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Canagliflozin regulates metabolic reprogramming in diabetic kidney disease by inducing fasting-like and aestivation-like metabolic patterns

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Abstract

Aims/hypothesis

Sodium–glucose co-transporter 2 (SGLT2) inhibitors (SGLT2i) are antihyperglycaemic drugs that protect the kidneys of individuals with type 2 diabetes mellitus. However, the underlying mechanisms mediating the renal benefits of SGLT2i are not fully understood. Considering the fuel switches that occur during therapeutic SGLT2 inhibition, we hypothesised that SGLT2i induce fasting-like and aestivation-like metabolic patterns, both of which contribute to the regulation of metabolic reprogramming in diabetic kidney disease (DKD).

Methods

Untargeted and targeted metabolomics assays were performed on plasma samples from participants with type 2 diabetes and kidney disease (n=35, 11 women) receiving canagliflozin (CANA) 100 mg/day at baseline and 12 week follow-up. Next, a systematic snapshot of the effect of CANA on key metabolites and pathways in the kidney was obtained using db/db mice. Moreover, the effects of glycine supplementation in db/db mice and human proximal tubular epithelial cells (human kidney-2 [HK-2]) cells were studied.

Results

Treatment of DKD patients with CANA for 12 weeks significantly reduced HbA1c from a median (interquartile range 25–75%) of 49.0 (44.0–57.0) mmol/mol (7.9%, [7.10–9.20%]) to 42.2 (39.7–47.7) mmol/mol (6.8%, [6.40–7.70%]), and reduced urinary albumin/creatinine ratio from 67.8 (45.9–159.0) mg/mmol to 47.0 (26.0–93.6) mg/mmol. The untargeted metabolomics assay showed downregulated glycolysis and upregulated fatty acid oxidation. The targeted metabolomics assay revealed significant upregulation of glycine. The kidneys of db/db mice undergo significant metabolic reprogramming, with changes in sugar, lipid and amino acid metabolism; CANA regulated the metabolic reprogramming in the kidneys of db/db mice. In particular, the pathways for glycine, serine and threonine metabolism, as well as the metabolite of glycine, were significantly upregulated in CANA-treated kidneys. Glycine supplementation ameliorated renal lesions in db/db mice by inhibiting food intake, improving insulin sensitivity and reducing blood glucose levels. Glycine supplementation improved apoptosis of human proximal tubule cells via the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway.

Conclusions/interpretation

In conclusion, our study shows that CANA ameliorates DKD by inducing fasting-like and aestivation-like metabolic patterns. Furthermore, DKD was ameliorated by glycine supplementation, and the beneficial effects of glycine were probably due to the activation of the AMPK/mTOR pathway.

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Abbreviations

AMPK:

AMP-activated protein kinase

BAX:

BCL-2 associated X

BCL-2:

B-cell lymphoma 2

CANA:

Canagliflozin

DEM:

Differentially expressed metabolite

DKD:

Diabetic kidney disease

FAO:

Fatty acid oxidation

FBG:

fasting blood glucose

GSH:

Glutathione

GSSG:

Oxidised GSH

H-CANA:

High-dose CANA group

H-GLY:

High-concentration glycine group

HK-2:

Human proximal tubular epithelial cells (human kidney-2)

L-CANA:

Low-dose CANA group

L-GLY:

Low-concentration glycine group

MDA:

Malondialdehyde

mTOR:

Mammalian target of rapamycin

NC:

Normal control (group)

OPLS-DA:

Orthogonal partial least-square discriminant analysis

PAS:

Periodic acid–Schiff

PCA:

Principal component analysis

PIOG:

Pioglitazone treatment group

SGLT2:

Sodium–glucose co-transporter 2

SGLT2i:

Sodium–glucose co-transporter 2 inhibitors

TEM:

Transmission electron microscopy

UACR:

Urinary albumin/creatinine ratio

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Authors and Affiliations

  1. Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

    Mingwei Shao, Qingzhu Wang, Feng Guo, Peijie Du, Yanxia Liu, Xiaojun Ma, Gaofei Ren, Yi Song, Yanyan Zhao & Guijun Qin

  2. Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

    Duo Chen, Fangyi Wei, Wei Zhang, Tian Gan, Yuanyuan Luo & Xunjie Fan

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  1. Mingwei Shao
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Correspondence to Yanyan Zhao or Guijun Qin.

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Acknowledgements

The authors would like to thank C. Song (Zhengzhou University of Public Health, Henan, China) for helpful discussions. We also thank all patients who participated in this study and generously provided us with blood samples.

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All data generated or analysed during this study are included in the manuscript and supporting files.

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81974110, 82170839).

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The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Contribution statement

MS, DC, YZ and GQ conceived and designed the research. MS, QW, FG, PD, YLiu, XM and GR contributed to the clinical trial and data collection. MS, DC, FW, WZ, TG, YLuo, XF and YS contributed to animal experiments and data collection. MS and FW contributed to cell experiments and data collection. MS and DC contributed to the analysis and interpretation of data. MS, DC and FW drafted the paper. WZ, TG, YLuo and XF revised the paper for important intellectual content. GQ revised the manuscript critically. All authors approved the final version of the manuscript prior to publication. YZ and GQ are the guarantors of this work, had full access to all of the study data and take responsibility for the integrity and accuracy of the data.

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Mingwei Shao and Duo Chen contributed equally to this manuscript as joint first authors.

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Shao, M., Chen, D., Wang, Q. et al. Canagliflozin regulates metabolic reprogramming in diabetic kidney disease by inducing fasting-like and aestivation-like metabolic patterns. Diabetologia 67, 738–754 (2024). https://doi.org/10.1007/s00125-023-06078-0

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