Targeted Inactivation of Kinesin-1 in Pancreatic β-Cells In Vivo Leads to Insulin Secretory Deficiency
- Ju Cui1,
- Zai Wang1,
- Qianni Cheng2,
- Raozhou Lin1,
- Xin-Mei Zhang1,
- Po Sing Leung2,
- Neal G. Copeland3,
- Nancy A. Jenkins3,
- Kwok-Ming Yao1 and
- Jian-Dong Huang1
- 1Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong;
- 2Department of Physiology, The Chinese University of Hong Kong, Hong Kong;
- 3Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore.
- Corresponding author: Jian-Dong Huang, , or Kwok-Ming Yao, .
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 (Kif5bfl/−: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, Kif5bfl/−: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 Kif5bfl/−: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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- Received July 26, 2009.
- Accepted September 20, 2010.
- © 2011 by the American Diabetes Association.
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