by autoimmune destruction of insulin-producing β cells located in the endocrine pancreas in areas known as islets of Langerhans. The current standard-of-care for T1D is exogenous insulin replacement therapy. Recent developments in this field include the hybrid closed-loop system for regulated insulin delivery and long-acting insulins. Clinical studies on prediction and prevention of diabetes-associated complications have demonstrated the importance of early treatment and glucose control for reducing the risk of developing diabetic complications. Transplantation of primary islets offers an effective approach for treating patients with T1D. However, this strategy is hampered by challenges such as the limited availability of islets, extensive death of islet cells, and poor vascular engraftment of islets post-transplantation. Accordingly, there are considerable efforts currently underway for enhancing islet transplantation efficiency by harnessing the beneficial actions of stem cells. This review will provide an overview of currently available therapeutic options for T1D, and discuss the growing evidence that supports the use of stem cell approaches to enhance therapeutic outcomes.

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          Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo.

          Development of a cell therapy for diabetes would be greatly aided by a renewable supply of human beta-cells. Here we show that pancreatic endoderm derived from human embryonic stem (hES) cells efficiently generates glucose-responsive endocrine cells after implantation into mice. Upon glucose stimulation of the implanted mice, human insulin and C-peptide are detected in sera at levels similar to those of mice transplanted with approximately 3,000 human islets. Moreover, the insulin-expressing cells generated after engraftment exhibit many properties of functional beta-cells, including expression of critical beta-cell transcription factors, appropriate processing of proinsulin and the presence of mature endocrine secretory granules. Finally, in a test of therapeutic potential, we demonstrate that implantation of hES cell-derived pancreatic endoderm protects against streptozotocin-induced hyperglycemia. Together, these data provide definitive evidence that hES cells are competent to generate glucose-responsive, insulin-secreting cells.
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            Type I diabetes mellitus. A chronic autoimmune disease.

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              Maturation of Human Embryonic Stem Cell–Derived Pancreatic Progenitors Into Functional Islets Capable of Treating Pre-existing Diabetes in Mice

              Diabetes is a chronic debilitating disease that results from insufficient production of insulin from pancreatic β-cells. Islet cell replacement can effectively treat diabetes but is currently severely limited by the reliance upon cadaveric donor tissue. We have developed a protocol to efficiently differentiate commercially available human embryonic stem cells (hESCs) in vitro into a highly enriched PDX1+ pancreatic progenitor cell population that further develops in vivo to mature pancreatic endocrine cells. Immature pancreatic precursor cells were transplanted into immunodeficient mice with streptozotocin-induced diabetes, and glycemia was initially controlled with exogenous insulin. As graft-derived insulin levels increased over time, diabetic mice were weaned from exogenous insulin and human C-peptide secretion was eventually regulated by meal and glucose challenges. Similar differentiation of pancreatic precursor cells was observed after transplant in immunodeficient rats. Throughout the in vivo maturation period hESC-derived endocrine cells exhibited gene and protein expression profiles that were remarkably similar to the developing human fetal pancreas. Our findings support the feasibility of using differentiated hESCs as an alternative to cadaveric islets for treating patients with diabetes.
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                Author and article information

                Journal
                Clin Med Insights Endocrinol Diabetes
                Clin Med Insights Endocrinol Diabetes
                END
                spend
                Clinical Medicine Insights. Endocrinology and Diabetes
                SAGE Publications (Sage UK: London, England )
                1179-5514
                03 May 2019
                2019
                : 12
                : 1179551419844521
                Affiliations
                [1 ]Centre for Experimental Medicine, Queen’s University Belfast, Belfast, United Kingdom
                [2 ]The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, United Kingdom
                Author notes
                [*]Varun Pathak, Centre for Experimental Medicine, Queen’s University Belfast, Belfast BT9 7BL, United Kingdom. Email: v.pathak@ 123456qub.ac.uk
                Article
                10.1177_1179551419844521
                10.1177/1179551419844521
                6501476
                31105434
                a04eff46-129f-4e9b-a1f1-6f9b4c045211
                © The Author(s) 2019

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 22 March 2019
                : 26 March 2019
                Funding
                Funded by: juvenile diabetes research foundation united kingdom, FundRef https://doi.org/10.13039/100008664;
                Funded by: leverhulme trust, FundRef https://doi.org/10.13039/501100000275;
                Funded by: national eye research centre, FundRef https://doi.org/10.13039/501100000305;
                Categories
                Review Article
                Custom metadata
                January-December 2019

                Endocrinology & Diabetes
                type 1 diabetes,insulin therapy,islet transplant,immune therapies,mesenchymal stem cells,induced pluripotent stem cells,endothelial colony forming cells

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