ArticleJournal of diabetes investigation2026
Neuregulin 4-dependent MAPK amplification mediates urate-induced β-cell dysfunction.
Article in Journal of diabetes investigation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
BACKGROUND AND
objectivesClinical 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.
methodsWe 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.
resultsMale 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.
conclusionOur 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.
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