Canagliflozin improves diabetic kidney disease by inducing fasting-like and aestivation-like metabolic patterns: Study

The study found that canagliflozin ameliorates diabetic kidney disease by inducing fasting-like and aestivation-like metabolic patterns. Furthermore, DKD was ameliorated by glycine supplementation, and glycine beneficial effects were probably due to the activation of the AMP-activated protein kinase (AMPK)/mammalian target of the rapamycin (mTOR) pathway.

Sodium–glucose co-transporter 2 (SGLT2) inhibitors are antihyperglycaemic drugs that protect the kidney of patients with type 2 diabetes (T2D). However, there is no clear understanding of the underlying mechanisms mediating the renal benefits of SGLT2 inhibitors. Considering the fuel switches that occur during therapeutic SGLT2 inhibition, Yanyan Zhao, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China, and colleagues hypothesized that SGLT2 inhibitors induce fasting-like and aestivation-like metabolic patterns, both of which contribute to the regulation of metabolic reprogramming in diabetic kidney disease.

For this purpose, the research team performed untargeted and targeted metabolomics on plasma samples from participants with T2D and kidney disease (n=35, 11 women) receiving 100 mg/day canagliflozin at baseline and 12 weeks follow-up. Next, using db/db mice, the researchers obtained a systematic snapshot of the effect of CANA on the key metabolites and pathways in the kidney. Moreover, they studied the effects of glycine supplementation in db/db mice and human proximal tubular epithelial cells (human kidney-2 [HK-2]) cells.

The study led to the following findings:

· Treatment of DKD patients with CANA for 12 weeks significantly reduced HbA1c from a median of 49.0 mmol/mol to 42.2 mmol/mol, and reduced urinary albumin/creatinine ratio from 67.8 mg/mmol to 47.0 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.

· 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/mammalian target of the rapamycin pathway.

"Our findings showed that CANA ameliorates DKD by inducing fasting-like and aestivation-like metabolic patterns," the researchers wrote. "Furthermore, diabetic kidney disease was ameliorated by glycine supplementation, and the beneficial effects of glycine were probably due to the activation of the AMPK/mTOR pathway."

Reference:

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 (2024). https://doi.org/10.1007/s00125-023-06078-0