Diabetes & Metabolism Journal最新文献

Background: Tubulointerstitial fibrosis (TIF) due to epithelial-mesenchymal transition (EMT) is an inseparable feature of diabetic renal fibrosis. Although stimulator of interferon genes (STING) has been shown to have potential in regulating EMT, whether and how it modulates EMT in diabetic kidney disease (DKD) mice remains unclear. Here, we investigated the role and the underlying mechanisms of STING-mediated EMT on TIF in DKD.

Methods: STING expression was detected in human renal biopsy tissues and serum samples with DKD. Mouse models with genetic deletion of STING or inhibition by a STING inhibitor (C176) were established to further investigate the functions of STING in vivo. The in vitro roles of STING were analyzed in human renal tubular epithelial (HK2) cells with STING overexpression or STING knockdown. RNA sequencing was used to explore the underlying mechanisms.

Results: STING was upregulated in the kidneys and serum from patients with DKD and negatively correlated with kidney function. STING deletion or pharmacologic inhibition with C176 ameliorated pathological lesions, renal function and fibrosis in mouse models of DKD. STING deficiency alleviated renal fibrosis in DKD mice via inhibiting EMT. Mechanistically, by RNA sequencing, inhibitor of differentiation 1 (ID1) was found to a downstream molecule of STING. Inhibition of ID1 on the basis of overexpression of STING could suppress EMT and renal fibrosis.

Conclusion: Our study provides evidence that STING deficiency relieves renal fibrosis by inhibiting ID1-mediated EMT and that inhibition of STING and ID1 has the potential therapeutic prospects for patients with DKD.

Background: Patients with type 2 diabetes mellitus (T2DM) and coronary ischemia face an exceptionally elevated risk, and the achievement of complete revascularization (CR) within this population could be challenging.

Methods: Patients with T2DM and coronary ischemia based on coronary angiography and retrospective angiographic fractional flow reserve analysis between 2014 and 2016 were included. The impact of the extent of revascularization on the improvement of endpoint events by sodium-glucose cotransporter 2 (SGLT2) inhibitors was analyzed. The primary study endpoint was major adverse cardiac events (MACE), while all-cause mortality served as secondary endpoints. Kaplan-Meier analysis and Cox proportional hazards regression model were adopted to assess the association between SGLT2 inhibitors and endpoint incidence.

Results: A total of 671 patients were identified. Among them, 206 (30.7%) were prescribed with SGLT2 inhibitors, while 484 (72.1%) achieved CR after the operation. During a mean 36-month follow-up, 100 MACE and 89 all-cause mortality were recorded. SGLT2 inhibitor users demonstrated lower rates of MACE (8.3% vs. 17.8%, P=0.002) and all-cause mortality (6.3% vs. 16.3%, P<0.001) compared to non-users. After adjusting for confounding factors in multivariable Cox analysis, the association between SGLT2 inhibitors and reduced MACE incidence remained consistent both in the CR and incomplete revascularization subgroups (hazard ratio [HR], 0.498; 95% confidence interval [CI], 0.246 to 0.938; P=0.040; and HR, 0.341; 95% CI, 0.123 to 0.805; P=0.023, respectively).

Conclusion: SGLT2 inhibitors were found to be associated with a reduced risk of 3-year MACE and all-cause mortality in patients with T2DM and coronary ischemia, regardless of extent of revascularization.

Background: Remnant cholesterol (RC) and low-grade inflammation are established contributors to cardiovascular disease (CVD) risks in diabetes. However, their combined prognostic impact remains unclear in dysglycemia. We evaluated the remnant cholesterol inflammation index (RCII), integrating RC and high-sensitivity C-reactive protein (hsCRP), for predicting mortality and CVD risks in diabetes/prediabetes.

Methods: This study included 2206 United States adults with diabetes/prediabetes from National Health and Nutrition Examination Survey 2015-2018. RCII was calculated as [RC (mg/dL)×hsCRP (mg/L)]/10. All-cause mortality was tracked via National Death Index until 2019; CVD risk was assessed cross-sectionally. Cox proportional hazard regression determined the hazard ratio (HR) and 95% confidence intervals (CIs) of RCII for all-cause mortality. Logistic regression models estimated the odds ratio (OR) and 95% CIs of RCII for CVD risks.

