Critical role of β1 integrin in postnatal beta-cell function and expansion
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Jason Peart1,2, Jinming Li1,3, Hojun Lee1,3, Matthew Riopel1, Zhi-Chao Feng1 and Rennian Wang1,3
1Children's Health Research Institute, London, Ontario, N6C 2V5, Canada
2Department of Pathology, University of Western Ontario, London, Ontario, N6A 3K7, Canada
3Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, N6A 3K7, Canada
Rennian Wang, email: [email protected]
Keywords: β1 integrin, mouse insulin promoter (MIP), glucose tolerance test, Cre recombinase, beta-cell mass
Received: November 01, 2016 Accepted: April 21, 2017 Published: May 18, 2017
β1 integrin is essential for pancreatic beta-cell development and maintenance in rodents and humans. However, the effects of a temporal beta-cell specific β1 integrin knockout on adult islet function are unknown. We utilized a mouse insulin 1 promoter driven tamoxifen-inducible Cre-recombinase β1 integrin knockout mouse model (MIPβ1KO) to investigate β1 integrin function in adult pancreatic beta-cells. Adult male MIPβ1KO mice were significantly glucose intolerant due to impaired glucose-stimulated insulin secretion in vivo and ex vivo at 8 weeks post-tamoxifen. The expression of Insulin and Pancreatic and duodenal homeobox-1 mRNA was significantly reduced in MIPβ1KO islets, along with reductions in insulin exocytotic proteins. Morphological analyses demonstrated that beta-cell mass, islet density, and the number of large-sized islets was significantly reduced in male MIPβ1KO mice. Significant reductions in the phosphorylation of signaling molecules focal adhesion kinase, extracellular signal-regulated kinases 1 and 2, and v-Akt murine thymoma viral oncogene were observed in male MIPβ1KO islets when compared to controls. MIPβ1KO islets displayed a significant increase in protein levels of the apoptotic marker cleaved-Poly (ADP-ribose) polymerase and a reduction of the cell cycle marker cyclin D1. Female MIPβ1KO mice did not develop glucose intolerance or reduced beta-cell mass until 16 weeks post-tamoxifen. Glucose intolerance remained in both genders of aged MIPβ1KO mice. This data demonstrates that β1 integrin is required for the maintenance of glucose homeostasis through postnatal beta-cell function and expansion.
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