Diabetes & Metabolism Journal最新文献

Background: Tau is a microtubule-associated protein whose abnormal phosphorylation disrupts the cytoskeleton and induces cell death. While its role is well known in neuro degenerative diseases, its function in kidney pathology, particularly diabetic nephropathy (DN), is not well understood.

Methods: DN was induced in NADPH oxidase 5 (NOX5) pod+ mice through a high-fat diet (HFD; 60% kcal fat) for 3, 6, and 12 weeks. Kidney tissues and cultured mesangial cells were analyzed for tau phosphorylation at specific residues (Ser202 and Thr205), fibrosis markers (e.g., α-smooth muscle actin), and endoplasmic reticulum (ER) stress. Tau phosphorylation was modulated using thousand and one amino acid kinase inhibitor and ER stress inhibitors. Immunohistochemistry was also performed on human renal biopsy samples from DN patients.

Results: pTau Ser202 and Thr205 expression levels were elevated by 6 weeks of the HFD and remained persistently upregulated at 12 weeks. Human biopsy analysis further revealed elevated pTau Ser202 and Thr205 expression in the patients with DN, which correlated with proteinuria. In NOX5 pod+ mice, early metabolic changes developed by HFD led to tau phosphorylation and kidney damage. Transforming growth factor β-induced fibrosis or thapsigargin-induced ER stress increased tau phosphorylation, while inhibiting tau phosphorylation or ER stress alleviated mesangial cell damage.

Conclusion: Our findings demonstrate that site-specific tau phosphorylation is associated with renal injury in DN and may serve as a potential marker of disease severity. The interplay between tau phosphorylation and ER stress appears to contribute to disease progression. Targeting tau phosphorylation and its upstream stress pathways may offer new therapeutic strategies for DN.

Background: Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus, characterized by neuroinflammation. Previous studies have shown that dorsal root ganglion (DRG) neurons can regulate microglial polarization. This study aims to investigate how exosomal circ_STAT1-AS from dexmedetomidine (DEX)-treated DRG neurons affects microglial polarization in DPN.

Methods: Exosomes were isolated from DRG neurons and identified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. DPN rat model was established by high sugar and fat diet combined with streptozotocin injection. The sciatic nerve conduction velocity, mechanical withdrawal threshold, and thermal withdrawal latency of rats were measured. Hematoxylin & eosin staining and immunohistochemical staining of S100B were used to detect spinal cord tissue injury. Chromatin immunoprecipitation quantitative polymerase chain reaction detected the interaction between histone deacetylase 5 (HDAC5) and unc-13 homolog D (UNC13D) promoter, as well as the H3 acetylation at lysine 27 (H3K27) acetylation level in UNC13D promoter region.

Results: Exosomal circ_STAT1-AS secretion from DRG neurons was enhanced by DEX treatment. These exosomes inhibited microglial M1 polarization and facilitated its M2 polarization by suppressing signal transducer and activator of transcription 1 (STAT1) translation. Mechanistically, the enhanced exosome secretion was attributed to the increased UNC13D expression, which resulted from HDAC5 inhibition and subsequent elevation of H3K27 acetylation modification at UNC13D promoter under DEX treatment. In DPN rat model, intrathecal administration of circ_STAT1-AS-enriched exosomes alleviated neuropathic symptoms and reduced neuroinflammation.

Conclusion: Exosomal circ_STAT1-AS delivery from DRG neurons was enhanced through DEX-mediated HDAC5/UNC13D axis. The increased exosomal circ_STAT1-AS absorbed by microglia suppressed STAT1 translation to inactivate JAK/STAT1 pathway, thereby modulating microglial M1/M2 polarization balance and alleviating DPN.

Background: Diabetic foot ulcers are a severe diabetic complication causing poor healing. Itaconate, a tricarboxylicacid cycle byproduct, has been shown to improve wound healing. This study investigated the potential of 4-octyl itaconate (4-OI), an esterified derivative of itaconate, to modulate efferocytosis andmacrophage pro-resolving function to promote diabetic wound healing.

