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Bilirubin Improves the Quality and Function of Hypothermic Preserved Islets by Its Antioxidative and Anti-inflammatory Effect

Yao, Qing PhD1; Jiang, Xue BS1; Huang, Zhi-Wei BS; Lan, Qing-Hua BS1; Wang, Li-Fen BS1; Chen, Rui BS1; Li, Xin-Ze BS1; Kou, Longfa PhD1; Xu, He-Lin PhD1; Zhao, Ying-Zheng PhD1

doi: 10.1097/TP.0000000000002882
Original Basic Science—General
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Background. Islet transplantation is a promising option for the treatment of type 1 diabetes. However, the current lack of practical techniques for the isolated islets preservation still hampers the advancement of life-saving islet transplantation. Islet suffers from internal or external stimuli–induced oxidative stress and subsequent inflammation during preservation, which leads to disappointing outcomes regarding islet yield, survival, and function. Reactive oxygen species (ROS) overproduction is the primary cause of oxidative stress that induces islet loss and dysfunction. Thus, in this article, we hypothesized that an endogenous antioxidant, bilirubin, that could efficiently scavenge ROS and inhibit inflammatory reactions could be beneficial for islet preservation.

Methods. Herein, we studied the effect of bilirubin on the hypothermic preserved (4°C) islets and evaluate the islets viability, insulin secretory function, oxidative stress levels, and in vivo transplantation performance.

Results. Bilirubin could prevent cellular damages during short-term preservation and maintain the cocultured islets viability and function. The protective role of bilirubin is associated with its antioxidative ability, which dramatically increased the activities of antioxidant enzymes (superoxide dismutase and glutathione peroxidase) and decreased the levels of ROS and malondialdehyde. Diabetic mice transplanted with bilirubin preserved islets were normoglycemic for 28 days, even overmatched the diabetic mouse transplanted with fresh islets. Mice receiving bilirubin cocultured islets required the least time to achieve normoglycemia among all groups and exhibited minimum inflammatory responses during the early transplantation stage.

Conclusions. By utilizing bilirubin, we achieved highly viable and functional islets after hypothermic preservation to reverse diabetes in mice.

1 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China.

Received 14 April 2019. Revision received 27 June 2019.

Accepted 4 July 2019.

Q.Y. and X.J. contributed equally to this project. Q.Y. and Y.-Z.Z. conceived the idea and designed and supervised the project. Q.Y. and X.J. performed most research and analyzed data. Z.-W.H. and Q.-H.L. developed the diabetic mouse model and participated in most animal study. L.-F.W., R.C., and X.-Z.L. helped with islet collection and cell study. Q.Y., L.K., H.-L.X., and Y.-Z.Z. wrote the manuscript.

The authors declare no conflicts of interest.

This research was supported by the Key Research and Development Program of Zhejiang Province (Grant No. 2018C03013), Zhejiang Province Natural Science Foundation (Grant No. LQ19H300001, LY19H180001, and LY17H180008), Zhejiang provincial program for the cultivation of high-level innovative health talents (Y.-Z.Z.), 151 talent project of Zhejiang province and 551 talent projects of Wenzhou (Y.-Z.Z.), Wenzhou Science and Technology Project (Grant No. Y20190177) and School Talent Start Fund of Wenzhou Medical University (Grant No. QTJ15020).

Correspondence: Ying-Zheng Zhao, PhD, Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China. (zyzpharm@163.com).

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