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      In vitro expression of NGN3 identifies RAB3B as the predominant Ras-associated GTP-binding protein 3 family member in human islets

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          Abstract

          Neurogenin 3 (NGN3) commits pancreatic progenitors to an islet cell fate. We have induced NGN3 expression and identified upregulation of the gene encoding the Ras-associated small molecular mass GTP-binding protein, RAB3B. RAB3B localised to the cytoplasm of human β-cells, both during the foetal period and post natally. Genes encoding alternative RAB3 proteins and RAB27A were unaltered by NGN3 expression and in human adult islets their transcripts were many fold less prevalent than those of RAB3B. The regulation of insulin exocytosis in rodent β-cells and responsiveness to incretins are reliant on Rab family members, notably Rab3a and Rab27a, but not Rab3b. Our results support an important inter-species difference in regulating insulin exocytosis where RAB3B is the most expressed isoform in human islets.

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          Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.

          Anna L. Gloyn, Ewan Pearson, Jennifer F Antcliff … (2004)
          Patients with permanent neonatal diabetes usually present within the first three months of life and require insulin treatment. In most, the cause is unknown. Because ATP-sensitive potassium (K(ATP)) channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, we hypothesized that activating mutations in the gene encoding the Kir6.2 subunit of this channel (KCNJ11) cause neonatal diabetes. We sequenced the KCNJ11 gene in 29 patients with permanent neonatal diabetes. The insulin secretory response to intravenous glucagon, glucose, and the sulfonylurea tolbutamide was assessed in patients who had mutations in the gene. Six novel, heterozygous missense mutations were identified in 10 of the 29 patients. In two patients the diabetes was familial, and in eight it arose from a spontaneous mutation. Their neonatal diabetes was characterized by ketoacidosis or marked hyperglycemia and was treated with insulin. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; three of them also had epilepsy and mild dysmorphic features. When the most common mutation in Kir6.2 was coexpressed with sulfonylurea receptor 1 in Xenopus laevis oocytes, the ability of ATP to block mutant K(ATP) channels was greatly reduced. Heterozygous activating mutations in the gene encoding Kir6.2 cause permanent neonatal diabetes and may also be associated with developmental delay, muscle weakness, and epilepsy. Identification of the genetic cause of permanent neonatal diabetes may facilitate the treatment of this disease with sulfonylureas. Copyright 2004 Massachusetts Medical Society
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            Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas.

            Xiaobo Xu, Joke D'Hoker, Geert Stangé … (2008)
            Novel strategies in diabetes therapy would obviously benefit from the use of beta (beta) cell stem/progenitor cells. However, whether or not adult beta cell progenitors exist is one of the most controversial issues in today's diabetes research. Guided by the expression of Neurogenin 3 (Ngn3), the earliest islet cell-specific transcription factor in embryonic development, we show that beta cell progenitors can be activated in injured adult mouse pancreas and are located in the ductal lining. Differentiation of the adult progenitors is Ngn3 dependent and gives rise to all islet cell types, including glucose responsive beta cells that subsequently proliferate, both in situ and when cultured in embryonic pancreas explants. Multipotent progenitor cells thus exist in the pancreas of adult mice and can be activated cell autonomously to increase the functional beta cell mass by differentiation and proliferation rather than by self-duplication of pre-existing beta cells only.
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              neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas.

              G Gradwohl, F Guillemot, A Dierich … (2000)
              In the mammalian pancreas, the endocrine cell types of the islets of Langerhans, including the alpha-, beta-, delta-, and pancreatic polypeptide cells as well as the exocrine cells, derive from foregut endodermal progenitors. Recent genetic studies have identified a network of transcription factors, including Pdx1, Isl1, Pax4, Pax6, NeuroD, Nkx2.2, and Hlxb9, regulating the development of islet cells at different stages, but the molecular mechanisms controlling the specification of pancreatic endocrine precursors remain unknown. neurogenin3 (ngn3) is a member of a family of basic helix-loop-helix transcription factors that is involved in the determination of neural precursor cells in the neuroectoderm. ngn3 is expressed in discrete regions of the nervous system and in scattered cells in the embryonic pancreas. We show herein that ngn3-positive cells coexpress neither insulin nor glucagon, suggesting that ngn3 marks early precursors of pancreatic endocrine cells. Mice lacking ngn3 function fail to generate any pancreatic endocrine cells and die postnatally from diabetes. Expression of Isl1, Pax4, Pax6, and NeuroD is lost, and endocrine precursors are lacking in the mutant pancreatic epithelium. Thus, ngn3 is required for the specification of a common precursor for the four pancreatic endocrine cell types.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Endocrinol
                Journal ID (publisher-id): JOE
                Title: The Journal of Endocrinology
                Publisher: BioScientifica (Bristol )
                ISSN (Print): 0022-0795
                ISSN (Electronic): 1479-6805
                Publication date (Print): November 2010
                Publication date (Electronic preprint): 31 August 2010
                Volume: 207
                Issue: 2
                Pages: 151-161
                Affiliations
                [1 ]simpleEndocrinology and Diabetes Group, Manchester Academic Health Science Centre simpleUniversity of Manchester A V Hill Building, Oxford Road, Manchester, M13 9PTUK
                [2 ]simpleHuman Genetics Division simpleUniversity of Southampton Southampton, SO16 6YDUK
                [3 ]simpleBeta-Cell Development and Function Group simpleKing's College London Guy's Campus, London, SE1 1ULUK
                [4 ]simplePeninsula Medical School simpleInstitute of Biomedical and Clinical Science Barrack Road, Exeter, EX2 5DWUK
                Author notes
                (Correspondence should be addressed to N A Hanley; Email: neil.hanley@ 123456manchester.ac.uk )
                Article
                Publisher ID: JOE100120
                DOI: 10.1677/JOE-10-0120
                PMC ID: 2951179
                PubMed ID: 20807725
                SO-VID: 5b400d37-3645-4d6d-9cb0-f04f4f32d9f6
                Copyright © © 2010 Society for Endocrinology
                License:

                This is an Open Access article distributed under the terms of the Society for Endocrinology's Re-use Licence which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date revision received : 5 August 2010
                Date accepted : 31 August 2010
                Funding
                Funded by: Juvenile Diabetes Research Foundation
                Funded by: Wellcome Trust
                Funded by: Manchester NIHR Biomedical Research Centre
                Categories
                Subject: Regular Papers

                ScienceOpen disciplines: Endocrinology & Diabetes
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes

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