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PICK1 is essential for insulin production and the maintenance of glucose homeostasis

Protein interacting with C-kinase 1 (PICK1) is a peripheral membrane protein that controls insulin granule formation, trafficking, and maturation in INS-1E cells. However, global Pick1-knockout mice showed only a subtle diabetes-like phenotype. This raises the possibility that compensatory effects f...

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Detalles Bibliográficos
Autores principales: Li, Jia, Mao, Zhuo, Huang, Jiandong, Xia, Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004578/
https://www.ncbi.nlm.nih.gov/pubmed/29298842
http://dx.doi.org/10.1091/mbc.E17-03-0204
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author Li, Jia
Mao, Zhuo
Huang, Jiandong
Xia, Jun
author_facet Li, Jia
Mao, Zhuo
Huang, Jiandong
Xia, Jun
author_sort Li, Jia
collection PubMed
description Protein interacting with C-kinase 1 (PICK1) is a peripheral membrane protein that controls insulin granule formation, trafficking, and maturation in INS-1E cells. However, global Pick1-knockout mice showed only a subtle diabetes-like phenotype. This raises the possibility that compensatory effects from tissues other than pancreatic beta cells may obscure the effects of insulin deficiency. To explore the role of PICK1 in pancreatic islets, we generated mice harboring a conditional Pick1 allele in a C57BL/6J background. The conditional Pick1-knockout mice exhibited impaired glucose tolerance, profound insulin deficiency, and hyperglycemia. In vitro experiments showed that the ablation of Pick1 in pancreatic beta cells selectively decreased the initial rapid release of insulin and the total insulin levels in the islets. Importantly, the specific ablation of Pick1 induced elevated proinsulin levels in the circulation and in the islets, accompanied by a reduction in the proinsulin processing enzymes prohormone convertase 1/3 (PC1/3). The deletion of Pick1 triggered the specific elimination of chromogranin B in pancreatic beta cells, which is believed to control granule formation and release. Collectively, these data demonstrate the critical role of PICK1 in secretory granule biogenesis, proinsulin processing, and beta cell function. We conclude that the beta cell–specific deletion of Pick1 in mice led to hyperglycemia and eventually to diabetes.
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spelling pubmed-60045782018-06-19 PICK1 is essential for insulin production and the maintenance of glucose homeostasis Li, Jia Mao, Zhuo Huang, Jiandong Xia, Jun Mol Biol Cell Articles Protein interacting with C-kinase 1 (PICK1) is a peripheral membrane protein that controls insulin granule formation, trafficking, and maturation in INS-1E cells. However, global Pick1-knockout mice showed only a subtle diabetes-like phenotype. This raises the possibility that compensatory effects from tissues other than pancreatic beta cells may obscure the effects of insulin deficiency. To explore the role of PICK1 in pancreatic islets, we generated mice harboring a conditional Pick1 allele in a C57BL/6J background. The conditional Pick1-knockout mice exhibited impaired glucose tolerance, profound insulin deficiency, and hyperglycemia. In vitro experiments showed that the ablation of Pick1 in pancreatic beta cells selectively decreased the initial rapid release of insulin and the total insulin levels in the islets. Importantly, the specific ablation of Pick1 induced elevated proinsulin levels in the circulation and in the islets, accompanied by a reduction in the proinsulin processing enzymes prohormone convertase 1/3 (PC1/3). The deletion of Pick1 triggered the specific elimination of chromogranin B in pancreatic beta cells, which is believed to control granule formation and release. Collectively, these data demonstrate the critical role of PICK1 in secretory granule biogenesis, proinsulin processing, and beta cell function. We conclude that the beta cell–specific deletion of Pick1 in mice led to hyperglycemia and eventually to diabetes. The American Society for Cell Biology 2018-03-01 /pmc/articles/PMC6004578/ /pubmed/29298842 http://dx.doi.org/10.1091/mbc.E17-03-0204 Text en © 2018 Li et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. http://creativecommons.org/licenses/by-nc-sa/3.0/ This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License.
spellingShingle Articles
Li, Jia
Mao, Zhuo
Huang, Jiandong
Xia, Jun
PICK1 is essential for insulin production and the maintenance of glucose homeostasis
title PICK1 is essential for insulin production and the maintenance of glucose homeostasis
title_full PICK1 is essential for insulin production and the maintenance of glucose homeostasis
title_fullStr PICK1 is essential for insulin production and the maintenance of glucose homeostasis
title_full_unstemmed PICK1 is essential for insulin production and the maintenance of glucose homeostasis
title_short PICK1 is essential for insulin production and the maintenance of glucose homeostasis
title_sort pick1 is essential for insulin production and the maintenance of glucose homeostasis
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004578/
https://www.ncbi.nlm.nih.gov/pubmed/29298842
http://dx.doi.org/10.1091/mbc.E17-03-0204
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