Methods: A diabetic mouse wound model was used. For in vitro analysis, RAW264.7 macrophages and apoptotic Jurkat cells were cocultured under high glucose (HG, 30 mM). To further evaluate the roles of macrophages, monocarboxylate transporter 1 (MCT1), and lactate in 4-OI-promoted diabetic wound healing, we used clodronate-liposomes (CLD-Lipo) to deplete macrophages, AZD3965 (an MCT1 inhibitors), telmisartan to validate our hypothesis.

Results: In diabetic mice, impaired apoptotic neutrophils clearance and persistent M1 activation delayed wound healing. 4-OI improved diabetic wound repair by enhancing efferocytosis, shifting macrophages toward M2 pro-resolving phenotype, and boosting angiogenesis. 4-OI showed a protective effect mediated by macrophages, while endothelial cells and neutrophils also played synergistic roles in diabetic wound healing. Moreover, 4-OI upregulated MCT1 which, in turn, increased release of lactate triggered by efferocytosis at the wound site. Lastly, we confirmed that pro-resolving effects of 4-OI onmacrophage function were mediated by promoting pro-resolving macrophage proliferation and polarization via efferocytosis-induced lactate release and subsequent activation of G protein-coupled receptor 132 (GPR132).

Conclusion: 4-OI promotes diabetic wound healing through macrophage-dependent/independent mechanisms. Moreover, the protective effect of 4-OI on macrophage was mediated through MCT1-mediated lactate release triggered by efferocytosis and subsequent GRP132 activation.

Background: In this study, we aimed to validate the potential of miR-374 in ameliorating hyperglycemia by regulating peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1α) expression in pancreatic islets and liver.

Methods: To identify miRNAs targeting PGC-1α, we performed miRNA chip analysis in rat islets under hyperglycemic and euglycemic conditions. Luciferase reporter assay was performed to identify miR binding sites in the 3'-untranslated region (3' UTR) of PGC-1α. In db/db mice, miRNA-encapsulated adenoviruses were administered and intraperitoneal glucose tolerance test and glucose stimulated insulin secretion tests were performed. For enhanced delivery to β-cells, we developed exendin-4 (Ex-4) coated cationic lipoparticles (CCLs) encapsulating miRNAs. The therapeutic potential of Ex-4-CCL-miRNA was further evaluated in insulin-producing cells derived from induced pluripotent stem cells.

Results: By analyzing miRNA expression in primary rat islets exposed under hyperglycemic environment, we identified miR-374 as a potential target. In vitro experiments confirmed that miR-374 significantly suppressed PGC-1α expression in β-cells and hepatocytes by binding to its 3'-UTR. In vivo experiments using adenovirus-mediated miR-374 (Ad-miR-374) delivering directly to the pancreas and liver of db/db mice demonstrated improved glycemic control, enhanced insulin secretion, and downregulated hepatic gluconeogenesis-related genes (G6Pase, Pepck, PC). To enhance the clinical applicability of miR-374, we developed Ex-4-CCLs. Ex-4-CCL-miR-374 successfully alleviated hyperglycemia, restored pancreatic islet function, and decreased gluconeogenesis gene expression in db/db mice. Furthermore, Ex-4-CCL-miR-374 improved insulin secretory function in glucotoxicity-exposed human induced pluripotent stem cell-derived insulin producing cells.

Conclusion: Based on these findings, we propose that Ex-4-CCL-miR-374 as a promising therapeutic approach to reverse β-cell dysfunction and improve hepatic insulin resistance in type 2 diabetes mellitus.

Backgruound: There is insufficient evidence to determine a precise blood pressure target in older adults with diabetes mellitus. In this study, we evaluated the potential relationship between blood pressure levels and end-stage renal disease (ESRD) in older type 2 diabetes mellitus (T2DM) patients without ESRD using a nationwide longitudinal population dataset.

Methods: We performed a retrospective, observational, cohort study including 267,156 older (≥65 years old) patients with T2DM and without ESRD from 2009 to 2018 based on the National Health Information Database. We divided the participants into eight groups based on their systolic blood pressure (SBP) and diastolic blood pressure (DBP). The primary outcome was ESRD. All outcomes were analyzed using Cox proportional hazards regression analysis while controlling for baseline covariates.

