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

Jennifer A. Schaub; Fadhl M. AlAkwaa; Phillip J. McCown; Abhijit S. Naik; Viji Nair; Sean Eddy; Rajasree Menon; Edgar A. Otto; Dawit Demeke; John Hartman; Damian Fermin; Christopher L. O’Connor; Lalita Subramanian; Markus Bitzer; Roger Harned; Patricia Ladd; Laura Pyle; Subramaniam Pennathur; Ken Inoki; Jeffrey B. Hodgin; Frank C. Brosius; Robert G. Nelson; Matthias Kretzler; Petter Bjornstad

doi:10.1172/JCI164486

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

Jennifer A. Schaub, Fadhl M. AlAkwaa, Phillip J. McCown, Abhijit S. Naik, Viji Nair, Sean Eddy, Rajasree Menon, Edgar A. Otto, Dawit Demeke, John Hartman, Damian Fermin, Christopher L. O’Connor, Lalita Subramanian, Markus Bitzer, Roger Harned, Patricia Ladd, Laura Pyle, Subramaniam Pennathur, Ken Inoki, Jeffrey B. HodginFrank C. Brosius, Robert G. Nelson, Matthias Kretzler, Petter Bjornstad

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Abstract

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.

Original language	English (US)
Article number	:e164486
Journal	Journal of Clinical Investigation
Volume	133
Issue number	5
DOIs	https://doi.org/10.1172/JCI164486
State	Published - Mar 1 2023
Externally published	Yes

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Medicine(all)

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10.1172/JCI164486

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Schaub, J. A., AlAkwaa, F. M., McCown, P. J., Naik, A. S., Nair, V., Eddy, S., Menon, R., Otto, E. A., Demeke, D., Hartman, J., Fermin, D., O’Connor, C. L., Subramanian, L., Bitzer, M., Harned, R., Ladd, P., Pyle, L., Pennathur, S., Inoki, K., ... Bjornstad, P. (2023). SGLT2 inhibitors mitigate kidney tubular metabolic and mTORC1 perturbations in youth-onset type 2 diabetes. Journal of Clinical Investigation, 133(5), [:e164486]. https://doi.org/10.1172/JCI164486

Schaub, JA, AlAkwaa, FM, McCown, PJ, Naik, AS, Nair, V, Eddy, S, Menon, R, Otto, EA, Demeke, D, Hartman, J, Fermin, D, O’Connor, CL, Subramanian, L, Bitzer, M, Harned, R, Ladd, P, Pyle, L, Pennathur, S, Inoki, K, Hodgin, JB, Brosius, FC, Nelson, RG, Kretzler, M & Bjornstad, P 2023, 'SGLT2 inhibitors mitigate kidney tubular metabolic and mTORC1 perturbations in youth-onset type 2 diabetes', Journal of Clinical Investigation, vol. 133, no. 5, :e164486. https://doi.org/10.1172/JCI164486

@article{7f53b5b6797f4aad95ab18dd425d0ee4,

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

abstract = "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.",

author = "Schaub, {Jennifer A.} and AlAkwaa, {Fadhl M.} and McCown, {Phillip J.} and Naik, {Abhijit S.} and Viji Nair and Sean Eddy and Rajasree Menon and Otto, {Edgar A.} and Dawit Demeke and John Hartman and Damian Fermin and O{\textquoteright}Connor, {Christopher L.} and Lalita Subramanian and Markus Bitzer and Roger Harned and Patricia Ladd and Laura Pyle and Subramaniam Pennathur and Ken Inoki and Hodgin, {Jeffrey B.} and Brosius, {Frank C.} and Nelson, {Robert G.} and Matthias Kretzler and Petter Bjornstad",

