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Vitamin D-binding protein is required for the maintenance of α-cell function and glucagon secretion

Katrina Viloria, View ORCID ProfileDaniela Nasteska, View ORCID ProfileLinford J.B. Briant, Silke Heising, View ORCID ProfileDean Larner, View ORCID ProfileNicholas H.F. Fine, View ORCID ProfileFiona B. Ashford, View ORCID ProfileGabriela da Silva Xavier, Maria Jiménez Ramos, Jocelyn E. Manning Fox, View ORCID ProfilePatrick E. MacDonald, View ORCID ProfileIldem Akerman, View ORCID ProfileGareth G. Lavery, Christine Flaxman, View ORCID ProfileNoel G. Morgan, View ORCID ProfileSarah J. Richardson, View ORCID ProfileMartin Hewison, View ORCID ProfileDavid J. Hodson
doi: https://doi.org/10.1101/2019.12.19.881185
Katrina Viloria
Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham, UKCentre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UKCentre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
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Daniela Nasteska
Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham, UKCentre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UKCentre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
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Linford J.B. Briant
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
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Silke Heising
Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham, UKCentre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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Dean Larner
Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham, UKCentre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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Nicholas H.F. Fine
Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham, UKCentre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UKCentre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
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Fiona B. Ashford
Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham, UKCentre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UKCentre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
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Gabriela da Silva Xavier
Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham, UKCentre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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Maria Jiménez Ramos
Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham, UKCentre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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Jocelyn E. Manning Fox
Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
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Patrick E. MacDonald
Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
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Ildem Akerman
Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham, UKCentre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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Gareth G. Lavery
Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham, UKCentre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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Christine Flaxman
University of Exeter, Medical School, Institute of Biomedical and Clinical Science, UK
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Noel G. Morgan
University of Exeter, Medical School, Institute of Biomedical and Clinical Science, UK
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Sarah J. Richardson
University of Exeter, Medical School, Institute of Biomedical and Clinical Science, UK
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Martin Hewison
Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham, UKCentre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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  • For correspondence: d.hodson@bham.ac.uk m.hewison@bham.ac.uk
David J. Hodson
Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham, UKCentre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UKCentre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
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  • For correspondence: d.hodson@bham.ac.uk m.hewison@bham.ac.uk
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ABSTRACT

Vitamin D-binding protein (DBP) or GC-globulin carries vitamin D metabolites from the circulation to target tissues. DBP expression is highly-localized to the liver and pancreatic α-cells. While DBP serum levels, gene polymorphisms and autoantigens have all been associated with diabetes risk, the underlying mechanisms remain unknown. Here, we show that DBP regulates α-cell morphology, α-cell function and glucagon secretion. Deletion of DBP led to smaller and hyperplastic α-cells, altered Na+ channel conductance, impaired α-cell activation by low glucose, and reduced rates of glucagon secretion. Mechanistically, this involved reversible changes in islet microfilament abundance and density, as well as changes in glucagon granule distribution. Defects were also seen in β-cell and δ-cell function. Immunostaining of human pancreata revealed generalized loss of DBP expression as a feature of late-onset and longstanding, but not early-onset type 1 diabetes. Thus, DBP is a critical regulator of α-cell phenotype, with implications for diabetes pathogenesis.

HIGHLIGHTS

  • DBP expression is highly-localized to mouse and human α-cells

  • Loss of DBP increases α-cell number, but decreases α-cell size

  • α-cells in DBP knockout islets are dysfunctional and secrete less glucagon

  • DBP expression is decreased in α-cells of donors with late-onset or longstanding type 1 diabetes

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 19, 2019.
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Vitamin D-binding protein is required for the maintenance of α-cell function and glucagon secretion
Katrina Viloria, Daniela Nasteska, Linford J.B. Briant, Silke Heising, Dean Larner, Nicholas H.F. Fine, Fiona B. Ashford, Gabriela da Silva Xavier, Maria Jiménez Ramos, Jocelyn E. Manning Fox, Patrick E. MacDonald, Ildem Akerman, Gareth G. Lavery, Christine Flaxman, Noel G. Morgan, Sarah J. Richardson, Martin Hewison, David J. Hodson
bioRxiv 2019.12.19.881185; doi: https://doi.org/10.1101/2019.12.19.881185
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Vitamin D-binding protein is required for the maintenance of α-cell function and glucagon secretion
Katrina Viloria, Daniela Nasteska, Linford J.B. Briant, Silke Heising, Dean Larner, Nicholas H.F. Fine, Fiona B. Ashford, Gabriela da Silva Xavier, Maria Jiménez Ramos, Jocelyn E. Manning Fox, Patrick E. MacDonald, Ildem Akerman, Gareth G. Lavery, Christine Flaxman, Noel G. Morgan, Sarah J. Richardson, Martin Hewison, David J. Hodson
bioRxiv 2019.12.19.881185; doi: https://doi.org/10.1101/2019.12.19.881185

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