Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Sodium-glucose cotransporter protein 2 inhibitors (SGLT2i) are antihyperglycemic agents that provide additional renal-protective effects in patients with DKD, independent of their glucose-lowering effects. However, the underlying mechanism remains unclear. This study hypothesized that SGLT2i could alleviate diabetic kidney injury by inhibiting ferroptosis and explored its potential mechanisms. C57BL/6J mice were randomly divided into the control, DKD, DKD+dapagliflozin, and DKD+insulin treatment groups. Blood glucose levels and body weight were monitored. Renal function, tissue pathology, mitochondrial morphology and function, and lipid peroxidation biomarkers (lipid peroxidation [LPO], malondialdehyde [MDA], glutathione peroxidase 4 [GPX4], glutathione [GSH], and cystine transporter solute carrier family 7 member 11 [SLC7A11]) were evaluated. Human proximal tubule cells (HK2 cells) were exposed to high glucose alone or in combination with dapagliflozin. The mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) level, NAD+/NADH ratio (oxidized/reduced ratio of nicotinamide adenine dinucleotide), and lipid peroxidation were measured. In addition, the role of the β-hydroxybutyrate- Calcium/Calmodulin Dependent Protein Kinase Kinase 2 (BHB-CaMKK2) axis in mediating dapagliflozin regulating ferroptosis was examined. Dapagliflozin significantly ameliorated kidney injury in mice with DKD. Typical changes in ferroptosis, including lipid peroxidation and impaired antioxidant capacity, increased in mice with DKD and HG-treated HK-2 cells. Dapagliflozin significantly improves ferroptosis-related lipid peroxidation and mitochondrial dysfunction. Furthermore, dapagliflozin suppressed the expression of CaMKK2, a key ferroptosis regulator. Specific CaMKK2 inhibitors alleviated mitochondrial damage and ferroptosis, whereas a CaMKK2 agonist counteracted the protective effects of dapagliflozin against mitochondrial, antioxidant, and anti-ferroptosis effects. In addition, dapagliflozin increased BHB production, which mediates its nephroprotective effects. Dapagliflozin improves DKD by inhibiting ferroptosis, promoting BHB production, and regulating CaMKK2.

Purpose: Dapagliflozin has been used extensively in patients with type 2 diabetes mellitus (T2DM). However, due to the potential diabetic ketoacidosis (DKA) risk of dapagliflozin, its use in type 1 diabetes mellitus (T1DM) is limited. Here, we reported an obese patient with T1DM and inadequate glycemic control. We carefully recommended she use dapagliflozin as an insulin adjuvant to achieve better glycemia control and to assess possible benefits and risks. Methods and Results: The patient was a 27-year-old female who had underlying T1DM for 17 years with a body weight of 75.0 kg, body mass index (BMI) of 28.2 kg/m², and glycated hemoglobin (HbA1c) 7.7% when admitted. To treat her diabetes, she had used an insulin pump for 15 years (the recent dosage of insulin was 45 IU/d) and oral metformin for 3 years (0.5 g qid). In order to decrease body weight and achieve better glycemic control, dapagliflozin (FORXIGA, AstraZeneca, Indiana) was administered as an insulin adjuvant. The patient presented sever DKA with a euglycemia (euDKA) after two days of the administration of dapagliflozin at a dose of 10 mg/d. euDKA occurred again after the administration of dapagliflozin at a dose of 3.3 mg/d. However, after using a smaller dose of dapagliflozin (1.5 mg/d), this patient achieved better glycemia control, with a significant reduction in daily insulin dosage and gradual weight loss, without significant hypoglycemia or DKA occurring. At the sixth month of the administration of dapagliflozin, the HbA1c was 6.2% for the patient, her daily insulin dosage was 22.5 IU, and her body weight was 60.2 kg. Conclusions: The appropriate dose of dapagliflozin is critical for a patient with T1DM patient therapy in order to find a correct balance between the benefits and risks.

Despite being the most common form of chronic liver disease, there are still no approved drugs for thetreatment of non-alcoholic fatty liver disease (NAFLD). The aim of this study was to elucidate the therapeutic effects and possible mechanisms of hydrogen (H2) inhalation in mice with NAFLD. Male C57BL/6 mice (6 weeks old) were fed either a 60% fat diet (high-fat diet [HFD]) or a 10% fat diet (normal diet) for 11 weeks. Then, H2 was administered to random HFD-fed mice for another 11 weeks before they were euthanized. Biochemical analysis of serum samples, histological analysis of liver and ileum samples, 16S rRNA sequencing analysis of stool samples, and analysis of the expression levels of related factors by enzyme-linked immunosorbent assay were conducted to determine the effect of H2 intervention on NAFLD. H2 inhalation alleviated hyperglycemia and impaired glucose tolerance; decreased the serum concentrations of triglycerides, cholesterol, alanine aminotransferase, aspartate aminotransferase, lipopolysaccharide, and tumor necrosis factor-alpha; and ameliorated liver injury by a HFD, although no weight loss was observed. Interestingly, H2 inhalation increased the relative abundance of Akkermansia muciniphila and decreased the Firmicutes-to-Bacteroidia ratio in the intestinal tract of NAFLD mice. These data indicate that H2 alleviated the symptoms of NAFLD by increasing the abundance of A. muciniphila in the intestine. Thus, H2 may be a new potential treatment strategy for patients with NAFLD.

Background Increasing evidence in recent years has suggested that Th1, Th17 cells act as a crucial regulatorin autoimmune hepatitis (AIH). Rapamycin, as a inhibitor of mammalian target of rapamycin (mTOR), which modulates T cell activation, differentiation and migration, is known to be able to selectively inhibit the activation of T helper cells including Th1 and Th17 subsets. However, little is known about the underlying regulatory mechanisms. Results In this study, we demonstrated that rapamycin ameliorated AIH in mice model by inhibiting Th1 and Th17 cells. Further analysis revealed that the suppressive function of rapamycin was associated with the downregulation of p70s6k-STAT3 signaling, which is downstream of mTOR, in AIH mice. Conclusions These findings suggest a previously unrecognized role for rapamycin immunoregulatory function and its protective effect on AIH, providing additional insight for the selection of alternative clinical protocols for autoimmune diseases.