Filipowska Joanna, Cisneros Zelda, Leon-Rivera Nancy, Wang Peng, Kang Randy, Lu Geming, Yuan Yate-Ching, Bhattacharya Supriyo, Dhawan Sangeeta, Garcia-Ocaña Adolfo, Kondegowda Nagesha Guthalu, Vasavada Rupangi C
bioRxiv. 2024 May 14:2024.05.10.593645. doi: 10.1101/2024.05.10.593645.
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. , 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 -conditional knockout (cko) mice exhibit normal glucose homeostasis but increased β-cell death in both sexes and decreased proliferation only in females. Male cko mice under stress display reduced β-cell proliferation and a further increase in β-cell death. Upon aging, both male and female 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.
LGR4 receptor is critical for maintaining β-cell health under basal and stressed conditions, through suppression of RANK.
胰腺β细胞应激促进糖尿病进展。本研究表明，富含亮氨酸重复序列的G蛋白偶联受体4（LGR4）对维持β细胞健康至关重要，并受应激源调节。LGR4敲低会降低啮齿动物β细胞的增殖和存活率，而过表达则可保护啮齿动物和人类β细胞免受细胞因子诱导的细胞死亡。从机制上讲，LGR4抑制核因子κB受体激活剂（NFκB）（RANK）及其随后的NFκB激活，以保护β细胞。β细胞特异性LGR4条件性敲除（cko）小鼠表现出正常的葡萄糖稳态，但两性的β细胞死亡均增加，仅雌性的增殖减少。处于应激状态的雄性cko小鼠β细胞增殖减少，β细胞死亡进一步增加。衰老时，雄性和雌性cko小鼠均表现出β细胞稳态受损，然而，只有雌性小鼠出现葡萄糖不耐受且血浆胰岛素降低。我们表明，通过抑制RANK，LGR4是在基础和应激诱导条件下维持β细胞健康所必需的。
LGR4受体通过抑制RANK，在基础和应激条件下对维持β细胞健康至关重要。
