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<p>Insulin deficiency from β-cell dysfunction underpins both type 1 and type 2 diabetes. However, the regulatory pathways underlying β-cell function remain incompletely understood. Here, we identify that March5 and Trim28 as key modulators of β-cell function. March5 is downregulated and Trim28 upregulated in islets from human or mouse with impaired glucose tolerance. Loss of March5 in β-cells impairs insulin production and glucose tolerance, while its overexpression improves both. Mechanistically, March5 inhibits Trim28 by targeting it for ubiquitination, thereby preventing Trim28-mediated Kindlin-2 degradation, which elevates MafA and insulin expression in male mice. Trim28 deletion in β-cells rescues glucose intolerance in March5-deficient male mice, highlighting their joint regulatory pathway. Furthermore, <i>March5</i> and <i>Kindlin-2</i> double haploinsufficiency significantly impair insulin production and glucose tolerance, underscoring their shared pathway. Importantly, islet transplantation with March5-overexpressing or Trim28-deficient β-cells effectively ameliorates glucose intolerance in streptozotocin-induced diabetic male mice. In conclusion, our results suggest that targeting the March5/Trim28/Kindlin-2/MafA pathway may offer a promising therapeutic strategy to restore β-cell function in diabetes.</p>

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March5-mediated Trim28 degradation preserves islet β-cell function in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月1日

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  • Yangshan Chen,
  • Wei Pang,
  • Guixing Ma,
  • Yongcong Yan,
  • Zhiyu Xiao,
  • Yong Chen,
  • Zhen Ding,
  • Litong Chen,
  • Xiaoting Hou,
  • Huiling Cao

摘要

Insulin deficiency from β-cell dysfunction underpins both type 1 and type 2 diabetes. However, the regulatory pathways underlying β-cell function remain incompletely understood. Here, we identify that March5 and Trim28 as key modulators of β-cell function. March5 is downregulated and Trim28 upregulated in islets from human or mouse with impaired glucose tolerance. Loss of March5 in β-cells impairs insulin production and glucose tolerance, while its overexpression improves both. Mechanistically, March5 inhibits Trim28 by targeting it for ubiquitination, thereby preventing Trim28-mediated Kindlin-2 degradation, which elevates MafA and insulin expression in male mice. Trim28 deletion in β-cells rescues glucose intolerance in March5-deficient male mice, highlighting their joint regulatory pathway. Furthermore, March5 and Kindlin-2 double haploinsufficiency significantly impair insulin production and glucose tolerance, underscoring their shared pathway. Importantly, islet transplantation with March5-overexpressing or Trim28-deficient β-cells effectively ameliorates glucose intolerance in streptozotocin-induced diabetic male mice. In conclusion, our results suggest that targeting the March5/Trim28/Kindlin-2/MafA pathway may offer a promising therapeutic strategy to restore β-cell function in diabetes.