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MAD2-Dependent Insulin Receptor Endocytosis Regulates Metabolic Homeostasis.
Authors Park J, Hall C, Hubbard B, LaMoia T, Gaspar R, Nasiri A, Li F, Zhang H, Kim J,
Haeusler RA, Accili D, Shulman GI, Yu H, Choi E
Submitted By Submitted Externally on 3/15/2024
Status Published
Journal Diabetes
Year 2023
Date Published 12/1/2023
Volume : Pages 72 : 1781 - 1794
PubMed Reference 37725942
Abstract Insulin activates insulin receptor (IR) signaling and subsequently triggers IR
endocytosis to attenuate signaling. Cell division regulators MAD2, BUBR1, and
p31comet promote IR endocytosis on insulin stimulation. Here, we show that
genetic ablation of the IR-MAD2 interaction in mice delays IR endocytosis,
increases IR levels, and prolongs insulin action at the cell surface. This in
turn causes a defect in insulin clearance and increases circulating insulin
levels, unexpectedly increasing glucagon levels, which alters glucose metabolism
modestly. Disruption of the IR-MAD2 interaction increases serum fatty acid
concentrations and hepatic fat accumulation in fasted male mice. Furthermore,
disruption of the IR-MAD2 interaction distinctly changes metabolic and
transcriptomic profiles in the liver and adipose tissues. Our findings establish
the function of cell division regulators in insulin signaling and provide
insights into the metabolic functions of IR endocytosis., The physiological role
of IR endocytosis in insulin sensitivity remains unclear. Disruption of the
IR-MAD2 interaction delays IR endocytosis and prolongs insulin signaling.
IR-MAD2 controls insulin clearance and glucose metabolism. IR-MAD2 maintains
energy homeostasis.


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