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

Journal article

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 hyper glucagonemia, 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.

Authors: Viloria, K; Nasteska, D; Ast, J; Hasib, A; Cuozzo, F

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Diabetes Association
• Journal: Diabetes
• Volume: 72
• Issue: 2
• Pages: 275–289
• Publication date: 2022-11-29
• Acceptance date: 2022-11-14
• DOI: 10.2337/db22-0326
• EISSN: 1939-327X
• ISSN: 0012-1797
• Language: English
• Keywords: α cell; glucagon; alpha cell; FFR; GC-globulin; obesity; vitamin D-binding protein; type 2 diabetes