GC-Globulin/Vitamin D-Binding Protein Is Required for Pancreatic α-Cell Adaptation to Metabolic Stress

Katrina Viloria, Daniela Nasteska, Julia Ast, Annie Hasib, Federica Cuozzo, Silke Heising, Linford J B Briant, Martin Hewison*, David J Hodson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)275-289
Number of pages15
Issue number2
Early online date29 Nov 2022
Publication statusPublished - Feb 2023

Bibliographical note

© 2023 by the American Diabetes Association.


  • Animals
  • Mice
  • Diabetes Mellitus, Type 2/metabolism
  • Globulins/metabolism
  • Glucagon/metabolism
  • Stress, Physiological
  • Vitamin D-Binding Protein/genetics


Dive into the research topics of 'GC-Globulin/Vitamin D-Binding Protein Is Required for Pancreatic α-Cell Adaptation to Metabolic Stress'. Together they form a unique fingerprint.

Cite this