Attenuated kidney oxidative metabolism in young adults with type 1 diabetes

Ye Ji Choi; Gabriel Richard; Guanshi Zhang; Jeffrey B. Hodgin; Dawit S. Demeke; Yingbao Yang; Jennifer A. Schaub; Ian M. Tamayo; Bhupendra K. Gurung; Abhijit S. Naik; Viji Nair; Carissa Birznieks; Alexis MacDonald; Phoom Narongkiatikhun; Susan Gross; Lynette Driscoll; Maureen Flynn; Kalie Tommerdahl; Kristen J. Nadeau; Viral N. Shah; Tim Vigers; Janet K. Snell-Bergeon; Jessica Kendrick; Daniel H. van Raalte; Lu Ping Li; Pottumarthi Prasad; Patricia Ladd; Bennett B. Chin; David Z. Cherney; Phillip J. McCown; Fadhl Alakwaa; Edgar A. Otto; Frank C. Brosius; Pierre Jean Saulnier; Victor G. Puelles; Jesse A. Goodrich; Kelly Street; Manjeri A. Venkatachalam; Aaron Ruiz; Ian H. de Boer; Robert G. Nelson; Laura Pyle; Denis P. Blondin; Kumar Sharma; Matthias Kretzler; Petter Bjornstad

doi:10.1172/JCI183984

Attenuated kidney oxidative metabolism in young adults with type 1 diabetes

Ye Ji Choi, Gabriel Richard, Guanshi Zhang, Jeffrey B. Hodgin, Dawit S. Demeke, Yingbao Yang, Jennifer A. Schaub, Ian M. Tamayo, Bhupendra K. Gurung, Abhijit S. Naik, Viji Nair, Carissa Birznieks, Alexis MacDonald, Phoom Narongkiatikhun, Susan Gross, Lynette Driscoll, Maureen Flynn, Kalie Tommerdahl, Kristen J. Nadeau, Viral N. ShahTim Vigers, Janet K. Snell-Bergeon, Jessica Kendrick, Daniel H. van Raalte, Lu Ping Li, Pottumarthi Prasad, Patricia Ladd, Bennett B. Chin, David Z. Cherney, Phillip J. McCown, Fadhl Alakwaa, Edgar A. Otto, Frank C. Brosius, Pierre Jean Saulnier, Victor G. Puelles, Jesse A. Goodrich, Kelly Street, Manjeri A. Venkatachalam, Aaron Ruiz, Ian H. de Boer, Robert G. Nelson, Laura Pyle, Denis P. Blondin, Kumar Sharma, Matthias Kretzler, Petter Bjornstad^*

^*Corresponding author af dette arbejde

Institut for Klinisk Medicin - Patologi

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

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Abstract

BACKGROUND. In type 1 diabetes (T1D), impaired insulin sensitivity may contribute to the development of diabetic kidney disease (DKD) through alterations in kidney oxidative metabolism. METHODS. Young adults with T1D (n = 30) and healthy controls (HCs) (n = 20) underwent hyperinsulinemic-euglycemic clamp studies, MRI, ¹¹C-acetate PET, kidney biopsies, single-cell RNA-Seq, and spatial metabolomics to assess this relationship. RESULTS. Participants with T1D had significantly higher glomerular basement membrane (GBM) thickness compared with HCs. T1D participants exhibited lower insulin sensitivity and cortical oxidative metabolism, correlating with higher insulin sensitivity. Proximal tubular transcripts of TCA cycle and oxidative phosphorylation enzymes were lower in T1D. Spatial metabolomics showed reductions in tubular TCA cycle intermediates, indicating mitochondrial dysfunction. The Slingshot algorithm identified a lineage of proximal tubular cells progressing from stable to adaptive/maladaptive subtypes, using pseudotime trajectory analysis, which computationally orders cells along a continuum of states. This analysis revealed distinct distribution patterns between T1D and HCs, with attenuated oxidative metabolism in T1D attributed to a greater proportion of adaptive/maladaptive subtypes with low expression of TCA cycle and oxidative phosphorylation transcripts. Pseudotime progression associated with higher HbA1c, BMI, and GBM, and lower insulin sensitivity and cortical oxidative metabolism. CONCLUSION. These early structural and metabolic changes in T1D kidneys may precede clinical DKD.

