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: Meteorin-like (Metrnl) is a novel adipokine which is highly expressed in adipose tissue and has a beneficial effect on glucose and lipid metabolism. High density lipoprotein cholesterol (HDL-C) is well recognized to be inversely associated with cardiovascular events. However, the relationship between serum Metrnl levels and HDL-C in the type 2 diabetes mellitus (T2DM) remains unclear. Therefore, the present study aimed to evaluate the association of serum Metrnl with HDL-C levels in T2DM. Materials and Methods: Eighty participants with T2DM were included in this cross-sectional study. They were divided into two groups according to HDL-C levels: Group1 (lower HDL-C group): HDL-C < 1.04 mmol/L; Group2 (higher HDL-C group): HDL-C ≥ 1.04 mmol/L. Serum Metrnl levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: As compared with lower HDL-C levels groups, serum Metrnl levels were significantly higher in the group with higher HDL-C. Binary logistic regression analysis showed serum Metrnl levels were positively associated with HDL-C group after adjustment with sex, age, body mass index (BMI), mean arterial pressure (MAP), fasting blood glucose (FPG), triglyceride (TG). Furthermore, serum Metrnl levels were inversely correlated with insulin resistance index (HOMA-IR). HDL-C levels were lowest in the group with the lowest Metrnl levels group and remained positively associated with Metrnl after adjustment for sex, age, BMI, TG, and HOMA-IR by using multivariate logistic regression analysis. Conclusion: Serum Metrnl levels were positively associated with HDL-C levels in patients with T2DM.This suggests that increasing serum Metrnl levels maybe a candidate for improving lipid metabolism and preventing cardiovascular events in T2DM. Registry and the Registration No. of the Study/Trial: The study was registered in the Chinese clinical trial registry (ChiCTR- 2100047148).

BACKGROUND Cognitive dysfunction is the main manifestation of central neuropathy. Although cognitive impairments tend to be overlooked in patients with diabetes mellitus (DM), there is a growing body of evidence linking DM to cognitive dysfunction. Hyperglycemia is closely related to neurological abnormalities, while often disregarded in clinical practice. Changes in cerebral neurotransmitter levels are associated with a variety of neurological abnormalities and may be closely related to blood glucose control in patients with type 2 DM (T2DM). AIM To evaluate the concentrations of cerebral neurotransmitters in T2DM patients exhibiting different hemoglobin A1c (HbA1c) levels. METHODS A total of 130 T2DM patients were enrolled at the Department of Endocrinology of Shanghai East Hospital. The participants were divided into four groups according to their HbA1c levels using the interquartile method, namely Q1 (< 7.875%), Q2 (7.875%-9.050%), Q3 (9.050%-11.200%) and Q4 (≥ 11.200%). Clinical data were collected and measured, including age, height, weight, neck/waist/hip circumferences, blood pressure, comorbidities, duration of DM, and biochemical indicators. Meanwhile, neurotransmitters in the left hippocampus and left brainstem area were detected by proton magnetic resonance spectroscopy. RESULTS The HbA1c level was significantly associated with urinary microalbumin (mALB), triglyceride, low-density lipoprotein cholesterol (LDL-C), homeostasis model assessment of insulin resistance (HOMA-IR), and beta cell function (HOMA-β), N-acetylaspartate/creatine (NAA/Cr), and NAA/choline (NAA/Cho). Spearman correlation analysis showed that mALB, LDL-C, HOMA-IR and NAA/Cr in the left brainstem area were positively correlated with the level of HbA1c (P < 0.05), whereas HOMA-β was negatively correlated with the HbA1c level (P < 0.05). Ordered multiple logistic regression analysis showed that NAA/Cho [Odds ratio (OR): 1.608, 95% confidence interval (95%CI): 1.004-2.578, P < 0.05], LDL-C (OR: 1.627, 95%CI: 1.119-2.370, P < 0.05), and HOMA-IR (OR: 1.107, 95%CI: 1.031-1.188, P < 0.01) were independent predictors of poor glycemic control. CONCLUSION The cerebral neurotransmitter concentrations in the left brainstem area in patients with T2DM are closely related to glycemic control, which may be the basis for the changes in cognitive function in diabetic patients.

Purpose: The dusk phenomenon refers to a spontaneous and transient pre-dinner hyperglycemia that affects glucose fluctuation and glycemic control, and the increasing use of continuous glucose monitoring (CGM) has facilitated its diagnosis. We investigated the frequency of the dusk phenomenon and its relationship with the time in range (TIR) in patients with type 2 diabetes mellitus (T2DM). Patients and Methods: This study involved 102 patients with T2DM who underwent CGM for 14 days. CGM-derived metrics and clinical characteristics were evaluated. A consecutive dusk blood glucose difference (pre-dinner glucose minus 2-hour post-lunch glucose) of ≥ 0 or once-only dusk blood glucose difference of < 0 was diagnosed as the clinical dusk phenomenon (CLDP). Results: We found that the percentage of CLDP was 11.76% (10.34% in men, 13.64% in women). Compared with the non-CLDP group, the CLDP group tended to be younger and have a lower percentage of TIR (%TIR^3.9-10) and higher percentage of time above range (%TAR^{> 10} and %TAR^{> 13.9}) (P ≤ 0.05). Adjusted for confounding factors, the binary logistic regression analysis showed a negative association of CLDP with %TIR (odds ratio < 1, P < 0.05). We repeated the correlation analysis based on 70%TIR and found significant differences in hemoglobin A1c, fasting blood glucose, mean blood glucose, standard deviation of the sensor glucose values, glucose coefficient of variation, largest amplitude of glycemic excursions, mean amplitude of glycemic excursions, glucose management indicator, and percentage of CLDP between the two subgroups of TIR ≤ 70% and TIR > 70% (P < 0.05). The negative association between TIR and CLDP still remained after adjustment by the binary logistic regression analysis. Conclusion: The CLDP was frequently present in patients with T2DM. The TIR was significantly correlated with the CLDP and could serve as an independent negative predictor.

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for type 2 diabetes mellitus (T2DM) and may influence reward-related pathways, suggesting potential effects on nicotine dependence and smoking-related outcomes. Randomized evidence in patients with T2DM remains limited. This trial evaluates the effects of GLP-1RAs on nicotine dependence and smoking exposure and explores potential neural mechanisms using functional MRI (fMRI). Methods and analysis: This single-center, parallel-group randomized controlled trial will enroll 46 male adults with T2DM who are current smokers with Fagerström Test for Nicotine Dependence (FTND) score ≥4. Participants will be randomized (1:1) to receive a GLP-1RA or a dipeptidyl peptidase-4 inhibitor (DPP-4i) for 24 weeks as part of routine glucose-lowering therapy optimization. No structured smoking cessation counseling or smoking cessation pharmacotherapy will be provided by the research team. The primary endpoint is change in FTND score from baseline, assessed at weeks 1, 4, 8, 12, and 24. Secondary endpoints include changes in exhaled carbon monoxide (CO) and smoking cessation rate at weeks 12 and 24, and changes in metabolic parameters. Exploratory endpoints include changes in resting-state fMRI measures from baseline to week 24 and their associations with smoking- and metabolic-related outcomes. Trial status: Recruitment started in June 2025 and is ongoing. Clinical Trial Registration: ClinicalTrials.gov , identifier (NCT06924697).