Evidence suggests that insulin resistance (IR) is an autonomous risk factor for cardiovascular disease (CVD). Nevertheless, the association between estimated glucose disposal rate (eGDR), a novel indicator of IR, and incident CVD and mortality in chronic kidney disease (CKD) patients without diabetes remains uncertain. The study included 19,906 participants from the UK Biobank who had an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m2 or a urinary albumin-to-creatinine ratio (UACR) ≥ 30 mg/g and no history of CVD and diabetes. Individuals were divided into three categories based on tertiles of eGDR. The outcome was a composite CVD (coronary heart disease (CHD) and stroke) and mortality (all-cause, non-accidental, and cardiovascular mortality). Furthermore, a cohort of 1,600 individuals from the US National Health and Nutrition Examination Survey (NHANES) was applied to validate the association between eGDR and mortality. The Cox proportional hazards regression models were used to examine the association between eGDR and event outcomes. During a follow-up of around 12 years, 2,860 CVD, 2,249 CHD, 783 stroke, 2,431 all-cause, 2,326 non-accidental and 492 cardiovascular deaths were recorded from UK Biobank. Higher eGDR level was not only associated with lower risk of CVD (hazard ratio [HR] 0.641, 95% confidence interval [CI] 0.559–0.734), CHD (HR 0.607, 95% CI 0.520–0.709), stroke (HR 0.748, 95% CI 0.579–0.966), but also related to reduced risk of all-cause (HR 0.803, 95% CI 0.698–0.923), non-accidental (HR 0.787, 95% CI 0.682–0.908), and cardiovascular mortality (HR 0.592, 95% CI 0.423–0.829). Validation analyses from NHANES yielded consistent relationship on mortality. In these two large cohorts of CKD patients without DM, a higher eGDR level was associated with a decreased risk of CVD and mortality.

Aim Insulin resistance is a feature of type 2 diabetes mellitus (T2DM). The estimated glucose disposal rate (eGDR), a validated marker for insulin resistance, is associated with complications of diabetes, but few studies have explored the relationship between eGDR and renal outcomes in T2DM. This study investigated the value of eGDR in predicting renal progression in T2DM. Methods A total of 956 T2DM patients with a baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73m²and a 5-year follow-up were enrolled. Primary outcomes were rapid eGFR decline, eGFR <60 mL/min/1.73m², and composite renal endpoint consisting of 50% eGFR decline, doubling of serum creatinine, or end-stage renal disease. A continuous scale with restricted cubic spline curves and a generalized linear model were applied to evaluate the associations between eGDR and primary outcomes. Results 23.95% of patients experienced rapid eGFR decline, 21.97% with eGFR <60 mL/min/1.73m², and 12.13% with the composite renal endpoint. eGDR showed a relationship with follow-up eGFR and percent change in eGFR (P<0.001). eGDR <6.34 mg/kg/min was an independent risk factor for rapid eGFR decline, eGFR<60 mL/min/1.73m²or the composite renal endpoint(P8.33 mg/kg/min decreased the risk of rapid eGFR decline by 75%, eGFR<60 mL/min/1.73m² by 60%, and the composite renal endpoint by 61%. Subgroup analysis was performed by sex, age, and diabetes duration, which showed that eGDR was associated with primary outcomes. Conclusions Lower eGDR is a predictive factor for renal deterioration in T2DM patients.

Aims: To evaluate the correlation of nesfatin-1, GSH and SOD levels with β-cell insulin secretion and their influence on insulin secretion in the development of type 2 diabetes mellitus (T2DM).Materials and methods: 75 patients with T2DM, 67 with prediabetes and 37 heathy participants were recruited in this study. Serum levels of nesfatin-1, GSH and SOD were quantified and statistically analyzed.Results: The levels of nesfatin-1, GSH and SOD in T2DM were significantly decreased (P < 0.001) compared to either in prediabetes or in healthy control, and significant reduction of these biomarkers was also observed in prediabetes when compared to the control (P < 0.001). Circulating nesfatin-1, GSH and SOD were not only strongly correlated with β-cell insulin secretion, but also exerted remarkable influence on the secretion.Conclusion: Serum nesfatin-1, GSH and SOD are important factors involving insulin secretion in the development of T2DM, which may help provide new ideas for forthcoming investigations on the roles of these factors in pathogenesis of T2DM, as well as for active prediction and prevention of prediabetes before it develops into overt T2DM.

Diabetic nephropathy (DN) is a serious complication of diabetes, and inflammation plays a crucial role. Sirtuin 2 (SIRT2), a NAD+-dependent deacetylase, which is involved in the regulation of cell metabolism, proliferation and longevity through deacetylation. Our previous research showed a positive correlation between urinary SIRT2 levels and renal injury markers in DN patients. Therefore, this study explored the specific role of SIRT2 in DN and its regulatory relationship with inflammatory response. Increased expression of SIRT2 was observed in kidney tissues of DN mice and in HK2 cells induced by HG/PA. SIRT2 knockout mice alleviated microalbuminuria, inflammatory responses, and kidney damage induced by HFD/STZ. In HK2 cells, reducing SIRT2 expression or inhibiting its acetylase activity alleviated the inflammatory response induced by HG/PA, whereas overexpression of SIRT2 exacerbated this response. Further investigation revealed that SIRT2 directly interacts with c-Jun/c-Fos, promoting their deacetylation. And inhibitors of c-Jun/c-Fos partially reversed the upregulation of inflammatory factors caused by SIRT2 overexpression. Meanwhile, disrupting SIRT2 reduced the binding activity between AP-1 and the MCP-1 promoter, while overexpressing SIRT2 further increased their binding activity in HK2 cells. Interestingly, SIRT2 increased its phosphorylation while deacetylating c-Jun, leading to nuclear accumulation of p-c-Jun. In conclusion, SIRT2 knockout can alleviate kidney injury and inflammatory response in HFD/STZ mice. The mechanism is related to the increased acetylation of c-Jun/c-Fos in renal tubular epithelial cells, accompanied by crosstalk between c-Jun phosphorylation and acetylation. Blocking SIRT2 could therefore be a potential therapeutic target for DN. Graphical Abstract

Fine particulate matter (PM_2.5)-related health issues have received increasing attention as a worldwide public health problem, and PM_2.5-related chronic kidney disease (CKD) has been emerging over the years. Limited research has focused on the mechanism of PM_2.5-induced kidney disease. To investigate the impact of PM_2.5 on the kidney and its potential mechanism, we generated a PM_2.5-exposed C57BL/6 mouse model by using Shanghai Meteorological and Environment Animal Exposure System (Shanghai-METAS) for 12 weeks, urine, blood and kidney tissues were collected. The pathological changes and the function of the kidney were measured after PM_2.5 exposure for 12 weeks. Along with glomerular damage, tubular damage was also severe in PM_2.5-induced mice. The results of mRNA-seq indicate that pyroptosis is involved. Pyroptosis is defined as caspase-1-dependent programmed cell death in response to insults. The expression of the nucleotide-binding and oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3), Caspase-1, gasdermin D (GSDMD) and IL-1β was detected. NLRP3 inflammasome activation and subsequent pyroptosis were observed in PM_2.5-exposed kidney tissues and PM_2.5-exposed Bumpt cells too. At the meantime, the inhibitors of NLRP3 and caspase-1 were applied to the PM_2.5 exposed Bumpt cells. It turned out to have a significant rescue effect of the inhibitors. This study revealed new insights into PM_2.5-induced kidney injury and specific kidney pathological damage, as well as morphological changes, and defined the important role of pyroptosis in PM_2.5-induced kidney dysfunction.