LGR4 is essential for maintaining beta-cell homeostasis through suppression of RANK

Abstract

Pancreatic {beta}-cell stress contributes to diabetes progression. This study demonstrates that Leucine-rich repeat-containing G-protein-coupled-receptor-4 (LGR4) is critical for maintaining {beta}-cell health and is modulated by stressors. In vitro, Lgr4 knockdown decreases proliferation and survival in rodent {beta}-cells, while overexpression protects against cytokine-induced cell death in rodent and human {beta}-cells. Mechanistically, LGR4 suppresses Receptor Activator of Nuclear Factor Kappa B (NF{kappa}B) (RANK) and its subsequent activation of NF{kappa}B to protect {beta}-cells. {beta}-cell-specific Lgr4-conditional knockout (cko) mice exhibit normal glucose homeostasis but increased {beta}-cell death in both sexes and decreased proliferation only in females. Male Lgr4cko mice under stress display reduced {beta}-cell proliferation and a further increase in {beta}-cell death. Upon aging, both male and female Lgr4cko mice display impaired {beta}-cell homeostasis, however, only female mice are glucose intolerant with decreased plasma insulin. We show that LGR4 is required for maintaining {beta}-cell health under basal and stress-induced conditions, through suppression of RANK. TeaserLGR4 receptor is critical for maintaining {beta}-cell health under basal and stressed conditions, through suppression of RANK.