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Cdk5 mediates impaired autophagy by regulating NGF/Sirt1 axis to cause diabetic islet β cell damage

Yuejia Tao1,2, Yipeng Liu3, Shijie Hou4

  • 1Department of Pathology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Nephrology, Shandong Lung Cancer Institute, Jinan, China.

Frontiers in Cell and Developmental Biology
|November 3, 2025
PubMed

Insights

Cyclin-dependent kinase 5 (Cdk5) activation worsens diabetes by damaging islet beta cells and impairing autophagy. Inhibiting Cdk5 protects these cells, suggesting the Cdk5-NGF/Sirt1 pathway is a potential diabetes treatment target.

Area of Science:

  • Endocrinology
  • Cell Biology
  • Metabolic Diseases

Background:

  • Diabetes mellitus is a growing global health concern.
  • Islet beta cell damage is a key factor in diabetes development.
  • The role of cyclin-dependent kinase 5 (Cdk5) in diabetes pathogenesis is not fully understood.

Purpose of the Study:

  • To investigate the specific role of Cdk5 in diabetic islet beta cell injury.
  • To elucidate the molecular mechanisms underlying Cdk5-mediated beta cell dysfunction.

Main Methods:

  • Examined Cdk5 expression in islet beta cells under diabetic conditions.
  • Assessed the impact of Cdk5 inhibition on beta cell injury and autophagy.
  • Investigated the relationship between nerve growth factor (NGF), Sirtuin 1 (Sirt1), and autophagy.
  • Utilized a mouse model to evaluate the therapeutic potential of targeting the Cdk5-NGF/Sirt1 axis.

Main Results:

  • Cdk5 is upregulated in islet beta cells in diabetes, leading to impaired autophagy and cell injury.
  • High glucose conditions reduce NGF and Sirt1 levels; NGF positively regulates Sirt1 and restores autophagy.
  • Inhibition of Cdk5 mitigates high glucose-induced beta cell injury in mice.
  • The NGF inhibitor K252a reversed the protective effects of Cdk5 inhibition.

Conclusions:

  • Cdk5 negatively regulates the NGF/Sirt1 pathway, causing impaired autophagy and dysfunction in islet beta cells under high glucose.
  • The Cdk5-NGF/Sirt1 axis represents a novel therapeutic target for managing diabetes and preventing beta cell damage.
Keywords:
Cdk5NGFSirt1autophagydiabetes

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