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Rosiglitazone protects against palmitate-induced pancreatic beta-cell death by activation of autophagy via 5′-AMP-activated protein kinase modulation

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Abstract

Promoting beta-cell survival is crucial for the prevention of beta-cell failure in diabetes. Thiazolidinediones, a widely used drug to improve insulin sensitivity in clinical practice, is found to have a protective effect on islet beta-cell. To date, the mechanism underlying the protective role of thiazolidinedione on beta-cell survival remain largely unknown. Activation of autophagy was detected by transmission electron microscopy, western blot, and GFP-LC3 transfection. Cell viability was examined by WST-8. Cell apoptosis was demonstrated by DAPI and Annexin V/PI staining. Colony formation assay was used to detect long-term cell viability. We demonstrated that rosiglitazone-treated beta-cells were more resistant to palmitate-induced apoptosis. The conversion of LC3-I to LC3-II and accumulated autophagosomes were found to be upregulated in rosiglitazone-treated cells. Inhibition of autophagy augmented palmitate-induced apoptosis with rosiglitazone treatment, suggesting that autophagy plays an important role in the survival function of rosiglitazone on beta-cells. Furthermore, we showed that rosiglitazone could induce AMP-activated protein kinase (AMPK) phosphorylation and reduce p70S6 kinase phosphorylation. Inhibition of AMPK impaired autophagy activation and enhanced palmitate-induced apoptosis during rosiglitazone treatment. These findings reveal that rosiglitazone-induced autophagy contributes to its protective function on beta-cells during palmitate treatment.

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Abbreviations

AMPK:

AMP-activated protein kinase

TEM:

Transmission electron microscopy

CQ:

Chloroquine

3-MA:

3-Methyladenine

TZDs:

Thiazolidinediones

PPAR-γ:

Peroxisome proliferator-activated receptor-γ

LC3:

Microtubule associated protein 1 light chain 3

DAPI:

4′,6′-Diamidino-2-phenylindole dihydrochloride

MAPK:

Mitogen-activated protein kinases

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Acknowledgments

This project was supported by the Special Funds for National Natural Science Foundation of China (Grant No. 81070619), the Commission of Science and Technology of Shanghai Municipality (No. 08411967100).

Conflict of interest

We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of the manuscript entitled.

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Authors and Affiliations

  1. Department of Endocrinology, Chang Hai Hospital, The Second Military Medical University, 168 Changhai Road, Shanghai, 200438, People’s Republic of China

    Jie Wu & Da-jin Zou

  2. Department of Endocrinology, Tong Ji Hospital, Tong Ji University, Shanghai, People’s Republic of China

    Jie Wu

  3. National Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, People’s Republic of China

    Jun-jie Wu

  4. Department of Oncology, Chang Hai Hospital, The Second Military Medical University, Shanghai, People’s Republic of China

    Lin-jun Yang

  5. Department of Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, People’s Republic of China

    Li-xin Wei

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  1. Jie Wu
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Correspondence to Da-jin Zou.

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Jie Wu and Jun-jie Wu have contributed equally to this study.

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Wu, J., Wu, Jj., Yang, Lj. et al. Rosiglitazone protects against palmitate-induced pancreatic beta-cell death by activation of autophagy via 5′-AMP-activated protein kinase modulation. Endocrine 44, 87–98 (2013). https://doi.org/10.1007/s12020-012-9826-5

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