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.

Vitamin D3 Activates Phosphatidylinositol-3-Kinase/Protein Kinase B via Insulin-Like Growth Factor-1 to Improve Testicular Function in Diabetic Rats.

OBJECTIVE: In diabetes mellitus, vitamin D3 deficiency affects sex hormone levels and male fertility; however, the mechanism leading to the disorder is unclear. This research was designed to investigate the mechanism of vitamin D3 deficiency and hypogonadism in diabetic rats. Our aim was to assess serum vitamin D3 levels and the relationship among vitamin D3, insulin-like growth factor-1 (IGF-1), and testicular function. MATERIALS AND METHODS: Rats with streptozotocin-induced diabetes were randomly divided into four groups and treated with different doses of vitamin D3: no vitamin D3, low (0.025 µg/kg/day), high (0.1 µg/kg/day), and high (0.1 µg/kg/day) with JB-1 (the insulin-like growth factor-1 receptor inhibitor group, 100 µg/kg/day). The groups were compared with wild-type rats, which function as the control group. Various parameters such as vitamin D3 and IGF-1 were compared between the experimental and wild-type groups, and their correlations were determined. RESULTS: Twelve weeks of vitamin D3 supplementation improved the testosterone levels, as shown by the increase in the level of serum IGF-1 in diabetic rats. Phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT), which was a downstream of the signaling pathway of IGF-1, was significantly increased after vitamin D3 treatment. CONCLUSIONS: The study shows that vitamin D3 may promote the expression of testosterone and improve testicular function in diabetic rats by activating PI3K/AKT via IGF-1.

Vitamin D3 supplementation improves testicular function in diabetic rats through peroxisome proliferator-activated receptor-γ/transforming growth factor-beta 1/nuclear factor-kappa B.

AIMS/INTRODUCTION: Vitamin D3 deficiency can lead to male hypogonadism in diabetes mellitus, but the target organs and the mechanism driving the disorder are unclear. This experiment was designed to study the relationship between vitamin D3 deficiency and hypogonadism in diabetes mellitus. MATERIALS AND METHODS: Rats with streptozotocin-induced diabetes were randomly divided into four groups and treated with different doses of vitamin D3 : blank (no vitamin D3 ), low (0.025 µg/kg/day), high (0.1 µg/kg/day), high (0.1 µg/kg/day) and with bisphenol A diglycidyl ether (peroxisome proliferator-activated receptor gamma inhibitor 30 mg/kg/day). They were compared with wild-type rats. RESULTS: After 12 weeks, the vitamin D3 supplements had partially restored testicular pathological changes, as shown by reduced testicular fibrosis related to downregulation transforming growth factor beta 1 and apoptosis related to downregulation of nuclear factor kappa B, but not the pituitary gland. The expression of peroxisome proliferator-activated receptor gamma, which can inhibit transforming growth factor beta 1 and nuclear factor kappa B, was significantly increased after treatment with vitamin D3 . CONCLUSIONS: These results suggest that treatment with vitamin D3 can improve testicular function in diabetic rats through the peroxisome proliferator-activated receptor gamma/transforming growth factor beta 1/nuclear factor kappa B signaling pathway.