Renal glycosuria triggers a coordinated mannose and glutamine metabolic program to maintain glucose homeostasis

Glycosuria, whether genetically induced or triggered by SGLT2 inhibitors, activates compensatory glucose-producing pathways that limit glucose lowering in type 2 diabetes. To define these pathways, we studied renal Glut2 knockout mice, which progressively lose Slc5a2 (encoding SGLT2) expression yet maintain normoglycemia despite marked urinary glucose loss. Metabolic profiling and isotope tracing revealed coordinated adaptations in mannose and glutamine metabolism during glycosuria. Skeletal muscle reduced glucose utilization and showed increased incorporation of mannose-derived carbon into oxidative metabolism while whole-body glycolysis declined, establishing a systemic glucose-sparing state. Disruption of glutamine transport or mannose utilization caused hypoglycemia in mice treated with an SGLT2 inhibitor, consistent with reliance on these substrates to maintain glucose homeostasis during glycosuria. Multiomic profiling revealed increased expression and chromatin accessibility of mannose and glutamine transport pathways. These findings identify a kidney-coordinated metabolic program associated with maintenance of systemic glucose homeostasis during glycosuria and may inform strategies to optimize the glucose-lowering efficacy of SGLT2 inhibitors.