Metabolic consequences of altered kidney glucose reabsorption under normoglycemic conditions

Objective

Kidney glucose reabsorption, primarily mediated by glucose transporter 2 (GLUT2), is essential for systemic glucose homeostasis. While GLUT2's role has been studied in diabetic conditions, its function in kidney proximal tubule cells (KPTCs) under normo-physiological conditions remains unclear. This study aimed to delineate the metabolic consequences of KPTC-specific GLUT2 deletion on renal and whole-body energy homeostasis.

Methods

We utilized a conditional mouse model with KPTC-specific deletion of GLUT2 to assess the impact of impaired renal glucose reabsorption on systemic metabolism. Comprehensive metabolic and behavioral phenotyping, tissue-specific glucose uptake assays, and multi-omics analyses were performed to evaluate changes in energy balance, organ-specific metabolism, and signaling pathways.

Results

Loss of KPTC-GLUT2 led to increased food intake, enhanced systemic carbohydrate oxidation, and elevated fat and muscle mass. These changes were accompanied by altered glucose utilization across metabolic organs and improvements in whole-body lipid profile. Mechanistically, the phenotype was linked to metabolic reprogramming in the kidney, characterized by increased reabsorption and bioavailability of taurine and creatine, overactivation of mTORC1 signaling, and elevated endocannabinoid tone.

Conclusions

KPTC-GLUT2 plays a previously unrecognized role in regulating renal and systemic energy metabolism. Its deletion induces a systemic energy-conserving phenotype driven by kidney-intrinsic changes, highlighting the kidney's contribution to whole-body metabolic homeostasis beyond glucose filtration.

Graphical abstract

Energy conserving phenotype - proposed mechanism in KPTC^GLUT2-/- mice. GLUT2 nullification inhibits glucose reabsorption by the kidney, resulting in glucose retention in the KPTCs and enhanced kidney energy metabolism. In turn, mTORC1 activation is enhanced in the KPTCs, accompanied by elevated levels of taurine, creatine, and AEA. These metabolic hubs enhanced kidney and systemic bioavailability results in a pronounced systemic energy-consuming/preservation phenotype. Figure created with BioRender.com. BCAA, branched-chain amino acids; DHAP, dihydroxyacetone phosphate; NATs, N-acyl taurines; NAEs, N-acylethanolamines; FAAH, fatty acid amid hydrolase; FFA, free fatty acid.