Originalsprog	Engelsk
Artikelnummer	e183984
Tidsskrift	Journal of Clinical Investigation
Vol/bind	134
Nummer	24
ISSN	0021-9738
DOI	https://doi.org/10.1172/JCI183984
Status	Udgivet - dec. 2024

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10.1172/JCI183984Licens: CC BY

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Choi, Y. J., Richard, G., Zhang, G., Hodgin, J. B., Demeke, D. S., Yang, Y., Schaub, J. A., Tamayo, I. M., Gurung, B. K., Naik, A. S., Nair, V., Birznieks, C., MacDonald, A., Narongkiatikhun, P., Gross, S., Driscoll, L., Flynn, M., Tommerdahl, K., Nadeau, K. J., ... Bjornstad, P. (2024). Attenuated kidney oxidative metabolism in young adults with type 1 diabetes. Journal of Clinical Investigation, 134(24), Artikel e183984. https://doi.org/10.1172/JCI183984

@article{33c0c14577a1497894fc26ee1fe491e8,

title = "Attenuated kidney oxidative metabolism in young adults with type 1 diabetes",

abstract = "BACKGROUND. In type 1 diabetes (T1D), impaired insulin sensitivity may contribute to the development of diabetic kidney disease (DKD) through alterations in kidney oxidative metabolism. METHODS. Young adults with T1D (n = 30) and healthy controls (HCs) (n = 20) underwent hyperinsulinemic-euglycemic clamp studies, MRI, 11C-acetate PET, kidney biopsies, single-cell RNA-Seq, and spatial metabolomics to assess this relationship. RESULTS. Participants with T1D had significantly higher glomerular basement membrane (GBM) thickness compared with HCs. T1D participants exhibited lower insulin sensitivity and cortical oxidative metabolism, correlating with higher insulin sensitivity. Proximal tubular transcripts of TCA cycle and oxidative phosphorylation enzymes were lower in T1D. Spatial metabolomics showed reductions in tubular TCA cycle intermediates, indicating mitochondrial dysfunction. The Slingshot algorithm identified a lineage of proximal tubular cells progressing from stable to adaptive/maladaptive subtypes, using pseudotime trajectory analysis, which computationally orders cells along a continuum of states. This analysis revealed distinct distribution patterns between T1D and HCs, with attenuated oxidative metabolism in T1D attributed to a greater proportion of adaptive/maladaptive subtypes with low expression of TCA cycle and oxidative phosphorylation transcripts. Pseudotime progression associated with higher HbA1c, BMI, and GBM, and lower insulin sensitivity and cortical oxidative metabolism. CONCLUSION. These early structural and metabolic changes in T1D kidneys may precede clinical DKD.",

author = "Choi, {Ye Ji} and Gabriel Richard and Guanshi Zhang and Hodgin, {Jeffrey B.} and Demeke, {Dawit S.} and Yingbao Yang and Schaub, {Jennifer A.} and Tamayo, {Ian M.} and Gurung, {Bhupendra K.} and Naik, {Abhijit S.} and Viji Nair and Carissa Birznieks and Alexis MacDonald and Phoom Narongkiatikhun and Susan Gross and Lynette Driscoll and Maureen Flynn and Kalie Tommerdahl and Nadeau, {Kristen J.} and Shah, {Viral N.} and Tim Vigers and Snell-Bergeon, {Janet K.} and Jessica Kendrick and {van Raalte}, {Daniel H.} and Li, {Lu Ping} and Pottumarthi Prasad and Patricia Ladd and Chin, {Bennett B.} and Cherney, {David Z.} and McCown, {Phillip J.} and Fadhl Alakwaa and Otto, {Edgar A.} and Brosius, {Frank C.} and Saulnier, {Pierre Jean} and Puelles, {Victor G.} and Goodrich, {Jesse A.} and Kelly Street and Venkatachalam, {Manjeri A.} and Aaron Ruiz and {de Boer}, {Ian H.} and Nelson, {Robert G.} and Laura Pyle and Blondin, {Denis P.} and Kumar Sharma and Matthias Kretzler and Petter Bjornstad",

note = "Publisher Copyright: {\textcopyright} 2024, Choi et al.",

year = "2024",

month = dec,

doi = "10.1172/JCI183984",

language = "English",

volume = "134",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "24",

}

Choi, YJ, Richard, G, Zhang, G, Hodgin, JB, Demeke, DS, Yang, Y, Schaub, JA, Tamayo, IM, Gurung, BK, Naik, AS, Nair, V, Birznieks, C, MacDonald, A, Narongkiatikhun, P, Gross, S, Driscoll, L, Flynn, M, Tommerdahl, K, Nadeau, KJ, Shah, VN, Vigers, T, Snell-Bergeon, JK, Kendrick, J, van Raalte, DH, Li, LP, Prasad, P, Ladd, P, Chin, BB, Cherney, DZ, McCown, PJ, Alakwaa, F, Otto, EA, Brosius, FC, Saulnier, PJ, Puelles, VG, Goodrich, JA, Street, K, Venkatachalam, MA, Ruiz, A, de Boer, IH, Nelson, RG, Pyle, L, Blondin, DP, Sharma, K, Kretzler, M & Bjornstad, P 2024, 'Attenuated kidney oxidative metabolism in young adults with type 1 diabetes', Journal of Clinical Investigation, bind 134, nr. 24, e183984. https://doi.org/10.1172/JCI183984

TY - JOUR

T1 - Attenuated kidney oxidative metabolism in young adults with type 1 diabetes

AU - Choi, Ye Ji

AU - Richard, Gabriel

AU - Zhang, Guanshi

AU - Hodgin, Jeffrey B.

AU - Demeke, Dawit S.

AU - Yang, Yingbao

AU - Schaub, Jennifer A.

