SGLT2 inhibitors mitigate kidney tubular metabolic and mTORC1 perturbations in youth-onset type 2 diabetes

Abstract

RenalytixAI, Travere, Regeneron, IONIS, consulting fees through the University of Michigan from Astellas, Poxel, Janssen and UCB. In addition, M.K. has a patent PCT/EP2014/073413 "Biomarkers and methods for progression prediction for chronic kidney disease" licensed.

Digging deep into cells to find mechanisms of kidney protection by SGLT2 inhibitors

“…Not all of the Schaub et al study findings fit neatly within the paradigm of receptor-mediated SGLT2 inhibition ( 18 ). Suppression of mTORC1 by lowered intracellular glucose and activation of AMPK may also reduce glycolysis ( 19 ).…”

“…In this issue of the JCI , Schaub et al describe changes in single-cell transcriptomics among young people with type 2 diabetes who were SGLT2 inhibitor users compared with nonusers and healthy controls ( 18 ). Although the comparison groups were small ( n = 6–10 each) and SGLT2 inhibitors were prescribed for clinical indications, the study observations provide detailed molecular information at the cellular level in the human kidney according to diabetes status and SGLT2 inhibitor use.…”

“…Suppression of mTORC1 by lowered intracellular glucose and activation of AMPK may also reduce glycolysis ( 19 ). Decreases in readouts for the mTORC1 pathway were observed throughout nephron segments, effectively uncoupling these changes from solute transport ( 18 ). Importantly, SGLT2 inhibition engenders relative cell starvation ( Figure 1B ), as opposed to a nutrient overload state, which may occur in a variety of cell types by non–SGLT2 receptor mechanisms ( 20 ).…”

“…Although the SGLT2 inhibitors appear to have a class effect for protecting the kidney that is largely dose independent, biases may also exist due to use of various SGLT2 inhibitors in different doses. Other kidney-protective agents (e.g., angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers) were also used more commonly in the SGLT2 inhibitor users (30%) than in nonusers (17%) ( 18 ).…”

Understanding renal phosphate handling: unfinished business

“…The effect of phosphate on glycolysis did not result in systemic changes in expression of metabolism genes. It is notable that another recent study of the effect of SGLT2 inhibitors in type I diabetes confirmed inhibition of glycolysis as one of the metabolic effects on kidney cells [28]. The investigators did not examine the effects on phosphate transport explicitly as the focus of this study was on metabolism.…”