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Targeted Inactivation of Kinesin-1 in Pancreatic β-Cells In Vivo Leads to Insulin Secretory Deficiency

OBJECTIVE: Suppression of Kinesin-1 by antisense oligonucleotides, or overexpression of dominant-negative acting kinesin heavy chain, has been reported to affect the sustained phase of glucose-stimulated insulin secretion in β-cells in vitro. In this study, we examined the in vivo physiological role...

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Autores principales: Cui, Ju, Wang, Zai, Cheng, Qianni, Lin, Raozhou, Zhang, Xin-Mei, Leung, Po Sing, Copeland, Neal G., Jenkins, Nancy A., Yao, Kwok-Ming, Huang, Jian-Dong
Formato: Texto
Lenguaje:English
Publicado: American Diabetes Association 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3012189/
https://www.ncbi.nlm.nih.gov/pubmed/20870970
http://dx.doi.org/10.2337/db09-1078
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author Cui, Ju
Wang, Zai
Cheng, Qianni
Lin, Raozhou
Zhang, Xin-Mei
Leung, Po Sing
Copeland, Neal G.
Jenkins, Nancy A.
Yao, Kwok-Ming
Huang, Jian-Dong
author_facet Cui, Ju
Wang, Zai
Cheng, Qianni
Lin, Raozhou
Zhang, Xin-Mei
Leung, Po Sing
Copeland, Neal G.
Jenkins, Nancy A.
Yao, Kwok-Ming
Huang, Jian-Dong
author_sort Cui, Ju
collection PubMed
description OBJECTIVE: Suppression of Kinesin-1 by antisense oligonucleotides, or overexpression of dominant-negative acting kinesin heavy chain, has been reported to affect the sustained phase of glucose-stimulated insulin secretion in β-cells in vitro. In this study, we examined the in vivo physiological role of Kinesin-1 in β-cell development and function. RESEARCH DESIGN AND METHODS: A Cre-LoxP strategy was used to generate conditional knockout mice in which the Kif5b gene is specifically inactivated in pancreatic β-cells. Physiological and histological analyses were carried out in Kif5b knockout mice as well as littermate controls. RESULTS: Mice with β-cell specific deletion of Kif5b (Kif5b(fl/−):RIP2-Cre) displayed significantly retarded growth as well as slight hyperglycemia in both nonfasting and 16-h fasting conditions compared with control littermates. In addition, Kif5b(fl/−):RIP2-Cre mice displayed significant glucose intolerance, which was not due to insulin resistance but was related to an insulin secretory defect in response to glucose challenge. These defects of β-cell function in mutant mice were not coupled with observable changes in islet morphology, islet cell composition, or β-cell size. However, compared with controls, pancreas of Kif5b(fl/−):RIP2-Cre mice exhibited both reduced islet size and increased islet number, concomitant with an increased insulin vesicle density in β-cells. CONCLUSIONS: In addition to being essential for maintaining glucose homeostasis and regulating β-cell function, Kif5b may be involved in β-cell development by regulating β-cell proliferation and insulin vesicle synthesis.
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spelling pubmed-30121892012-01-01 Targeted Inactivation of Kinesin-1 in Pancreatic β-Cells In Vivo Leads to Insulin Secretory Deficiency Cui, Ju Wang, Zai Cheng, Qianni Lin, Raozhou Zhang, Xin-Mei Leung, Po Sing Copeland, Neal G. Jenkins, Nancy A. Yao, Kwok-Ming Huang, Jian-Dong Diabetes Genetics OBJECTIVE: Suppression of Kinesin-1 by antisense oligonucleotides, or overexpression of dominant-negative acting kinesin heavy chain, has been reported to affect the sustained phase of glucose-stimulated insulin secretion in β-cells in vitro. In this study, we examined the in vivo physiological role of Kinesin-1 in β-cell development and function. RESEARCH DESIGN AND METHODS: A Cre-LoxP strategy was used to generate conditional knockout mice in which the Kif5b gene is specifically inactivated in pancreatic β-cells. Physiological and histological analyses were carried out in Kif5b knockout mice as well as littermate controls. RESULTS: Mice with β-cell specific deletion of Kif5b (Kif5b(fl/−):RIP2-Cre) displayed significantly retarded growth as well as slight hyperglycemia in both nonfasting and 16-h fasting conditions compared with control littermates. In addition, Kif5b(fl/−):RIP2-Cre mice displayed significant glucose intolerance, which was not due to insulin resistance but was related to an insulin secretory defect in response to glucose challenge. These defects of β-cell function in mutant mice were not coupled with observable changes in islet morphology, islet cell composition, or β-cell size. However, compared with controls, pancreas of Kif5b(fl/−):RIP2-Cre mice exhibited both reduced islet size and increased islet number, concomitant with an increased insulin vesicle density in β-cells. CONCLUSIONS: In addition to being essential for maintaining glucose homeostasis and regulating β-cell function, Kif5b may be involved in β-cell development by regulating β-cell proliferation and insulin vesicle synthesis. American Diabetes Association 2011-01 2010-09-24 /pmc/articles/PMC3012189/ /pubmed/20870970 http://dx.doi.org/10.2337/db09-1078 Text en © 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Genetics
Cui, Ju
Wang, Zai
Cheng, Qianni
Lin, Raozhou
Zhang, Xin-Mei
Leung, Po Sing
Copeland, Neal G.
Jenkins, Nancy A.
Yao, Kwok-Ming
Huang, Jian-Dong
Targeted Inactivation of Kinesin-1 in Pancreatic β-Cells In Vivo Leads to Insulin Secretory Deficiency
title Targeted Inactivation of Kinesin-1 in Pancreatic β-Cells In Vivo Leads to Insulin Secretory Deficiency
title_full Targeted Inactivation of Kinesin-1 in Pancreatic β-Cells In Vivo Leads to Insulin Secretory Deficiency
title_fullStr Targeted Inactivation of Kinesin-1 in Pancreatic β-Cells In Vivo Leads to Insulin Secretory Deficiency
title_full_unstemmed Targeted Inactivation of Kinesin-1 in Pancreatic β-Cells In Vivo Leads to Insulin Secretory Deficiency
title_short Targeted Inactivation of Kinesin-1 in Pancreatic β-Cells In Vivo Leads to Insulin Secretory Deficiency
title_sort targeted inactivation of kinesin-1 in pancreatic β-cells in vivo leads to insulin secretory deficiency
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3012189/
https://www.ncbi.nlm.nih.gov/pubmed/20870970
http://dx.doi.org/10.2337/db09-1078
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