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GC-globulin/vitamin D-binding protein is required for pancreatic α cell adaptation to metabolic stress

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posted on 2022-11-29, 18:48 authored by Katrina Viloria, Daniela Nasteska, Julia Ast, Annie Hasib, Federica Cuozzo, Silke Heising, Linford J.B. Briant, Martin Hewison, David J. Hodson

GC-globulin (GC), or vitamin D-binding protein, is a multifunctional protein involved in transport of circulating vitamin 25(OH)D and fatty acids, as well as actin-scavenging. In the pancreatic islets, the gene encoding GC, GC, is highly-localized to glucagon-secreting α cells. Despite this, the role of GC in α cell function is poorly understood. We previously showed that GC is essential for α cell morphology, electrical activity and glucagon secretion. We now show that loss of GC exacerbates α cell failure during metabolic stress. High fat diet-fed GC-/- mice have basal hyperglucagonemia, which is associated with decreased α cell size, impaired glucagon secretion and Ca2+ fluxes, and changes in glucose-dependent F-actin remodelling. Impairments in glucagon secretion can be rescued using exogenous GC to replenish α cell GC levels, increase glucagon granule area and restore the F-actin cytoskeleton. Lastly, GC levels decrease in α cells of donors with type 2 diabetes, which is associated with changes in α cell mass, morphology and glucagon expression. Together, these data demonstrate an important role for GC in α cell adaptation to metabolic stress.

Funding

D.J.H. was supported by MRC (MR/S025618/1) and Diabetes UK (17/0005681) Project Grants, as well as a UKRI ERC Frontier Research Guarantee Grant (EP/X026833/1). 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. The research was funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Human pancreas sections were provided by the Alberta Diabetes Institute IsletCore at the University of Alberta in Edmonton (http://www.bcell.org/adi-isletcore.html) with the assistance of the Human Organ Procurement and Exchange (HOPE) program, Trillium Gift of Life Network (TGLN) and other Canadian organ procurement organizations. The funders had no role in study design, data collection, data analysis, interpretation or writing of the paper.

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