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, PKCε 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 → PKCε → IRKT1160 axis in renal cortical insulin resistance and highlight renal gluconeogenesis as a driver of dysregulated glucose homeostasis.
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Acknowledgements
We thank Wanling Zhu, Xiaoxian Ma, Fitsum Guebre-Egziabher and John Stack for their excellent technical assistance. This study was supported by grants from the United States Public Health Service: NIH/NIDDK F30DK131846 [B.T.H.], T32GM136651 [B.T.H.] F31DK126362 [T.E.L.], T32 GM007324 [T.E.L.], P30DK034989, R01DK119968 [G.I.S.], R01DK113984 [G.I.S.], P30DK045735 [G.I.S.], R01DK133143 [G.I.S.]; RC2DK120534; and the Novo Nordisk Foundation: NNF25SA0106990 [G.I.S.].
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Hubbard, B.T., Ma, Y., Gaspar, R.C. et al. Insulin receptorT1160 phosphorylation mediates renal cortical insulin resistance but not excess gluconeogenesis from glycerol. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73016-0
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DOI: https://doi.org/10.1038/s41467-026-73016-0
