Journal of diabetes investigation · 2026
Neuregulin 4-dependent MAPK amplification mediates urate-induced β-cell dysfunction.
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Wang Yunyang, Zhang Kun, Li Zhiyuan, Hu Shuhui, Zhang Yiru, Zhao Yulei, Liu Xiaohan, Lu Jie
Аннотация
BACKGROUND AND OBJECTIVES: Clinical research indicates an association between hyperuricemia (HU) and diabetes; however, the precise impact of soluble serum urate on glucose metabolism is still unclear. Using a novel spontaneous HU mouse model, this study seeks to characterize glucose metabolism and elucidate the associated molecular mechanisms.
METHODS: We employed targeted disruption of the Uricase (Uox) gene and established an original mouse model exhibiting a robust spontaneous HU phenotype. To seek the candidate gene(s) in the proapoptosis process in pancreatic β cells, we analyzed the microarray data of the isolated islets from Uox knockout (KO) mice and wild-type counterparts. Apoptosis levels and expression of associated proteins in MIN6 cells transfected with candidate siRNA were quantified by flow cytometry and Western blotting, respectively.
RESULTS: Male Uox-KO mice exhibited glucose intolerance without concomitant insulin resistance. TUNEL staining showed an elevated apoptosis level in pancreatic tissues of male Uox-KO mice. Microarray analysis identified neuregulin-4 (Nrg4) as a potential mediator of hyperuricemia (HU)-induced β-cell apoptosis. In vitro studies using the mouse β-cell line MIN6 demonstrated that urate upregulates Nrg4 expression and triggers apoptosis, with Nrg4 being essential for urate-induced cell death. Mechanistically, urate promotes pancreatic β-cell apoptosis by elevating Nrg4, which subsequently amplifies urate-induced mitogen-activated protein kinase (MAPK) activation.
CONCLUSION: Our findings collectively establish that HU disrupts glucose homeostasis and induces pancreatic β-cell apoptosis via Nrg4 upregulation and subsequent amplification of the MAPK signaling cascade.
METHODS: We employed targeted disruption of the Uricase (Uox) gene and established an original mouse model exhibiting a robust spontaneous HU phenotype. To seek the candidate gene(s) in the proapoptosis process in pancreatic β cells, we analyzed the microarray data of the isolated islets from Uox knockout (KO) mice and wild-type counterparts. Apoptosis levels and expression of associated proteins in MIN6 cells transfected with candidate siRNA were quantified by flow cytometry and Western blotting, respectively.
RESULTS: Male Uox-KO mice exhibited glucose intolerance without concomitant insulin resistance. TUNEL staining showed an elevated apoptosis level in pancreatic tissues of male Uox-KO mice. Microarray analysis identified neuregulin-4 (Nrg4) as a potential mediator of hyperuricemia (HU)-induced β-cell apoptosis. In vitro studies using the mouse β-cell line MIN6 demonstrated that urate upregulates Nrg4 expression and triggers apoptosis, with Nrg4 being essential for urate-induced cell death. Mechanistically, urate promotes pancreatic β-cell apoptosis by elevating Nrg4, which subsequently amplifies urate-induced mitogen-activated protein kinase (MAPK) activation.
CONCLUSION: Our findings collectively establish that HU disrupts glucose homeostasis and induces pancreatic β-cell apoptosis via Nrg4 upregulation and subsequent amplification of the MAPK signaling cascade.