Results: During a median follow-up of 7.26 years, the incidence rate of ESRD was 2.03 per 1,000 person-years. In multivariable Cox proportional hazard modeling, the risk of the primary outcome was the lowest in groups with an SBP of 100-119 mm Hg and DBP of <80 mm Hg. In subgroup analysis according to the use of hypertension medication, there was a significant difference in DBP (P for interaction=0.026) but no difference in SBP (P for interaction=0.247). The risk of ESRD was the lowest in patients with an SBP of 110-129 mm Hg taking hypertension medication and the highest in the group with an SBP of ≥160 mm Hg.

Conclusion: Maintaining blood pressure at less than 120/80 mm Hg might prevent progression to ESRD in older T2DM patients without cardiovascular disease.

Backgruound: The prevalence of type 2 diabetes mellitus (T2DM) increases with age, and cellular senescence of pancreatic β-cells plays a key role in T2DM pathogenesis. As canagliflozin and acarbose have been shown to increase lifespan in mice, we investigated the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitor, α-glucosidase inhibitor or both on the cellular senescence of β-cells in a T2DM mouse model.

Methods: Enavogliflozin (0.3 mg/kg), acarbose (10 mg/kg), or vehicle was orally administered daily to db/db mice for 6 weeks. The levels of senescence markers (p16, p21, and p53) in the pancreas and kidney were measured through real-time polymerase chain reaction (PCR), immunofluorescence staining, and Western blot. In an in vitro analysis, isolated pancreatic islets were exposed to H2O2 to induce cellular senescence, then treated with β-hydroxybutyrate (β-HB), and subsequently assessed for levels of senescent markers.

Results: Enavogliflozin alone or combined with acarbose effectively lowered blood glucose levels in db/db mice. The combined treatment resulted in the greatest increase in β-cell function calculated using insulinogenic index and homeostasis model assessment of β-cell function compared to the vehicle. Additionally, the combined treatment significantly reversed the increase in p16, with a similar trend observed in p21 and p53 in the islets. Treatment increased circulating β-HB and in vitro analysis suggested the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by β-HB in reducing senescence in the islets.

Conclusion: The combined administration of enavogliflozin and acarbose significantly reduced blood glucose, improved β-cell function, and reduced senescent β-cells in db/db mice. This combination therapy holds potential as a senotherapeutic strategy for managing T2DM.

Backgruound: Hyperglycemia during pregnancy increases the risk of adverse perinatal outcomes and birth defects. Evidence regarding the long-term safety of antidiabetic drugs during pregnancy is still lacking.

Methods: A two-sample Mendelian randomization (MR) study was performed to assess the causal association between six antidiabetic drug targets (ABCC8, DPP4, INSR, GLP1R, PPARG, and SLC5A2) and seven adverse perinatal outcomes and five congenital malformation outcomes. Inverse variance weighted (IVW) was adopted as the main MR method, and sensitivity analysis using traditional MR methods was performed to evaluate the robustness of the results.

Results: We observed strong evidence that sodium-glucose cotransporter 2 (SGLT2) inhibitors (odds ratio [OR], 0.084; 95% confidence interval [CI], 0.009 to 0.834; P=0.034) reduces the risk of preterm birth; genetic variation in sulfonylurea drug targets (OR, 0.015; 95% CI, 2.50E-04 to 0.919; P=0.045) and genetic variation in thiazolidinedione drug targets (OR, 0.007; 95% CI, 4.16E-04 to 0.121; P=0.001) reduced the risk of eclampsia/preeclampsia; glucagon-like peptide 1 (GLP-1) analogues target (β=-0.549; 95% CI, -0.958 to -0.140; P=0.009) was inversely associated with fetal birth weight; thiazolidinedione target was inversely associated with gestational age (β=-0.952; 95% CI, -1.785 to -0.118; P=0.025); SGLT2 inhibitors reduced the risk of cardiocirculatory malformations (OR, 0.001; 95% CI, 8.75E-06 to 0.126; P=0.005).

Conclusion: Most antidiabetic drugs are safe when used during the perinatal period. Of note, GLP-1 analogues may lead to a risk of low birth weight, while thiazolidinediones may lead to a reduction in fetal gestational age.