Regulation of Glucose Handling in the Kidney

The kidney is a major contributor to glucose homeostasis, playing a dual role by reabsorbing filtered glucose and producing new glucose through gluconeogenesis. Its contribution to systemic gluconeogenesis is substantial, accounting for up to 20%–25% in the fasting state. In diabetes, this gluconeogenic activity increases further, aggravating hyperglycemia and contributing to broader metabolic dysregulation. Most of the approximately 180 g of glucose filtered daily by the glomeruli is reabsorbed in the proximal tubule through sodium-glucose cotransporter 2 (SGLT2) in the S1/S2 segments and SGLT1 in the S3 segment, with basolateral exit through glucose transporter 2 (GLUT2) and GLUT1, respectively.¹ This transport process is tightly coupled to sodium reabsorption, driven by the Na⁺/K⁺-ATPase and reliant on mitochondrial ATP and oxygen availability.¹

In diabetes, increased SGLT2 expression promotes excessive glucose and sodium reabsorption, leading to reduced sodium delivery to the macula densa, impaired tubuloglomerular feedback, afferent arteriolar vasodilation, and glomerular hyperfiltration, a hallmark of early diabetic nephropathy. SGLT2 inhibitors counteract this by increasing distal sodium delivery, normalizing glomerular hemodynamics, and reducing proximal tubule oxygen demand, thereby improving renal energy efficiency and mitigating tissue hypoxia.²

Although much attention has focused on SGLT2 pharmacology, the upstream cellular regulation of glucose transport and gluconeogenesis in the kidney has remained incompletely understood. Insulin signaling has been shown to influence both processes, but the role of key intracellular effectors such as mammalian target of rapamycin (mTOR) complexes has only recently come into focus.

Mechanistic Target of Rapamycin Complex 2 Controls Proximal Tubule Glucose Transport and Metabolism

In the kidney tubule, mTOR signaling is particularly active in the metabolically demanding proximal tubule cells and orchestrates diverse physiologic processes, including nutrient reabsorption, endocytosis, and electrolyte balance as well as pathophysiologic processes such as epithelial integrity and cyst formation.^3–5 Mechanistic target of rapamycin complex 2 (mTORC2), although less well characterized, is emerging as a key regulator of tubular transport functions, including potassium handling.⁵

Together, mTOR signaling is known as a master integrator of metabolic and proliferative cues in the kidney tubule. In this context, the new findings by Demko et al., published in this issue of JASN, on mTORC2's role in regulating glucose handling add a crucial dimension to our understanding of renal physiology and disease.⁶ Using inducible tubule-specific Rictor knockout (TRKO) and proximal tubule–specific Rictor knockout mouse models, they demonstrate that the loss of mTORC2 activity results in pronounced glycosuria, despite normal blood glucose levels, due to reduced apical membrane expression of SGLT2 and SGLT1. This defect was observed specifically in the fed state and correlated with impaired protein kinase B, PKB (AKT) phosphorylation and reduced activation of the transcription factor forkhead box O 4 (FOXO4). Notably, TRKO mice exhibited increased renal expression of the gluconeogenic enzymes phosphoenolpyruvate carboxykinase and G6Pase, elevated fasting insulin, and higher hemoglobin A1c levels, indicating that mTORC2 deletion disrupts not only glucose reabsorption but also renal gluconeogenesis. Importantly, these abnormalities could be partially reversed by dietary potassium supplementation. High K⁺ intake normalized glycosuria and suppressed gluconeogenic enzyme expression in TRKO mice, without restoring AKT or FOXO4 phosphorylation, indicating the existence of an mTORC2-independent regulatory pathway.

Mechanistic Implications

This study establishes mTORC2 as a central integrator of insulin signaling in the proximal tubule, coordinating SGLT-mediated glucose reabsorption with suppression of gluconeogenesis. The reduction in plasma membrane SGLT1/2 observed in mTORC2-deficient mice suggests a post-translational regulatory mechanism, potentially involving trafficking or stability, rather than gene expression. Although previous work linked AKT signaling to SGLT regulation,⁷ these findings now establish that mTORC2 is required for correct localization of SGLT proteins at the apical membrane in vivo.

The identification of FOXO4, not FOXO1, as a key transcriptional effector downstream of mTORC2-AKT in the kidney is another novel and intriguing finding. In hepatic gluconeogenesis, FOXO1 is the canonical regulator.⁸ That FOXO4 plays this role in proximal tubules suggests tissue-specific specialization of the mTORC2-AKT-FOXO axis, aligned with the kidney's dual role in glucose reclamation and production.

Equally remarkable is the finding that a high-potassium diet ameliorates glycosuria and suppresses gluconeogenic gene expression in the absence of mTORC2 signaling. These results confirm earlier observations that potassium modulates glucose metabolism,⁹ and they hint at an alternative pathway, possibly involving changes in tubular pH or membrane potential, that bypasses canonical insulin-mTOR signaling. This potassium effect could be clinically relevant, particularly in insulin-resistant states where conventional signaling pathways are impaired.