AU - Tamayo, Ian M.

AU - Gurung, Bhupendra K.

AU - Naik, Abhijit S.

AU - Nair, Viji

AU - Birznieks, Carissa

AU - MacDonald, Alexis

AU - Narongkiatikhun, Phoom

AU - Gross, Susan

AU - Driscoll, Lynette

AU - Flynn, Maureen

AU - Tommerdahl, Kalie

AU - Nadeau, Kristen J.

AU - Shah, Viral N.

AU - Vigers, Tim

AU - Snell-Bergeon, Janet K.

AU - Kendrick, Jessica

AU - van Raalte, Daniel H.

AU - Li, Lu Ping

AU - Prasad, Pottumarthi

AU - Ladd, Patricia

AU - Chin, Bennett B.

AU - Cherney, David Z.

AU - McCown, Phillip J.

AU - Alakwaa, Fadhl

AU - Otto, Edgar A.

AU - Brosius, Frank C.

AU - Saulnier, Pierre Jean

AU - Puelles, Victor G.

AU - Goodrich, Jesse A.

AU - Street, Kelly

AU - Venkatachalam, Manjeri A.

AU - Ruiz, Aaron

AU - de Boer, Ian H.

AU - Nelson, Robert G.

AU - Pyle, Laura

AU - Blondin, Denis P.

AU - Sharma, Kumar

AU - Kretzler, Matthias

AU - Bjornstad, Petter

PY - 2024/12

Y1 - 2024/12

N2 - BACKGROUND. In type 1 diabetes (T1D), impaired insulin sensitivity may contribute to the development of diabetic kidney disease (DKD) through alterations in kidney oxidative metabolism. METHODS. Young adults with T1D (n = 30) and healthy controls (HCs) (n = 20) underwent hyperinsulinemic-euglycemic clamp studies, MRI, 11C-acetate PET, kidney biopsies, single-cell RNA-Seq, and spatial metabolomics to assess this relationship. RESULTS. Participants with T1D had significantly higher glomerular basement membrane (GBM) thickness compared with HCs. T1D participants exhibited lower insulin sensitivity and cortical oxidative metabolism, correlating with higher insulin sensitivity. Proximal tubular transcripts of TCA cycle and oxidative phosphorylation enzymes were lower in T1D. Spatial metabolomics showed reductions in tubular TCA cycle intermediates, indicating mitochondrial dysfunction. The Slingshot algorithm identified a lineage of proximal tubular cells progressing from stable to adaptive/maladaptive subtypes, using pseudotime trajectory analysis, which computationally orders cells along a continuum of states. This analysis revealed distinct distribution patterns between T1D and HCs, with attenuated oxidative metabolism in T1D attributed to a greater proportion of adaptive/maladaptive subtypes with low expression of TCA cycle and oxidative phosphorylation transcripts. Pseudotime progression associated with higher HbA1c, BMI, and GBM, and lower insulin sensitivity and cortical oxidative metabolism. CONCLUSION. These early structural and metabolic changes in T1D kidneys may precede clinical DKD.

AB - BACKGROUND. In type 1 diabetes (T1D), impaired insulin sensitivity may contribute to the development of diabetic kidney disease (DKD) through alterations in kidney oxidative metabolism. METHODS. Young adults with T1D (n = 30) and healthy controls (HCs) (n = 20) underwent hyperinsulinemic-euglycemic clamp studies, MRI, 11C-acetate PET, kidney biopsies, single-cell RNA-Seq, and spatial metabolomics to assess this relationship. RESULTS. Participants with T1D had significantly higher glomerular basement membrane (GBM) thickness compared with HCs. T1D participants exhibited lower insulin sensitivity and cortical oxidative metabolism, correlating with higher insulin sensitivity. Proximal tubular transcripts of TCA cycle and oxidative phosphorylation enzymes were lower in T1D. Spatial metabolomics showed reductions in tubular TCA cycle intermediates, indicating mitochondrial dysfunction. The Slingshot algorithm identified a lineage of proximal tubular cells progressing from stable to adaptive/maladaptive subtypes, using pseudotime trajectory analysis, which computationally orders cells along a continuum of states. This analysis revealed distinct distribution patterns between T1D and HCs, with attenuated oxidative metabolism in T1D attributed to a greater proportion of adaptive/maladaptive subtypes with low expression of TCA cycle and oxidative phosphorylation transcripts. Pseudotime progression associated with higher HbA1c, BMI, and GBM, and lower insulin sensitivity and cortical oxidative metabolism. CONCLUSION. These early structural and metabolic changes in T1D kidneys may precede clinical DKD.

UR - http://www.scopus.com/inward/record.url?scp=85212271634&partnerID=8YFLogxK

U2 - 10.1172/JCI183984

DO - 10.1172/JCI183984

M3 - Journal article

C2 - 39436695

AN - SCOPUS:85212271634

SN - 0021-9738

VL - 134

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 24

M1 - e183984

ER -

Attenuated kidney oxidative metabolism in young adults with type 1 diabetes

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