Results: For CVD risks, Q4 vs. Q1 demonstrated increased odds (OR, 2.32; 95% CI, 1.23 to 4.37), though per-standard deviation (SD) increments were non-significant (OR, 1.15; 95% CI, 0.98 to 1.35; P=0.083). During a median of 38 months follow-up, higher RCII quartiles showed graded associations with all-cause mortality (Q4 vs. Q1: HR, 2.45; 95% CI, 1.08 to 5.58; per 1-SD increase: HR, 1.21; 95% CI, 1.08 to 1.35). Restricted cubic splines confirmed dose-dependent relationships for CVD risks and all-cause mortality (all P=0.005 for overall). Subgroup analyses revealed consistent mortality associations but sex-specific CVD interactions (P=0.047 for interaction).

Conclusion: Our study found the RCII as a biomarker for predicting all-cause mortality and CVD risks in individuals with prediabetes or diabetes, highlighting the synergistic effects of RC and low-grade inflammation on adverse outcomes in this population and may facilitate early identification of individuals at heightened risk for CVD.

Background: Contrast-induced acute kidney injury (CIAKI) is the third cause of hospital-acquired acute kidney injury and diabetes mellitus (DM) was identified as a risk factor for CIAKI. However, the molecular mechanism underlying DM-CIAKI remains unclear, which needs further investigation.

Methods: DM-CIAKI models of mice and cells were established. The functions of kidneys were evaluated by detecting indicators and using hematoxylin and eosin staining. The abundance of genes and proteins was evaluated by real-time quantitative reverse transcription polymerase chain reaction, immunohistochemistry, immunofluorescence, and Western blot. Glutathione peroxidase, superoxide dismutase, and malondialdehyde were measured using commercial kits and reactive oxygen species was detected using dihydroethidium (DHE) probe and 2',7'-dichloroflfluorescein diacetate (DCFH-DA) method. Apoptosis of tissues and cells was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Cell viability and proliferation were measured using Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine (EdU) assay. The interaction between pumilio RNA binding family member 2 (PUM2) and histone deacetylase 9 (HDAC9) was validated using RNA immunoprecipitation (RIP) and RNA pull-down.

Results: PUM2 expression was observably reduced in DM-CIAKI models while HDAC9 expression was notably boosted. Subsequently, PUM2 silencing resulted in aggravation of kidney injury in DM-CIAKI mice through enhancing oxidative stress and suppressing autophagy, while HDAC9 inhibitor or HDAC9 silencing achieved the opposite results. In terms of mechanism, PUM2 could suppress stability of HDAC9 mRNA to attenuate HDAC9 expression. Furthermore, HDAC9 overexpression abolished PUM2 overexpression-mediated oxidative stress inhibition and autophagy promotion in high glucose and contrast media treatments-induced human kidney-2 (HK-2) cells.

Conclusion: PUM2 overexpression suppressed oxidative stress and promoted autophagy to alleviate renal injury in DM-CIAKI through interacting with HDAC9 mRNA, which mediated degradation of HDAC9 mRNA and inhibition of HDAC9 expression.

Background: Diabetic foot ulcer (DFU) represents a challenging complication of diabetes mellitus, characterized by slow healing processes. Protein kinase C delta (PKCδ) has been identified as a significant factor in the pathogenesis of various diabetic complications, including DFU. However, the precise underlying mechanisms remain to be fully elucidated.

Methods: Human umbilical vein endothelial cells (HUVECs) were cultivated under high glucose conditions and PKCδ was knocked down by siRNA. The proliferation, migration, and tube formation of HUVECs were detected. A metabolomics sequencing was done to identify potential metabolites contributing to the changes. HUVECs proliferation, migration, tube formation, and apoptosis were detected after regulating the production of selected metabolite. And finally, the effect of the metabolite on diabetic wound healing was detected.