Interestingly, the elevated hemoglobin A1c and fasting insulin levels observed in the Rictor KO seems to diverge from the clinical effect of the SGLT2 inhibitors, which are known to lower both parameters in people with diabetes. It can be speculated whether (1) chronic hyperactivation of mTORC2 signaling in diabetes may attenuate the therapeutic benefits of SGLT2 inhibition or (2) SGLT2 blockade might secondarily downregulate mTORC2 activity, potentially contributing to its metabolic effects. At present, data to directly address this hypothesis are lacking.

Clinical Perspective

The findings by Demko et al. raise important translational questions. SGLT2 inhibitors are now mainstays of therapy in diabetes, heart failure, and CKD, but their efficacy is usually framed for pharmacologic inhibition of a fixed transporter activity. This study highlights that transporter expression and membrane localization are dynamically regulated by cellular metabolic status. In pathologic states such as type 2 diabetes, where mTORC2 may be hyperactivated, increased glucose reabsorption through SGLT2 could contribute to sustained hyperglycemia. Conversely, impaired mTORC2 signaling may diminish SGLT2 expression and alter drug responsiveness. Moreover, the potential of dietary potassium to modulate renal glucose handling independently of insulin opens a new avenue for metabolic intervention. Given the widespread dysregulation of potassium homeostasis in diabetes and CKD, optimizing potassium intake could become a novel adjunctive strategy to improve glycemic control or enhance the effectiveness of SGLT2 inhibitors.

Outlook and Future Directions

The proximal tubule is emerging not just as a passive site of injury in metabolic kidney disease but as an active regulator of systemic energy balance. Experimental data now indicate that nutrient-sensing pathways, transcriptional regulators such as FOXO4, and dietary factors such as potassium intake converge in this segment of the nephron to fine-tune glucose transport and gluconeogenesis. This points toward intriguing future research directions.

Clarifying the Mechanisms Governing SGLT Trafficking and Membrane Localization

Although it is now evident that mTORC2 activity influences the presence of SGLT1 and SGLT2 in the apical membrane of proximal tubular cells, the precise molecular mechanisms underlying this regulation remain unclear. Future studies should aim to delineate how intracellular signaling pathways—such as those involving AKT or other post-translational modifiers—control transporter trafficking, membrane insertion, stability, or retrieval. Identifying these steps will be critical for understanding how proximal tubule glucose reabsorption is dynamically adjusted in health and disease.

Defining the Role of FOXO4 in the Human Kidney

Given that most prior work on gluconeogenesis has focused on hepatic FOXO1, confirming FOXO4's role in human proximal tubule physiology represents a next step. This includes investigating FOXO4 expression patterns, target genes, and regulatory interactions under different metabolic conditions and in diabetic nephropathy.

Dissecting mTORC2-Independent Pathways of Potassium Sensing

A striking finding of the study is that high dietary potassium can rescue glycosuria and suppress gluconeogenesis in the absence of mTORC2 signaling. This suggests the existence of a distinct potassium-responsive signaling axis that modulates glucose metabolism independently of canonical insulin-AKT-mTOR pathways. Future work should aim to identify the molecular sensors, ion transporters, or transcriptional effectors responsible for this potassium-mediated regulation to open new perspectives on electrolyte-metabolic cross-talk in renal physiology.

Evaluating the Clinical Relevance in People with Diabetes

It remains to be determined whether alterations in mTORC2 activity, FOXO4 function, or potassium balance contribute to variability in glucose handling, insulin sensitivity, or responsiveness to SGLT2 inhibitors among patients with diabetes. Clinical studies investigating correlations between dietary potassium intake, serum K⁺ levels, tubular transporter expression, and glycemic control could help validate these experimental findings and inform novel therapeutic strategies.

In summary, the study of Demko et al. adds a critical new layer to our understanding of renal glucose handling, with implications for basic physiology and the therapeutic landscape of diabetes and kidney disease (Figure 1).

Figure 1.

Regulation of glucose handling in the kidney and new layers of complexity. This illustration highlights the regulatory levels of renal glucose reabsorption, including cellular metabolism (e.g., mTORC2) and dietary influences, which act in addition to SGLT1/2 inhibition, patient characteristics, and genetics in the context of diabetes treatment. FOXO4, forkhead box O 4; GLUT2, glucose transporter 2; mTORC2, mechanistic target of rapamycin complex 2; SGLT2, sodium-glucose cotransporter 2.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/F331.

Author Contributions

Conceptualization: Tobias B. Huber.

Visualization: Nicola Wanner.

Writing – original draft: Tobias B. Huber, Nicola Wanner.

Writing – review & editing: Tobias B. Huber, Nicola Wanner.

Funding

N. Wanner: Deutsche Forschungsgemeinschaft (TRR 422 and SFB 1192). T.B. Huber: Deutsche Forschungsgemeinschaft (TRR 422 and SFB 1192) and HORIZON EUROPE European Research Council (Cure FSGS, ERC advanced grant, ID: 101141768).