Insulin receptor<sup>T1160</sup> phosphorylation mediates renal cortical insulin resistance but not excess gluconeogenesis from glycerol.
basic_science · Level V
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- Record sourced from PubMed, PMID 42168167.
- Also identified by DOI 10.1038/s41467-026-73016-0.
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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)<sup>T1160</sup> 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 IRK<sup>T1150A</sup> knockin mice, except for glycerol-derived gluconeogenesis. Our findings implicate the sn-1,2-DAG → PKCε → IRK<sup>T1160</sup> axis in renal cortical insulin resistance and highlight renal gluconeogenesis as a driver of dysregulated glucose homeostasis.