Coordinated Regulation of Renal Glucose Reabsorption and Gluconeogenesis by mTORC2 and Potassium.

KEY POINTS: The insulin-regulated kinase, mammalian target of rapamycin complex 2 (mTORC2), coordinates regulation of sodium-glucose cotransport and gluconeogenesis in the kidney proximal tubule. Dietary potassium can bypass mTORC2 to regulate sodium-glucose cotransport and gluconeogenesis in mTORC2 knockout mice. The transcription factor forkhead box O4 may have an unexpected role in mediating mTORC2 effects on renal tubule glucose homeostasis. BACKGROUND: The kidney is uniquely responsible for reabsorption of filtered glucose and gluconeogenesis. Insulin stimulates glucose transport and suppresses gluconeogenesis in the proximal tubule; however, the signaling mechanisms and coordinated regulation of these processes are poorly understood. The kinase complex mammalian target of rapamycin complex 2 (mTORC2) is critical for regulation of growth, metabolism, solute transport, and electrolyte homeostasis in response to a wide array of inputs. In this study, we examined its role in the regulation of renal glucose reabsorption and gluconeogenesis. METHODS: Rictor, an essential component of mTORC2, was knocked out using the Pax8-LC1 system to generate inducible tubule–specific Rictor knockout (KO) mice. A second Rictor KO model was generated using Cre-loxP technology and a proximal tubule–specific promoter. Animals were fasted and refed on normal- or high-potassium (K(+)) diets. Metabolic parameters, including glucose homeostasis and kidney function, were assessed. Kidneys and livers were harvested for molecular analysis of gluconeogenic enzymes, glucose transporters, and mTORC2-regulated signaling targets. RESULTS: On a normal-K(+) diet, mTORC2 KO mice had marked glycosuria despite normal blood glucose. Immunofluorescence microscopy and immunostaining of plasma membrane protein fractions showed lower proximal tubule apical membrane sodium-glucose cotransporter 2 and sodium-glucose cotransporter 1 in the fed state of KO mice. Metabolic testing showed elevated fasting insulin, impaired pyruvate tolerance, and elevated hemoglobin A1c. In addition, renal gluconeogenic enzymes were increased, consistent with abnormal renal gluconeogenesis in KO mice. These effects correlated with reduced downstream phosphorylation of Akt and the transcription factor forkhead box O4, identifying a novel role of forkhead box O4 in the kidney tubules. Interestingly, high dietary K(+) rapidly lowered glycosuria and gluconeogenesis, despite persistent reduction in mTORC2 substrate phosphorylation. CONCLUSIONS: Renal tubule mTORC2 is critical for coordinated regulation of sodium-glucose cotransporter membrane localization and renal gluconeogenesis. In the absence of mTORC2, dietary K(+) promotes glucose reabsorption and suppresses gluconeogenesis independent of insulin signaling. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2025_05_29_ASN0000000703.mp3