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

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.

Compound Danshen Dripping Pills moderate intestinal flora and the TLR4/MyD88/NF-κB signaling pathway in alleviating cognitive dysfunction in type 2 diabetic KK-Ay mice.

BACKGROUD: Bidirectional communications between the gut microbiota and the brain may play a critical role in diabetes-related cognitive impairment. Compound Danshen Dripping Pills (CDDP) treatment has shown remarkable improvement in cognitive impairment in people with type 2 diabetes mellitus (T2DM) in clinical settings, but the underlying mechanisms remain unknown. PURPOSE: An extensive detailed strategy via in vivo functional experiments, transcriptomics, metabolomics, and network pharmacology was adopted to investigate the CDDP-treatment mechanism in diabetic cognitive dysfunction. METHODS: For 12 weeks, KK-Ay mice, a spontaneous T2DM model, were intragastrically administered various doses of CDDP solution or an equivalent volume of water, and the nootropic drug piracetam was orally administered as a positive control. At the 12th week, cognition was assessed using Morris water maze tests and brain magnetic resonance imaging (MRI). Furthermore, transcriptomics, metabolomics, and network pharmacology analyses were applied to reveal novel molecular mechanisms of CDDP-treatment in diabetic cognitive dysfunction of KK-Ay mice, which were then validated using quantitative real-time polymerase chain reaction and Western blot. RESULTS: Here we verified that CDDP can suppress inflammatory response and alleviate the cognitive dysfunction in KK-Ay mice. Also, as demonstrated by 16S rRNA sequencing and short-chain fatty acids (SCFAs) analysis, CDDP attenuated intestinal flora disorder as well as increases of metabolites including butyric acid, hexanoic acid, and isohexic acid. Given the integrated analyses of network pharmacology, transcriptomic, metabolomic data, and molecular biology, the TLR4/MyD88/NF-κB signaling pathway was activated in diabetes, which could be reversed by CDDP. CONCLUSIONS: Our findings demonstrate that CDDP restructures the gut microbiota composition and increased the intestinal SCFAs in KK-Ay mice, which might inhibit neuroinflammation, and thus improve diabetic mice cognitive disorder.