Abstract
SummaryVitamin-D-binding protein (DBP) or group-specific component of serum (GC-globulin) carries vitamin D metabolites from the circulation to target tissues. DBP is highly localized to the liver and pancreatic α cells. Although DBP serum levels, gene polymorphisms, and autoantigens have all been associated with diabetes risk, the underlying mechanisms remain unknown. Here, we show that DBP regulates α cell morphology, α cell function, and glucagon secretion. Deletion of DBP leads to smaller and hyperplastic α cells, altered Na+ channel conductance, impaired α cell activation by low glucose, and reduced rates of glucagon secretion both in vivo and in vitro. Mechanistically, this involves reversible changes in islet microfilament abundance and density, as well as changes in glucagon granule distribution. Defects are also seen in β cell and δ cell function. Immunostaining of human pancreata reveals generalized loss of DBP expression as a feature of late-onset and long-standing, but not early-onset, type 1 diabetes. Thus, DBP regulates α cell phenotype, with implications for diabetes pathogenesis.
Highlights
Vitamin-D-binding protein (DBP), a 52- to 59-kDa protein known as group-specific component of serum (GC-globulin), is the primary plasma carrier for circulating vitamin D and its metabolites (White and Cooke, 2000)
We show that DBP contributes to proper a cell function and glucagon secretion, with related effects for d cell morphology and insulin release
DBP expression was clearly decreased in DBPÀ/À animals (% area DBP expression = 10.75% ± 2.05% versus 1.60% ± 0.36%, DBP+/+ versus DBPÀ/À, respectively; p < 0.01; Mann-Whitney test), a very faint signal could still be detected in the cytoplasm of some a cells using fluorescent immunohistochemistry (Figure 1A)
Summary
Vitamin-D-binding protein (DBP), a 52- to 59-kDa protein known as group-specific component of serum (GC-globulin), is the primary plasma carrier for circulating vitamin D and its metabolites (White and Cooke, 2000). Because the GC promoter region contains celltype-selective open chromatin regions, GC can be classified as an a cell signature gene, to prototypical hits, such as ARX, glucagon (GCG), IRX2, and DPP4 (Ackermann et al, 2016; Lam et al, 2019). Despite these findings, the role of DBP in the regulation of islet function and glucagon release remains enigmatic
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