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.

Coordinated interactions between endothelial cells and macrophages in the islet microenvironment promote β cell regeneration

“…By deconstructing the contributions of the cellular components of the islet microenvironment of βVEGF-A mice, we were able to uncover a role for ECM remodeling and signaling in β cell proliferation. MΦs, ECs, and β cells all show transcriptional regulation of integrin receptors and ECM remodeling enzymes, some of which have been shown previously to affect β cell proliferation 22 , 58 – 60 . Importantly, there is mounting evidence that ECM modulates human β cell proliferation and that these components can be manipulated to promote β cell growth in vitro 61 – 63 .…”

Coordinated interactions between endothelial cells and macrophages in the islet microenvironment promote β cell regeneration

“…By deconstructing the contributions of the cellular components of the islet microenvironment of βVEGF-A mice, we were able to uncover a role for ECM remodeling and signaling in β cell proliferation. MΦs, ECs, and β cells all show transcriptional regulation of integrin receptors and ECM remodeling enzymes, some of which have been shown previously to affect β cell proliferation 22,[60][61][62] . In addition to shaping cell-matrix signaling, ECM reorganization can also lead to the release and/or activation of matrix-sequestered growth factors [63][64][65][66] .…”

Identifying novel therapeutic targets for diabetes through improved understanding of islet adhesion receptors

“…In addition, impaired islet function has been observed following deletion or inhibition of adhesion receptors. For example, reduced β1 integrin expression in islets results in impaired glucose tolerance and reductions in insulin secretion and islet mass [13], while inhibition of E-cadherin prevents the formation of pseudoislets, which are -cell clusters that have been configured to resemble native islets and show improved insulin secretion compared to dispersed cells [14]. All adhesion receptors are involved in cell-cell or cell-ECM interactions.…”