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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.
Original language | English |
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Pages (from-to) | 275-289 |
Number of pages | 15 |
Journal | Diabetes |
Volume | 72 |
Issue number | 2 |
Early online date | 29 Nov 2022 |
DOIs | |
Publication status | Published - Feb 2023 |
Bibliographical note
© 2023 by the American Diabetes Association.Keywords
- Animals
- Mice
- Diabetes Mellitus, Type 2/metabolism
- Globulins/metabolism
- Glucagon/metabolism
- Stress, Physiological
- Vitamin D-Binding Protein/genetics
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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.Projects
- 1 Finished
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Investigating the role of immature beta cells in insulin release from the intact islet
Nasteska, D. & Hodson, D.
1/08/19 → 30/11/22
Project: Research