note = "Funding Information: We like to thank Yingbao Yang for his expert technical support. This work was supported in part by the University of Michigan O{\textquoteright}Brien Kidney Translational Core Center grant (P30 DK081943) and a grant from the JDRF Center for Excellence (5-COE-2019-861-S-B) to MK and SP. The Renal HEIR, IMPROVE-T2D, and CROCODILE studies were supported by the NIDDK (K23 DK116720, R01 DK132399, UC2 DK114886, and P30 DK116073), JDRF (2-SRA-2019-845-S-B, 3-SRA-2022-1097-M-B), the Boettcher Foundation, and in part by the Intramural Research Program at NIDDK and the Centers for Disease Control and Prevention (CKD Initiative) under inter-agency agreement #21FED2100157DPG. PB receives salary and research support from the NIDDK (R01 DK129211, R01 DK132399, RO1 HL165433, R21 DK129720, K23 DK116720, and UC2 DK114886), JDRF (3-SRA-2022-1097-M-B, 3-SRA-2022-1243-M-B, and 3-SRA-2022-1230-M-B), the Boettch-er Foundation, the American Heart Association (20IPA35260142), the Ludeman Family Center for Women{\textquoteright}s Health Research at the University of Colorado, the Department of Pediatrics, Section of Endocrinology, and the Barbara Davis Center for Diabetes at University of Colorado School of Medicine. JAS receives salary and research support from the NIDDK (K08 DK124449) and the Michigan Diabetes Research Center. ASN receives salary and research support from the NIDDK (K23 DK125529). MB was supported by R01 DK100449. KI receives salary and research support from the NIDDK and the National Institute of General Medical Sciences (NIGMS) (R01 DK124709, R01 GM145631). Publisher Copyright: Copyright: {\textcopyright} 2023, Schaub et al.",

year = "2023",

month = mar,

day = "1",

doi = "10.1172/JCI164486",

language = "English (US)",

volume = "133",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "The American Society for Clinical Investigation",

number = "5",

}

TY - JOUR

T1 - SGLT2 inhibitors mitigate kidney tubular metabolic and mTORC1 perturbations in youth-onset type 2 diabetes

AU - Schaub, Jennifer A.

AU - AlAkwaa, Fadhl M.

AU - McCown, Phillip J.

AU - Naik, Abhijit S.

AU - Nair, Viji

AU - Eddy, Sean

AU - Menon, Rajasree

AU - Otto, Edgar A.

AU - Demeke, Dawit

AU - Hartman, John

AU - Fermin, Damian

AU - O’Connor, Christopher L.

AU - Subramanian, Lalita

AU - Bitzer, Markus

AU - Harned, Roger

AU - Ladd, Patricia

AU - Pyle, Laura

AU - Pennathur, Subramaniam

AU - Inoki, Ken

AU - Hodgin, Jeffrey B.

AU - Brosius, Frank C.

AU - Nelson, Robert G.

AU - Kretzler, Matthias

AU - Bjornstad, Petter

N1 - Funding Information: We like to thank Yingbao Yang for his expert technical support. This work was supported in part by the University of Michigan O’Brien Kidney Translational Core Center grant (P30 DK081943) and a grant from the JDRF Center for Excellence (5-COE-2019-861-S-B) to MK and SP. The Renal HEIR, IMPROVE-T2D, and CROCODILE studies were supported by the NIDDK (K23 DK116720, R01 DK132399, UC2 DK114886, and P30 DK116073), JDRF (2-SRA-2019-845-S-B, 3-SRA-2022-1097-M-B), the Boettcher Foundation, and in part by the Intramural Research Program at NIDDK and the Centers for Disease Control and Prevention (CKD Initiative) under inter-agency agreement #21FED2100157DPG. PB receives salary and research support from the NIDDK (R01 DK129211, R01 DK132399, RO1 HL165433, R21 DK129720, K23 DK116720, and UC2 DK114886), JDRF (3-SRA-2022-1097-M-B, 3-SRA-2022-1243-M-B, and 3-SRA-2022-1230-M-B), the Boettch-er Foundation, the American Heart Association (20IPA35260142), the Ludeman Family Center for Women’s Health Research at the University of Colorado, the Department of Pediatrics, Section of Endocrinology, and the Barbara Davis Center for Diabetes at University of Colorado School of Medicine. JAS receives salary and research support from the NIDDK (K08 DK124449) and the Michigan Diabetes Research Center. ASN receives salary and research support from the NIDDK (K23 DK125529). MB was supported by R01 DK100449. KI receives salary and research support from the NIDDK and the National Institute of General Medical Sciences (NIGMS) (R01 DK124709, R01 GM145631). Publisher Copyright: Copyright: © 2023, Schaub et al.

PY - 2023/3/1

Y1 - 2023/3/1

N2 - 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.

AB - 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.

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JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

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ER -

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

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