Critical role of β1 integrin in postnatal beta-cell function and expansion

Abstract

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.