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

• Published in: The Journal of clinical investigation 2023-03, Vol.133 (5)
• Main Authors: Schaub, Jennifer A, AlAkwaa, Fadhl M, McCown, Phillip J, Naik, Abhijit S, Nair, Viji, Eddy, Sean, Menon, Rajasree, Otto, Edgar A, Demeke, Dawit, Hartman, John, Fermin, Damian, O'Connor, Christopher L, Subramanian, Lalita, Bitzer, Markus, Harned, Roger, Ladd, Patricia, Pyle, Laura, Pennathur, Subramaniam, Inoki, Ken, Hodgin, Jeffrey B, Brosius, 3rd, Frank C, Nelson, Robert G, Kretzler, Matthias, Bjornstad, Petter
• Format: Article
• Language: English
• Subjects: Adolescent; Animals; Child; Complications and side effects; Development and progression; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetic nephropathies; Drug therapy; Humans; Hypoglycemic agents; Kidney - metabolism; Kidney Glomerulus - metabolism; Mechanistic Target of Rapamycin Complex 1; Metabolism; Mice; Nephrology; Pediatric research; Physiological aspects; Prevention; Risk factors; Sodium-Glucose Transporter 2 - genetics; Sodium-Glucose Transporter 2 Inhibitors - pharmacology; Type 2 diabetes; Young Adult
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI164486

The molecular mechanisms of sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) remain incompletely understood. Single-cell RNA sequencing and morphometric data were collected from research kidney biopsies donated by young persons with type 2 diabetes (T2D), aged 12 to 21 years, and healthy controls (HCs). Participants with T2D were obese and had higher estimated glomerular filtration rates and mesangial and glomerular volumes than HCs. Ten T2D participants had been prescribed SGLT2i (T2Di[+]) and 6 not (T2Di[-]). Transcriptional profiles showed SGLT2 expression exclusively in the proximal tubular (PT) cluster with highest expression in T2Di(-) patients. However, transcriptional alterations with SGLT2i treatment were seen across nephron segments, particularly in the distal nephron. SGLT2i treatment was associated with suppression of transcripts in the glycolysis, gluconeogenesis, and tricarboxylic acid cycle pathways in PT, but had the opposite effect in thick ascending limb. Transcripts in the energy-sensitive mTORC1-signaling pathway returned toward HC levels in all tubular segments in T2Di(+), consistent with a diabetes mouse model treated with SGLT2i. Decreased levels of phosphorylated S6 protein in proximal and distal tubules in T2Di(+) patients confirmed changes in mTORC1 pathway activity. We propose that SGLT2i treatment benefits the kidneys by mitigating diabetes-induced metabolic perturbations via suppression of mTORC1 signaling in kidney tubules.