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Theranostics 2018; 8(21):5960-5971. doi:10.7150/thno.28960 This issue Cite

Research Paper

Islet α-cell Inflammation Induced By NF-κB inducing kinase (NIK) Leads to Hypoglycemia, Pancreatitis, Growth Retardation, and Postnatal Death in Mice

Xinzhi Li1,2, Linna Jia1, Xiaoyue Chen1, Ying Dong1, Xiaomeng Ren1, Yuefan Dong1, Ying Chen1, Liwei Xie6, Ming Liu4, Chiyo Shiota5, George K. Gittes5, Liangyou Rui3, Zheng Chen2✉

1. Key Laboratory of Molecular Epigenetics of the Ministry of Education (MOE), School of Life Sciences, Northeast Normal University, Changchun, 130024, China
2. HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China
3. Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA
4. Department of endocrinology and metabolism, Tianjin Medical University General Hospital, Tianjin, China
5. Division of Pediatric Surgery, Department of Surgery, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, USA
6. State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangzhou 510070, China.

✉ Corresponding author: Zheng Chen, Ph.D. HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China, TEL: +86 45186402029 E-mail: chenzhengedu.cn

Citation:
Li X, Jia L, Chen X, Dong Y, Ren X, Dong Y, Chen Y, Xie L, Liu M, Shiota C, Gittes GK, Rui L, Chen Z. Islet α-cell Inflammation Induced By NF-κB inducing kinase (NIK) Leads to Hypoglycemia, Pancreatitis, Growth Retardation, and Postnatal Death in Mice. Theranostics 2018; 8(21):5960-5971. doi:10.7150/thno.28960. https://www.thno.org/v08p5960.htm
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Abstract

Graphic abstract

Islet α-cell dysfunction has been shown to contribute to type 2 diabetes; however, whether islet α-cell inflammation is involved in the occurrence of pancreatitis is largely unknown. The aims of this study were to investigate how NF-κB inducing kinase (NIK) regulates pancreatic α-cell function, both in vitro and in vivo, and to assess how islet α-cell inflammation induced by NIK affects the development of pancreatitis.

Methods: We utilized adenovirus-mediated NIK overexpression, ELISA, qPCR, RNA-seq, and Western blot analyses to study the role of NIK in islet α cells in vitro. Islet α-cell-specific NIK overexpressing (α-NIK-OE) mice were generated, and pancreatic α/β-cell function and the occurrence of pancreatitis in these mice were assessed via ELISA, qPCR, and immunohistochemical analyses.

Results: The LTβR/noncanonical NF-κB signaling pathway is present in islet α cells. Overexpression of NIK in αTC1-6 cells induces inflammation and cell death, contributing to a decrease in the expression and secretion of glucagon. Additionally, α-cell specific overexpression of NIK (α-NIK-OE) results in α-cell death, lower serum glucagon levels, and hypoglycemia in mice. Strikingly, α-NIK-OE mice also display a reduced β-cell mass, growth retardation, pancreatitis, and postnatal death.

Conclusions: Islet α-cell specific overexpression of NIK results in islet α-cell dysfunction and causes islet β-cell death and pancreatitis, which are most likely due to paracrine secretion of cytokines and chemokines from islet α cells, thus leading to hypoglycemia, growth retardation, and postnatal death in mice.

Keywords: islet α cell, NF-κB inducing kinase, inflammation, pancreatitis, chemokine

Citation styles

APA
Li, X., Jia, L., Chen, X., Dong, Y., Ren, X., Dong, Y., Chen, Y., Xie, L., Liu, M., Shiota, C., Gittes, G.K., Rui, L., Chen, Z. (2018). Islet α-cell Inflammation Induced By NF-κB inducing kinase (NIK) Leads to Hypoglycemia, Pancreatitis, Growth Retardation, and Postnatal Death in Mice. Theranostics, 8(21), 5960-5971. https://doi.org/10.7150/thno.28960.

ACS
Li, X.; Jia, L.; Chen, X.; Dong, Y.; Ren, X.; Dong, Y.; Chen, Y.; Xie, L.; Liu, M.; Shiota, C.; Gittes, G.K.; Rui, L.; Chen, Z. Islet α-cell Inflammation Induced By NF-κB inducing kinase (NIK) Leads to Hypoglycemia, Pancreatitis, Growth Retardation, and Postnatal Death in Mice. Theranostics 2018, 8 (21), 5960-5971. DOI: 10.7150/thno.28960.

NLM
Li X, Jia L, Chen X, Dong Y, Ren X, Dong Y, Chen Y, Xie L, Liu M, Shiota C, Gittes GK, Rui L, Chen Z. Islet α-cell Inflammation Induced By NF-κB inducing kinase (NIK) Leads to Hypoglycemia, Pancreatitis, Growth Retardation, and Postnatal Death in Mice. Theranostics 2018; 8(21):5960-5971. doi:10.7150/thno.28960. https://www.thno.org/v08p5960.htm

CSE
Li X, Jia L, Chen X, Dong Y, Ren X, Dong Y, Chen Y, Xie L, Liu M, Shiota C, Gittes GK, Rui L, Chen Z. 2018. Islet α-cell Inflammation Induced By NF-κB inducing kinase (NIK) Leads to Hypoglycemia, Pancreatitis, Growth Retardation, and Postnatal Death in Mice. Theranostics. 8(21):5960-5971.

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