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Aims/hypothesis <p>Clinical studies revealed that serum spexin level is positively associated with beta cell function. However, the role of spexin in beta cells remains unclear. We hypothesise that spexin treatment could influence beta cell function and modulate glucose homeostasis in vivo.</p> Methods <p>We analysed glucose-stimulated insulin secretion (GSIS) and beta cell proliferation in mice and isolated mouse islets. Using mice fed a high-fat diet (HFD) and an HFD/streptozocin (STZ)-induced diabetes mouse model, we investigated the effects of spexin on glucose homeostasis and beta cell function. We performed a pull-down/MS assay and a cell-based binding assay to identify the binding partner of spexin on the beta cell surface. An ion pump activity assay and <i>Atp1a1</i><sup>+/−</sup> mice were used to explore the underlying regulatory mechanisms. The effects of spexin on beta cell function were further measured on isolated human islets.</p> Results <p>We observed that spexin treatment increased GSIS in chow-diet-fed mice and isolated mouse islets. Spexin treatment also promoted beta cell proliferation in mouse islets and pancreatectomised mice. Furthermore, spexin treatment improved glucose tolerance in HFD-fed mice and attenuated hyperglycaemia in an HFD/STZ-induced diabetes mouse model, along with an elevated serum insulin level and increased beta cell proliferation. Spexin showed specific binding to the beta cell surface. The pull-down/MS assay demonstrated that spexin bound to the α1 subunit of sodium–potassium ATPase (ATP1A1), resulting in pump activity inhibition and subsequent membrane depolarisation. In <i>Atp1a1</i><sup>+/−</sup> mice, which had 50% lower levels of ATP1A1, the effects of spexin on GSIS, beta cell proliferation and hyperglycaemia decreased. Importantly, spexin-treated human islets showed increased GSIS and proliferation.</p> Conclusions/interpretation <p>Our study highlights that spexin is a stimulatory factor for beta cell function and proliferation, and suggests that spexin is a diabetes therapeutic target for beta cell intervention.</p> Graphical Abstract <p></p>

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Peptide hormone spexin restores beta cell function and improves glycaemic control in mice via regulation of the sodium–potassium pump

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月8日

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  • Yaojing Jiang,
  • Di Wu,
  • Yunzhi Ni,
  • Ying Liu,
  • Huixia Ren,
  • Shan Liu,
  • Chengfang Pan,
  • Jiarong Dai,
  • Quanya Sun,
  • Anran Ma,
  • Ge Qin,
  • Jiali Qian,
  • Lijin Ji,
  • Hangping Zheng,
  • Chao Tang,
  • Yehong Yang,
  • Changlong Hu,
  • Hao Yin,
  • Yiming Li,
  • Rui Liu

摘要

Aims/hypothesis

Clinical studies revealed that serum spexin level is positively associated with beta cell function. However, the role of spexin in beta cells remains unclear. We hypothesise that spexin treatment could influence beta cell function and modulate glucose homeostasis in vivo.

Methods

We analysed glucose-stimulated insulin secretion (GSIS) and beta cell proliferation in mice and isolated mouse islets. Using mice fed a high-fat diet (HFD) and an HFD/streptozocin (STZ)-induced diabetes mouse model, we investigated the effects of spexin on glucose homeostasis and beta cell function. We performed a pull-down/MS assay and a cell-based binding assay to identify the binding partner of spexin on the beta cell surface. An ion pump activity assay and Atp1a1+/− mice were used to explore the underlying regulatory mechanisms. The effects of spexin on beta cell function were further measured on isolated human islets.

Results

We observed that spexin treatment increased GSIS in chow-diet-fed mice and isolated mouse islets. Spexin treatment also promoted beta cell proliferation in mouse islets and pancreatectomised mice. Furthermore, spexin treatment improved glucose tolerance in HFD-fed mice and attenuated hyperglycaemia in an HFD/STZ-induced diabetes mouse model, along with an elevated serum insulin level and increased beta cell proliferation. Spexin showed specific binding to the beta cell surface. The pull-down/MS assay demonstrated that spexin bound to the α1 subunit of sodium–potassium ATPase (ATP1A1), resulting in pump activity inhibition and subsequent membrane depolarisation. In Atp1a1+/− mice, which had 50% lower levels of ATP1A1, the effects of spexin on GSIS, beta cell proliferation and hyperglycaemia decreased. Importantly, spexin-treated human islets showed increased GSIS and proliferation.

Conclusions/interpretation

Our study highlights that spexin is a stimulatory factor for beta cell function and proliferation, and suggests that spexin is a diabetes therapeutic target for beta cell intervention.

Graphical Abstract