PTP1B mediates the inhibitory effect of MFGE8 on insulin signaling through the ß5 integrin.

Integrins are cell adhesion receptors that dimerize to mediate cell-cell interactions and regulate processes, including proliferation, inflammation, and tissue repair. The role of integrins in regulating insulin signaling is incompletely understood. We have previously shown that binding of the integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) to the αvß5 integrin promotes termination of insulin receptor signaling in mice. Upon ligation of MFGE8, integrin ß5 complexes with the insulin receptor beta (IRß) in skeletal muscle, resulting in dephosphorylation of IRß and reduction of insulin-stimulated glucose uptake. Here, we investigate the mechanism by which the interaction between ß5 and IRß impacts IRß phosphorylation status. We show in in vitro and in vivo in skeletal muscle in mice that antibody-mediated blockade of the ß5 integrin inhibits and recombinant MFGE8 promotes PTP1B binding to and dephosphorylation of IRß resulting in increased or reduced insulin-stimulated glucose uptake, respectively. The ß5-PTP1B complex is recruited by MFGE8 to IRß leading to termination of canonical insulin signaling. ß5 blockade enhances insulin-stimulated glucose uptake in wildtype but not Ptp1b KO mice indicating that PTP1B functions downstream of MFGE8 in modulating insulin receptor signaling. Furthermore, in a human cohort, we report serum MFGE8 levels correlate with indices of insulin resistance. These data provide mechanistic insights into the role of MFGE8 and ß5 in regulating insulin signaling.

Complicating critical discussions in gender sexuality alliances: Youth desire for intersectional conversations and the experience of fragmentation.

Gender sexuality alliances (GSAs) represent consciousness-raisings that hold potential for critical consciousness development in youth. In this study, we focus on critical reflection-the understanding that oppression is structured and maintained by human action. We engage intersectionality as our analytical framework and analyze both student interview data (n = 38) and advisor closed-ended and open-ended survey data (n = 58) to examine: (1) the nature/content of critically reflective discussions in GSAs and (2) how advisors support critically reflective discussions in GSAs and their role in these discussions. Our findings suggest that (1) conversations centering race and its intersections with other socio-structural axes occur, albeit infrequently; (2) youth recognize and understand the concept of intersectionality in nuanced ways, desire to have critical intersectional conversations, and experience fragmentation from conversations around race, sexuality, and gender if they are situated at privileged locations on those axes; and (3) students want advisors to engage in critically reflective discussions in GSAs. The findings suggest that interventions and programming are needed that could cultivate advisors' and youth leaders' skills in facilitating intersectional dialogues for critical reflection among members.