Vitamin D binding protein/GC-globulin: a novel regulator of alpha cell function and glucagon secretion

J Physiol. 2022 Mar;600(5):1119-1133. doi: 10.1113/JP280890. Epub 2021 May 1.


The contribution of glucagon to type 1 and type 2 diabetes has long been known, but the underlying defects in alpha cell function are not well-described. During both disease states, alpha cells respond inappropriately to stimuli, leading to dysregulated glucagon secretion, impaired glucose tolerance and hypoglycaemia. The mechanisms involved in this dysfunction are complex, but possibly include changes in alpha cell glucose-sensing, alpha cell de-differentiation, paracrine feedback, as well as alpha cell mass. However, the molecular underpinnings of alpha cell failure are still poorly understood. Recent transcriptomic analyses have identified vitamin D binding protein (DBP), encoded by GC/Gc, as an alpha cell signature gene. DBP is highly localized to the liver and alpha cells and is virtually absent from other tissues and cell types under non-pathological conditions. While the vitamin D transportation role of DBP is well characterized in the liver and circulation, its function in alpha cells remains more enigmatic. Recent work reveals that loss of DBP leads to smaller and hyperplastic alpha cells, which secrete less glucagon in response to low glucose concentration, despite vitamin D sufficiency. Alpha cells lacking DBP display impaired Ca2+ fluxes and Na+ conductance, as well as changes in glucagon granule distribution. Underlying these defects is an increase in the ratio of cytoskeletal F-actin to G-actin, highlighting a novel intracellular actin scavenging role for DBP in islets.

Keywords: GC; GC-globulin; alpha cell; glucagon; metabolism; type 1 diabetes; type 2 diabetes; vitamin D; vitamin D-binding protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Diabetes Mellitus, Type 2*
  • Globulins* / metabolism
  • Glucagon
  • Glucose
  • Humans
  • Vitamin D / metabolism
  • Vitamin D-Binding Protein / genetics
  • Vitamin D-Binding Protein / metabolism


  • Actins
  • Globulins
  • Vitamin D-Binding Protein
  • Vitamin D
  • Glucagon
  • Glucose