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 of Kinesin-1 in β-cell development and function.


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.
Cui
Ju
J
Department of Biochemistry, The University of Hong Kong, Hong Kong.
Wang
Zai
Z
Cheng
Qianni
Q
Lin
Raozhou
R
Zhang
Xin-Mei
XM
Leung
Po Sing
PS
Copeland
Neal G
NG
Jenkins
Nancy A
NA
Yao
Kwok-Ming
KM
Huang
Jian-Dong
JD
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000172:deficiency / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology*; D007515:Islets of Langerhans / Q000378:metabolism; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000172:deficiency / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry
D017931:DNA Primers; D007328:Insulin; C470243:KIF11 protein, human; D016376:Oligonucleotides, Antisense; D010446:Peptide Fragments; C475469:Kif5b protein, mouse; D016547:Kinesins