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 beta-cells in vitro. In this study, we examined the in vivo physiological role of Kinesin-1 In beta-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 beta-cells. Physiological and histological analyses were carried out in Kif5b knockout mice as well as littermate controls. RESULTS-Mice with beta-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 beta-cell function in mutant mice were not coupled with observable changes in islet morphology, islet cell composition, or beta-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 beta-cells. CONCLUSIONS-In addition to being essential for maintaining glucose homeostasis and regulating beta-cell function, Kif5b may be involved in beta-cell development by regulating beta-cell proliferation and insulin vesicle synthesis.
↧