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Vitamin-D-Binding Protein Contributes to the Maintenance of α Cell Function and Glucagon Secretion
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.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.D.J.H. was supported by MRC ( MR/N00275X/1 and MR/S025618/1 ) and Diabetes UK ( 17/0005681 ) project grants. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Starting Grant 715884 to D.J.H.). L.J.B.B. was supported by a Sir Henry Wellcome Postdoctoral Fellowship ( Wellcome Trust ; 201325/Z/16/Z ) and a Junior Research Fellowship from Trinity College, Oxford . P.E.M. was funded by a foundation grant from the Canadian Institutes of Health Research (grant 148451 ). G.G.L. was supported by a Wellcome Trust Senior Research Fellowship ( 104612/Z/14/Z ). N.G.M. and S.J.R. were supported by Diabetes UK ( 15/0005156 and 16/0005480 ), MRC ( MR/P010695/1 ), and JDRF ( 2-SRA-2018-474-S-B ) project grants. We thank Dr. Deirdre Kavanagh and COMPARE for microscopy assistance. Human pancreas sections were provided by the Alberta Diabetes Institute IsletCore at the University of Alberta in Edmonton, with the assistance of the Human Organ Procurement and Exchange (HOPE) program, Trillium Gift of Life Network (TGLN), and other Canadian organ procurement organizations.published version, accepted version, submitted versio