Vitamin D-binding protein is required for the maintenance of α-cell function and glucagon secretion

Vitamin D-binding protein (DBP) or GC-globulin carries vitamin D metabolites from the circulation to target tissues. DBP expression is highly-localized to the liver and pancreatic -cells. While 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 -cell morphology, -cell function and glucagon secretion. Deletion of DBP led to smaller and hyperplastic -cells, altered Na+ channel conductance, impaired -cell activation by low glucose, and reduced rates of glucagon secretion. Mechanistically, this involved reversible changes in islet microfilament abundance and density, as well as changes in glucagon granule distribution. Defects were also seen in {beta}-cell and {delta}-cell function. Immunostaining of human pancreata revealed generalized loss of DBP expression as a feature of late-onset and longstanding, but not early-onset type 1 diabetes. Thus, DBP is a critical regulator of -cell phenotype, with implications for diabetes pathogenesis. HIGHLIGHTSO_LIDBP expression is highly-localized to mouse and human -cells C_LIO_LILoss of DBP increases -cell number, but decreases -cell size C_LIO_LI-cells in DBP knockout islets are dysfunctional and secrete less glucagon C_LIO_LIDBP expression is decreased in -cells of donors with late-onset or longstanding type 1 diabetes C_LI