Insulin receptorT1160 phosphorylation mediates renal cortical insulin resistance but not excess gluconeogenesis from glycerol
Year: 2026
Type: article
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. Here the authors report that a high fat diet causes renal cortical insulin resistance via insulin receptor T1160 phosphorylation. They also identify elevated renal gluconeogenesis as a potential driver of dysregulated whole-body glucose homeostasis.
Source: Nature Communications
Institutions: Yale University, Howard Hughes Medical Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G1236451951, Development of Controlled Release Mitochondrial Protonophore (CRMP) as a Novel Treatment for Type-2 Diabetes and Non-Alcoholic Steatohepatitis in Dysmetabolic Non-Human Primates, G2409594733, G2490750684, G2555113698, G2641931136, G2654666551, Institutional National Research Service Award, G5300833861, G570462279, G5803916899, G7314688813, G73615776, G8088548095, G8995048626, G9000010113, G9000020556, G9000030757, G9000045692, G9000203025, Yale Center for Metabolic Phenotyping in Live Models of Obesity and Diabetes, Elucidating the pathophysiology and molecular mechanisms of renal insulin resistance
OpenAlex ID: W7162013615