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

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