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

摘要

Objective-suppression of kinesin-1 by antisense oligonu-cleotides, or overexpression of dominant-negative acting kinesin heavy chain, has been reported to affect the sustained phase of glucose-stimulated insulin secretion in p-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 p-cells. Physiological and histological analyses were carried out in kif5b knockout mice as well as littermate controls. Results-mice with p-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 p-cell function in mutant mice were not coupled with observable changes in islet morphology, islet cell composition, or p-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 p-cells. Conclusions-in addition to being essential for maintaining glucose homeostasis and regulating p-cell function, kif5b may be involved in p-cell development by regulating β-cell proliferation and insulin vesicle synthesis. Diabetes 60:320-330, 2011