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Role of BMP signaling and ASNA1 in β-cells
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Patients with type II diabetes present alterations in glucose homeostasis due to insufficient amount of insulin (β-cell dysfunction) and inability to properly use the insulin that is secreted (insulin resistance). Combined genetical and environmental factors are believed to be responsible for these dysfunctions and the resulting impairment in glucose homeostasis. The pancreatic gland is composed of exocrine and endocrine tissues. The endocrine part of the organ couples glucose sensing to insulin release. Within this endocrine gland, also known as islets of Langerhans, the insulin secreting β-cell is the main player and therefore highly important for proper glucose metabolism. In this thesis, mice were developed in order to assess the role of BMP signaling molecule and Arsenite induced ATPase-1 (Asna1) for pancreas development and β-cell function.

The mature β-cell responds to elevated glucose levels by secreting insulin in a tightly controlled manner. This physiological response of the β-cell to elevated blood glucose levels is critical for maintenance of normoglycaemia and impaired Glucose stimulated insulin secretion (GSIS) is a prominent feature of overt type 2 diabetes. Thus, the identification of signals and pathways that ensure and stimulate GSIS in β-cells is of great clinical interest. Here we show (Paper I) that BMPRIA and its high affinity ligand BMP4 are expressed in fetal and adult islets. We also provide evidence that BMPRIA signaling in adult β-cell is required for GSIS, and that both transgenic expression of Bmp4 in β-cells or systemic administration of BMP4 protein to mice enhances GSIS. Thus, BMP4-BMPRIA signaling in β-cells positively regulates the genetic machinery that ensures GSIS.

Arsenite induced ATPase (Asna1), the homologue of the bacterial ArsA ATPase, is expressed in insulin producing cells of both mammals and the nematode Caenorhabditis elegans (C.elegans). Asna1 has been proposed to act as an evolutionary conserved regulator of insulin/insulin like factor signaling. In C.elegans, asna-1 has been shown to regulate growth in a non-cell autonomous and IGF-receptor dependent manner. Here we show that transgenic expression of ASNA1 in β-cells of mice leads to enhanced Aktactivity and β-cell hyperplasia (manuscript). ASNA1 transgenic mice develop, however, diabetes due to impaired insulin secretion. The expression of genes involved in secretion stimulus coupling and insulin exocytosis is perturbed in islets of these mice. These data suggest that activation of ASNA1, here mimicked by enhanced expression, positively influences β-cell mass but negatively affects insulin secretion.

Place, publisher, year, edition, pages
Umeå: Medicinsk och klinisk genetik , 2008. , 66 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1214
Keyword [en]
type 2 diabetes, BMP4-BMPR1A signaling molecules, GSIS, incretins, BMP4, BMPR1A, Asna-1, ATP, β-cell mass
Research subject
Medical Cell Biology
URN: urn:nbn:se:umu:diva-1810ISBN: 978-91-7264-601-8OAI: diva2:142067
Public defence
2008-09-25, hörsal Betula, 6M, Norrlands Universitets sjukhus, Umeå, 09:00 (English)
Available from: 2008-09-05 Created: 2008-09-05 Last updated: 2010-04-14Bibliographically approved
List of papers
1. BMP4-BMPR1A signaling in beta cells is required for and augments glucose-stimulated insulin secretion.
Open this publication in new window or tab >>BMP4-BMPR1A signaling in beta cells is required for and augments glucose-stimulated insulin secretion.
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2007 (English)In: Cell Metabolism, ISSN 1550-4131, Vol. 5, no 3, 207-219 p.Article in journal (Refereed) Published
Animals, Autocrine Communication, Bone Morphogenetic Protein Receptors; Type I/genetics/*metabolism, Bone Morphogenetic Proteins/administration & dosage/*metabolism/pharmacology, Diabetes Mellitus; Type 2/drug therapy/genetics/metabolism, Female, Gene Expression, Glucose/metabolism, Glucose Intolerance/drug therapy, Homeodomain Proteins/genetics, Insulin/genetics/*secretion, Insulin-Secreting Cells/metabolism/*secretion, Male, Mice, Mice; Inbred C57BL, Mice; Inbred CBA, Mice; Transgenic, Signal Transduction, Trans-Activators/genetics
urn:nbn:se:umu:diva-5922 (URN)17339028 (PubMedID)
Available from: 2007-12-03 Created: 2007-12-03 Last updated: 2013-03-14Bibliographically approved
2. Diabetes and β-cell hyperplasia in mice over-expressing the ATPase Asna-1
Open this publication in new window or tab >>Diabetes and β-cell hyperplasia in mice over-expressing the ATPase Asna-1
(English)Manuscript (Other (popular science, discussion, etc.))
urn:nbn:se:umu:diva-3392 (URN)
Available from: 2008-09-05 Created: 2008-09-05 Last updated: 2010-01-14Bibliographically approved

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