| First Author | Datta R | Year | 2021 |
| Journal | Proc Natl Acad Sci U S A | Volume | 118 |
| Issue | 18 | PubMed ID | 33903257 |
| Mgi Jnum | J:313791 | Mgi Id | MGI:6707786 |
| Doi | 10.1073/pnas.2102171118 | Citation | Datta R, et al. (2021) Autoregulation of insulin receptor signaling through MFGE8 and the alphavbeta5 integrin. Proc Natl Acad Sci U S A 118(18):e2102171118 |
| abstractText | The role of integrins, in particular alphav integrins, in regulating insulin resistance is incompletely understood. We have previously shown that the alphavbeta5 integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) regulates cellular uptake of fatty acids. In this work, we evaluated the impact of MFGE8 on glucose homeostasis. We show that acute blockade of the MFGE8/beta5 pathway enhances while acute augmentation dampens insulin-stimulated glucose uptake. Moreover, we find that insulin itself induces cell-surface enrichment of MFGE8 in skeletal muscle, which then promotes interaction between the alphavbeta5 integrin and the insulin receptor leading to dampening of skeletal-muscle insulin receptor signaling. Blockade of the MFGE8/beta5 pathway also enhances hepatic insulin sensitivity. Our work identifies an autoregulatory mechanism by which insulin-stimulated signaling through its cognate receptor is terminated through up-regulation of MFGE8 and its consequent interaction with the alphavbeta5 integrin, thereby establishing a pathway that can potentially be targeted to improve insulin sensitivity. |
