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

Viloria, Katrina, Nasteska, Daniela, Ast, Julia, Hasib, Annie ORCID: https://orcid.org/0000-0002-5388-6461, Cuozzo, Federica, Heising, Silke, Briant, Linford JB, Hewison, Martin and Hodson, David J (2023) GC-globulin/vitamin D–binding protein is required for pancreatic α-cell adaptation to metabolic stress. Diabetes, 72 (2). pp. 275-289. ISSN 0012-1797

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Abstract

GC-globulin (GC), or vitamin D–binding protein, is a multifunctional protein involved in the transport of circulating vitamin 25(OH)D and fatty acids, as well as actin scavenging. In the pancreatic islets, the gene encoding GC, 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.