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1,25(OH)2D3 inhibits pancreatic stellate cells activation and promotes insulin secretion in T2DM

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Abstract

Purpose

To evaluate the effect and mechanism of 1,25(OH)2D3 on pancreatic stellate cells (PSCs) in type 2 diabetes mellitus (T2DM).

Methods

A mouse model of T2DM was successfully established by high-fat diet (HFD) /streptozotocin (STZ) and administered 1,25(OH)2D3 for 3 weeks. Fasting blood glucose (FBG), glycated hemoglobin A1c (GHbA1c), insulin (INS) and glucose tolerance were measured. Histopathology changes and fibrosis of pancreas were examined by hematoxylin and eosin staining and Masson staining. Mouse PSCs were extracted, co-cultured with mouse insulinoma β cells (MIN6 cells) and treated with 1,25(OH)2D3. ELISA detection of inflammatory factor expression. Tissue reactive oxygen species (ROS) levels were also measured. Immunofluorescence or Western blotting were used to measure fibrosis and inflammation-related protein expression.

Results

PSCs activation and islets fibrosis in T2DM mice. Elevated blood glucose was accompanied by significant increases in serum inflammatory cytokines and tissue ROS levels. 1,25(OH)2D3 attenuated islet fibrosis by reducing hyperglycemia, ROS levels, and inflammatory factors expression. Additionally, the co-culture system confirmed that 1,25(OH)2D3 inhibited PSCs activation, reduced the secretion of pro-inflammatory cytokines, down-regulated the expression of fibrosis and inflammation-related proteins, and promoted insulin secretion.

Conclusion

Our findings identify that PSCs activation contributes to islet fibrosis and β-cell dysfunction. 1,25(OH)2D3 exerts beneficial effects on T2DM potentially by inhibiting PSCs activation and inflammatory response, highlighting promising control strategies of T2DM by vitamin D.

Graphical Abstract

Fig. 7 Molecular mechanism of 1,25(OH)2D3 in β cell damage following PSCs activation in T2DM mice.

Highlights

  • PSCs activation leads to islet fibrosis in T2DM mice.

  • TGF- β, IL-1 β, TNF-α, ROS induce PSCs activation, thereby inhibiting MIN6 cell proliferation and function.

  • 1,25(OH)2D3 inhibits PSCs activation by downregulating the expression of factors such as TGF-β, protecting β cell function.

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Data Availability

No datasets were generated or analysed during the current study.

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Acknowledgements

Funding from the National Natural Science Foundation of China (grant numbers 31970505) is gratefully acknowledged.

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Author notes

  1. These authors contributed equally: Lewen Zhang, Xun Wei, Aiqing Wang

Authors and Affiliations

  1. Laboratory Animal Center of Suzhou Medical college, Soochow University, Suzhou, China

    Zhengyu Zhou, Lewen Zhang, Yudie Hu, Min Xiao & Yuxuan Zheng

  2. Center of Laboratory Animal, Shanghai Jiao Tong University, Shanghai, China

    Xun Wei

  3. Suzhou Medical college of Soochow University, Suzhou, China

    Aiqing Wang

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  1. Zhengyu Zhou
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Contributions

Conceptualization, Z.Z.; Data curation, X.W.; Formal analysis, X.W.; A.W.; Funding acquisition, Z.Z.; Investigation, L.Z., X.W. and Y.Z.; Methodology, X.W. and Z.Z.; Project administration, Z.Z.; Resources, X.W., Z.Z., and A.W.; Software, X.W.; Supervision, Z.Z.; Validation, L.Z., X.W., A.W., and Y.Z.; Visualization, L.Z., X.W. and A.W.; Writing – original draft, L.Z., X.W., Y.H., M.X., and Y.Z.; Writing – review & editing, L.Z., Y.H., M.X. A.W., and Z.Z. All authors reviewed the manuscript.

Corresponding author

Correspondence to Zhengyu Zhou.

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All of the experimental procedures involving animals were conducted in accordance with the Institutional Animal Care guidelines of Soochow University, China and approved by the Ethics Committee of Soochow University, Jiangsu Province, China.

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Zhou, Z., Zhang, L., Wei, X. et al. 1,25(OH)2D3 inhibits pancreatic stellate cells activation and promotes insulin secretion in T2DM. Endocrine (2024). https://doi.org/10.1007/s12020-024-03833-0

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