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Publication
Insulin receptorT1160 phosphorylation mediates renal cortical insulin resistance
but not excess gluconeogenesis from glycerol.
Authors Hubbard BT, Ma Y, Gaspar RC, LaMoia TE, Zhang D, Kahn M, Dufour S, Nasiri A,
Shulman GI
Submitted By Submitted Externally on 7/6/2026
Status Published
Journal Nature communications
Year 2026
Date Published 5/21/2026
Volume : Pages Not Specified : Not Specified
PubMed Reference 42168167
Abstract Impaired suppression of endogenous glucose production (EGP) drives end-organ
damage in insulin resistance and type 2 diabetes. Although the liver is
traditionally thought to mediate dysregulated EGP, the role of the renal cortex
is less understood. Here, we investigate if high-fat diet (HFD) induces renal
cortical insulin resistance while assessing renal glucose production (RGP) and
mitochondrial metabolism in male mice. HFD increases plasma membrane
sn-1,2-DAGs, PKCe translocation, and Insulin Receptor Kinase (IRK)T1160
phosphorylation while blunting insulin-stimulated pyruvate oxidation and insulin
signaling. In HFD mice, RGP is elevated 6.5-fold and accounts for 60% of EGP
during hyperinsulinemia. Excess RGP is derived equally from glycerol and
mitochondrial sources, chiefly pyruvate. Signaling and flux defects are
abrogated in HFD-fed IRKT1150A knockin mice, except for glycerol-derived
gluconeogenesis. Our findings implicate the sn-1,2-DAG???PKCe???IRKT1160 axis in
renal cortical insulin resistance and highlight renal gluconeogenesis as a
driver of dysregulated glucose homeostasis.




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