High Potassium Suppresses Glycosuria and Gluconeogenesis in Tubule-specific mTORC2 Knockout Mice

Background: Insulin promotes renal proximal tubule glucose reabsorption and suppresses gluconeogenesis (GNG). The kinase mTORC2 is critical for insulin signaling in multiple cell types. In the kidney tubules, mTORC2 knockout has recently been shown to cause glycosuria via reduced plasma membrane SGLT2 and SGLT1 as well as inappropriately increased renal GNG. Potassium (K + ) also plays an important role in systemic glucose homeostasis. However, the overall importance of K + for the regulation of renal glucose reabsorption and GNG is poorly understood. Methods: Rictor, an essential component of mTORC2, was knocked out using the Pax8-LC1 system to generate inducible tubule specific Rictor knockout (TRKO) mice. To examine the role of dietary K + on renal glucose homeostasis, TRKO mice and wild-type (WT) littermates were fed with either a normal 0.5% K + diet or high 3% K + diet while in balance cages. Kidney tissue was harvested after feeding and processed to study plasma membrane glucose transporters, gluconeogenic enzymes, and mTORC2-regulated targets by western blot and qPCR. Results: On a normal K + diet, TRKO mice had marked glycosuria despite indistinguishable blood glucose relative to WT controls. Kidney plasma membrane fractions showed decreased SGLT2 and SGLT1, supporting reduced renal glucose reabsorption. Additional metabolic testing provided evidence for renal insulin resistance with elevated fasting insulin, impaired pyruvate tolerance, elevated hemoglobin A1c, and increased renal gluconeogenic enzymes. On a high K + diet, glycosuria resolved and plasma membrane SGLT2 and SGLT1 were restored in TRKO mice. In addition, TRKO animals fed with a high K + diet had suppressed gluconeogenic enzymes compared to WT mice. Regardless of dietary K + content, TRKO animals had similar reductions in phosphorylation of mTORC2 substrates compared to WT controls. Conclusion: Renal tubule mTORC2 is critical for coordinated glucose reabsorption by SGLT2 and SGLT1 as well as suppression of renal GNG. High dietary K + promotes sodium-glucose cotransport by restoring plasma membrane SGLT2 and SGLT1 in TRKO mice. High dietary K + also prevents excessive GNG in TRKO mice. High K + appears to regulate these processes independently of mTORC2 and its downstream substrates, such as Akt. High K + could potentially provide an alternative signaling mechanism to regulate renal glucose reabsorption and GNG in states of insulin resistance. Grants from the NIH (T32, R01) and The James Hilton Manning and Emma Austin Manning Foundation. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.