Cell Reports (Jun 2020)
Vitamin-D-Binding Protein Contributes to the Maintenance of α Cell Function and Glucagon Secretion
- Katrina Viloria,
- Daniela Nasteska,
- Linford J.B. Briant,
- Silke Heising,
- Dean P. Larner,
- Nicholas H.F. Fine,
- Fiona B. Ashford,
- Gabriela da Silva Xavier,
- Maria Jiménez Ramos,
- Annie Hasib,
- Federica Cuozzo,
- 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
Affiliations
- Katrina Viloria
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK
- Daniela Nasteska
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK
- Linford J.B. Briant
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK
- Silke Heising
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK
- Dean P. Larner
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK
- Nicholas H.F. Fine
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK
- Fiona B. Ashford
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK
- Gabriela da Silva Xavier
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK
- Maria Jiménez Ramos
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK
- Annie Hasib
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK
- Federica Cuozzo
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK
- Jocelyn E. Manning Fox
- Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Patrick E. MacDonald
- Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Ildem Akerman
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK
- Gareth G. Lavery
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK
- Christine Flaxman
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK
- Noel G. Morgan
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK
- Sarah J. Richardson
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK
- Martin Hewison
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK; Corresponding author
- David J. Hodson
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK; Corresponding author
- Journal volume & issue
-
Vol. 31,
no. 11
p. 107761
Abstract
Summary: Vitamin-D-binding protein (DBP) or group-specific component of serum (GC-globulin) carries vitamin D metabolites from the circulation to target tissues. DBP is highly localized to the liver and pancreatic α cells. Although 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 leads to smaller and hyperplastic α cells, altered Na+ channel conductance, impaired α cell activation by low glucose, and reduced rates of glucagon secretion both in vivo and in vitro. Mechanistically, this involves reversible changes in islet microfilament abundance and density, as well as changes in glucagon granule distribution. Defects are also seen in β cell and δ cell function. Immunostaining of human pancreata reveals generalized loss of DBP expression as a feature of late-onset and long-standing, but not early-onset, type 1 diabetes. Thus, DBP regulates α cell phenotype, with implications for diabetes pathogenesis.
