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<p>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 <i>sn</i>−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 <i>sn</i>−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.</p>

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Insulin receptorT1160 phosphorylation mediates renal cortical insulin resistance but not excess gluconeogenesis from glycerol

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月21日

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  • Brandon T. Hubbard,
  • Yumin Ma,
  • Rafael C. Gaspar,
  • Traci E. LaMoia,
  • Dongyan Zhang,
  • Mario Kahn,
  • Sylvie Dufour,
  • Ali Nasiri,
  • Gerald I. Shulman

摘要

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.