Vitamin-D-binding protein contributes to the maintenance of α cell function and glucagon secretion

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Vitamin-D-binding protein contributes to the maintenance of α cell function and glucagon secretion. / Viloria, Katrina Muriel; Nasteska, Daniela; Briant, Linford J. B.; Heising, Silke; Larner, Dean; Fine, Nick; Ashford, Fiona; Da Silva Xavier, Gaby; Jimenez-Gonzalez, Maria; Hasib, Annie; Cuozzo, Federica; Manning Fox, Jocelyn ; MacDonald, Patrick ; Akerman, Ildem; Lavery, Gareth; Flaxman, Christine; Morgan, Noel ; Richardson, Sarah; Hewison, Martin; Hodson, David.

In: Cell Reports, Vol. 31, No. 11, 107761, 16.06.2020.

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@article{0448dac892ea4ddcab022ac7e86a291c,
title = "Vitamin-D-binding protein contributes to the maintenance of α cell function and glucagon secretion",
abstract = "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.",
keywords = "α-cell, glucagon, GC-globulin, vitamin D, vitamin D-binding protein, type 1 diabetes",
author = "Viloria, {Katrina Muriel} and Daniela Nasteska and Briant, {Linford J. B.} and Silke Heising and Dean Larner and Nick Fine and Fiona Ashford and {Da Silva Xavier}, Gaby and Maria Jimenez-Gonzalez and Annie Hasib and Federica Cuozzo and {Manning Fox}, Jocelyn and Patrick MacDonald and Ildem Akerman and Gareth Lavery and Christine Flaxman and Noel Morgan and Sarah Richardson and Martin Hewison and David Hodson",
year = "2020",
month = jun,
day = "16",
doi = "10.1016/j.celrep.2020.107761",
language = "English",
volume = "31",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Elsevier",
number = "11",

}

RIS

TY - JOUR

T1 - Vitamin-D-binding protein contributes to the maintenance of α cell function and glucagon secretion

AU - Viloria, Katrina Muriel

AU - Nasteska, Daniela

AU - Briant, Linford J. B.

AU - Heising, Silke

AU - Larner, Dean

AU - Fine, Nick

AU - Ashford, Fiona

AU - Da Silva Xavier, Gaby

AU - Jimenez-Gonzalez, Maria

AU - Hasib, Annie

AU - Cuozzo, Federica

AU - Manning Fox, Jocelyn

AU - MacDonald, Patrick

AU - Akerman, Ildem

AU - Lavery, Gareth

AU - Flaxman, Christine

AU - Morgan, Noel

AU - Richardson, Sarah

AU - Hewison, Martin

AU - Hodson, David

PY - 2020/6/16

Y1 - 2020/6/16

N2 - 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.

AB - 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.

KW - α-cell

KW - glucagon

KW - GC-globulin

KW - vitamin D

KW - vitamin D-binding protein

KW - type 1 diabetes

UR - http://www.scopus.com/inward/record.url?scp=85086396893&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2020.107761

DO - 10.1016/j.celrep.2020.107761

M3 - Article

C2 - 32553153

VL - 31

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 11

M1 - 107761

ER -