Results: In vitro, knockdown of PKCδ upregulated glutamate decarboxylase 1 (GAD1) expression and gamma-aminobutyric acid (GABA) levels, which enhanced proliferation, migration, and tube formation and suppressed apoptosis of HUVECs under high glucose conditions. Interestingly, inhibition of GAD1 in normal glucose-treated HUVECs resulted in decreased proliferation, migration, tube formation, and increased apoptosis. Furthermore, in vivo experiments demonstrated that topical administration of GABA accelerated the healing of diabetic wounds in streptozotocin-induced type 2 diabetes mellitus mice, manifested as higher angiogenesis and proliferation.

Conclusion: The inhibition of GAD1-GABA pathway by PKCδ suppresses the proliferation, migration, tube formation and promotes the apoptosis of endothelial cells under high glucose and leads to delayed diabetic wound healing.

Background: The long-term clinical efficacy of intraportal islet transplantation is hampered by islet loss due to inflammation, oxidative stress, and insufficient vascularization. This study explores the venous sac as an alternative implantation site for islet transplantation in large animal models.

Methods: An immunosuppressed, diabetic cynomolgus monkey received allogeneic islet implants in its mesenteric venous sac, with metabolic assessments over 112 days. Dogs underwent islet autotransplantation into various venous sacs, with their glycemic control and other metabolic parameters monitored for 1 month.

Results: In an nonhuman primate, the mesenteric venous sac site improved glycemic control over a 3-month period, followed by destabilization of graft function. Histologic studies revealed healthy islets. The lack of mononuclear cell infiltrate suggested no signs of graft rejection. Saphenous venous sacs in dogs showed superior glycemic control, reduced insulin requirements, and maintained C-peptide levels, comparable to intraportal transplantation. Histological analyses confirmed islet preservation and graft vascularization in saphenous venous sacs.

Conclusion: This study provides preclinical evidence in support of the venous sac as a valuable extrahepatic location for pancreatic islet implantation. We found that the saphenous vein is a more effective site for islet engraftment than the mesenteric vein. This study offers potential benefits for improving the success rates of clinical islet transplantation.

Background: This study aimed to investigate the association between adiponectin levels and the incidence of metabolic dysfunction- associated steatotic liver disease (MASLD) and nonalcoholic fatty liver disease (NAFLD), and to explore the predictive value of adiponectin in the onset of these conditions.

Methods: A 17-year follow-up of 35,026 individuals from the Korean Cancer Prevention Study-II biobank cohort (2004-2021) was conducted. Adiponectin levels were categorized into quintiles. Outcomes were defined as: NAFLD (10th revision of the International Classification of Diseases [ICD-10] K76.0); MASLD (K76.0 with cardiometabolic factors); NAFLD-cardiometabolic (K76.0 without cardiometabolic factors); and non-steatotic liver disease. The cause-specific Cox model accounted for death as a competing risk, with interaction terms for non-proportional hazards.

Results: Our findings indicated a heightened risk of MASLD in individuals in low adiponectin groups. Hazard ratios (HRs) for different adiponectin levels, using Gadipo 5 (≥17.21 μg/mL) as the reference, were: Gadipo 1, HR 3.20 (95% confidence interval [CI], 2.08 to 4.92); Gadipo 2, HR 2.45 (95% CI, 1.59 to 3.76); Gadipo 3, HR 2.02 (95% CI, 1.32 to 3.11); and Gadipo 4, HR 1.59 (95% CI, 1.02 to 2.46). These associations remained consistent across outcomes and models. Sex stratification revealed a stronger association among females. Furthermore, lower adiponectin levels were associated with increased MASLD and NAFLD risk. Similar associations were also observed in individuals with NAFLD-cardiometabolic, indicating consistency across subtypes.

Conclusion: Different adiponectin levels revealed distinct risks. This study emphasizes adiponectin's potential as a predictive indicator of MASLD and NAFLD, stressing the need for further investigation across diverse demographic groups.

Background: Acute hyperinsulinemia may directly affect blood cells. In this study a hyperinsulinemic-euglycemic clamp (HEC) and multiomics methods were used to explore the epigenetic regulation by hyperinsulinemia in blood cells.

