Chhabra, K. H. | bioRxiv Science

bioRxiv2026

Metabolic Reprogramming Coordinates Mannose and Glutamine Metabolism to Maintain Glucose Homeostasis During Glycosuria

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 instead oxidized mannose, 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, demonstrating dependence 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-driven metabolic program that preserves systemic glucose homeostasis during glycosuria and may inform strategies to optimize the glucose-lowering efficacy of SGLT2 inhibitors.

physiology↗

bioRxiv2023

A kidney-hypothalamus axis promotes compensatory glucose production in response to glycosuria

The kidneys facilitate energy conservation through reabsorption of nutrients including glucose. Almost all the filtered blood glucose is reabsorbed by the kidneys. Loss of glucose in urine (glycosuria) is offset by an increase in endogenous glucose production to maintain normal energy supply in the body. How the body senses this glucose loss and consequently enhances glucose production is unclear. Using renal Glut2 knockout mice, we demonstrate that elevated glycosuria activates the hypothalamic-pituitary-adrenal axis, which in turn drives endogenous glucose production. This phenotype was attenuated by selective afferent renal denervation, indicating the involvement of the afferent nerves in promoting the compensatory increase in glucose production. In addition, through plasma proteomics analyses we observed that acute phase proteins - which are usually involved in bodys defense mechanisms against a threat - were the top candidates which were either upregulated or downregulated in renal Glut2 KO mice. Overall, afferent renal nerves contribute to promoting endogenous glucose production in response to elevated glycosuria and loss of glucose in urine is sensed as a biological threat in mice. These findings may be useful in improving efficiency of drugs like SGLT2 inhibitors that are intended to treat hyperglycemia by enhancing glycosuria but are met with a compensatory increase in endogenous glucose production.

physiology↗