Integrated analysis of the adipocyte plasma membrane proteome reveals KCC1 and PIT2 as novel insulin-responsive transporters
Year: 2026
Type: article
Abstract: The plasma membrane (PM) is a dynamic interface that integrates environmental cues with cellular responses. Insulin is known to remodel the PM primarily by stimulating the translocation of glucose transporter GLUT4, but the full scope of insulin's PM remodeling remains poorly defined. Here, we performed a meta-analysis of insulin-regulated PM proteins in adipocytes by integrating nine independent proteomic datasets generated using complementary PM enrichment strategies. The meta-analysis identified 37 insulin-regulated candidates detected in at least three datasets, including 30 proteins not previously implicated in insulin action. Among these, we experimentally characterized the insulin-stimulated translocation of two transporters: potassium-chloride cotransporter 1 KCC1 (SLC12A4) and sodium-dependent phosphate transporter PIT2 (SLC20A2), which showed robust and reproducible recruitment to the PM in response to insulin. siRNA-mediated knockdown of KCC1 or PIT2 impaired insulin-stimulated glucose transport, suggesting a role for these transporters in insulin action. Live-cell and fixed-cell imaging revealed that both proteins localize across multiple endosomal compartments, undergo insulin dose-dependent trafficking to the PM, and require PI3K-AKT signaling for their mobilization. Strikingly, insulin-induced translocation of KCC1 and PIT2 to the PM was impaired in adipocytes rendered insulin resistant by chronic hyperinsulinemia, accompanied by increased perinuclear retention under basal conditions. Together, our work provides a valuable resource for understanding insulin-regulated PM remodeling in adipocytes, establishes KCC1 and PIT2 as novel insulin-responsive transporters, and supports the idea that insulin resistance involves defects in cell-surface delivery that extend beyond GLUT4.
Source: Journal of Biological Chemistry
Authors: Yiju Zhang, Kristen C. Cooke, Jonathan Scavuzzo, Harry B. Cutler, Søren Madsen, Alison L. Kearney, Olivia J. Conway, Bethan L. Hawkins, Dilip Menon, Sean J. Humphrey, Françoise Koumanov, Jacqueline Stöckli, Thomas A. Geddes, Daniel J. Fazakerley, Alexis Diaz-Vegas, James G. Burchfield, David E. James
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,430
Awards: Molecular mechanisms of impaired glucose transport in insulin resistance, Unravelling a canonical mitochondrial stress response pathway, Dissecting The Role of Selective Insulin Resistance In Type 2 Diabetes, Dissecting Rapamycin sensitive and insensitive effects of mTOR, Novel regulators of insulin-stimulated glucose disposal in humans, Treating Cardiometabolic Disease by Targeting Mitochondrial Defects, G8155761622
OpenAlex ID: W7128734331