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Thiazolidinediones protect mouse pancreatic β-cells directly from cytokine-induced cytotoxicity through PPARγ-dependent mechanisms

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Abstract

Since most of the current studies of thiazolidinediones (TZDs) are only focused on improving glycemic control, increasing insulin sensitivity, and regulating inflammatory states in Type 2 Diabetes, it is still controversial whether TZDs have direct, protective effects on pancreatic β-cells in autoimmune diabetes. Here, we show the protective effects of TZDs on mouse pancreatic β-cell line cells (NIT-1) impaired by exposure to inflammatory cytokines (IL-1β and IFN-γ) and explore the potential mechanisms for this. The apoptosis rate and caspase-3 activity were remarkably increased, and insulin secretion response to glucose was impaired severely by exposure to IL-1β/IFN-γ for 48 h compared to control cells, whereas apoptosis rate and caspase-3 activity were significantly decreased in cells with treatment of rosiglitazone (RGZ) or pioglitazone (PIG), and the capacity for insulin secretion response to glucose was recovered. TZDs protect pancreatic β-cells from cytokine-induced cytotoxicity through PPARγ activation. The protective effects of the TZDs on NIT-1 cells disappeared when PPARγ was blocked with PPARγ-siRNA interference or treatment with GW9662, the PPARγ antagonist. Additionally, the enhancement of PPARγ expression by treatment with TZDs inhibited the expression of caspase 3 in IL-1β/IFN-γ-induced NIT-cells. Also, the inhibition of caspase 3 expression by TZDs was blocked by co-treatment with GW9662 or infection with PPARγ-siRNA. Taken together, our data suggest that TZDs might serve to protect pancreatic β-cells directly from cytokine-induced cytotoxicity through a PPARγ-dependent pathway, and caspase-3 may play an important role in the mechanisms involved.

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Acknowledgments

This study was supported by grants from National Natural Science Foundation of China (30600298, 30670991), National 973 Project (2006CB503901) and two project of Natural Science Foundation of Hunan province (08JJ4007, 06JJ2086). We would like to thank all the participants in the study. We gratefully acknowledge Prof. Xiao Han (School Of Basic Medical Sciences, Nanjing Medical University, China) for his kindly provide of NIT-1 cells line.

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Authors and Affiliations

  1. Diabetes Center, Metabolic Syndrome Research Center, Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China

    An-ping Wang, Xia Li, Ying Zheng, Bi-lian Liu, Gan Huang, Xiang Yan & Zhiguang Zhou

  2. Metabolism Syndrome Research Center, Second Xiangya Hospital, Central South University, Changsha, Hunan, China

    Bi-lian Liu

  3. Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA, USA

    Zhenqi Liu

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  1. An-ping Wang
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  2. Xia Li
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Correspondence to Zhiguang Zhou.

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An-ping Wang and Xia Li contributed equally to this work.

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Wang, Ap., Li, X., Zheng, Y. et al. Thiazolidinediones protect mouse pancreatic β-cells directly from cytokine-induced cytotoxicity through PPARγ-dependent mechanisms. Acta Diabetol 50, 163–173 (2013). https://doi.org/10.1007/s00592-010-0239-8

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