Methods: To assess short-term changes in DNA methylation (within 2 hours), blood samples were collected from five non-diabetic adults before and after HEC. mRNA sequencing (mRNA-seq) and targeted bisulfite sequencing (methyl-seq) were performed. Using mRNA-seq, 697 differentially expressed genes (DEGs) were identified, and methyl-seq was used to select those with changes in promoter or gene body methylation. In vitro validation study was also performed in THP1 and 3T3-L1 cells after acute insulin treatment.

Results: Among the 697 DEGs, 119 (henceforth, 'methyl-DEGs') showed methylation changes. Of these 697 DEGs, 45 ('publictrait- DEGs') were associated with pathways such as oxidative stress, insulin signaling, inflammation, and carbohydrate metabolism. Interaction networks between methyl-DEGs and public-trait-DEGs revealed that six genes (B3GALNT1, ESR1, FGF4, PER1, PRKAR1B, and TNFSF4) were affected by DNA methylation and linked to insulin response or diabetes. In response to acute insulin treatment, ESR1, PRKAR1B, PER1, and B3GALNT1 expression decreased in THP1 cells. Similar trends were seen in 3T3-L1 cells, except B3GALNT1. PER1 displayed consistent and significant downregulation across the clamp study and the two cell lines, indicating it as a key circadian-responsive gene under acute hyperinsulinemia.

Conclusion: These results provide epigenetic evidence for the role of DNA methylation in CpG regions and gene bodies in hyperinsulinemia- mediated regulation of gene expression in blood cells, which warrants further studies in relation to diabetes-related pathophysiology.

Background: Central obesity contributes to an increased risk of cardiovascular disease (CVD) and mortality. The waist-to-height ratio (WHtR) is a practical marker of central obesity across sexes, ages, and ethnicities. However, its association with comprehensive cardiovascular (CV) outcomes in patients with type 1 diabetes mellitus (T1DM) remains unclear.

Methods: From a nationwide cohort database (2006-2020), 16,928 Korean adults with T1DM were included. Participants were categorized by their WHtR values using three criteria: a three-group classification (<0.5, 0.5 to <0.6, and ≥0.6) and two binary classifications (≥0.5 vs. <0.5; ≥0.6 vs. <0.6). The primary outcomes were composite CV events, including heart failure (HF), myocardial infarction (MI), ischemic stroke, and CVD-related deaths, with each component analyzed as a secondary outcome.

Results: During a median follow-up of 6.7 years (interquartile range, 5.2 to 8.8), 4,293 composite CV events occurred. Compared to the WHtR <0.5 group, the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for the composite CV outcome were 1.14 (1.05 to 1.24) in the WHtR 0.5 to <0.6 group and 1.62 (1.38 to 1.90) in the WHtR ≥0.6 group (P for trend <0.001). Increasing trends in aHRs were noted with rising WHtR values for each component of the composite outcome. Compared to the WHtR <0.6 group, the aHRs for the WHtR ≥0.6 group were as follows: HF, 1.49 (95% CI, 1.28 to 1.73); MI, 1.31 (95% CI, 1.02 to 1.68); ischemic stroke, 1.24 (95% CI, 1.02 to 1.51); and CVD-related death, 2.09 (95% CI, 1.49 to 2.92).

Conclusion: High WHtR is associated with an increased risk of CV events in adults with T1DM.

This study evaluated whether a stage 4 smart insulin pen (SIP) provides superior glycemic control compared with a traditional insulin pen (TIP) in individuals with intensively insulin-treated diabetes. Forty-two adults with continuous glucose monitoring (CGM), multiple daily insulin injections, and no prior SIP use were included. After diabetes self-management education (DSME), the SIP group (n=21) initiated SIP, whereas the TIP group (n=21) continued their usual regimens. Glycemic metrics were assessed using CGM before and 2 weeks after DSME. Both groups demonstrated significant improvements in glycemic outcomes. However, SIP users exhibited superior improvements in the percentage of time in range, percentage of time below range (%TBR) <70 mg/dL, %TBR <54 mg/dL, and glycemic risk index compared with TIP users (between-group difference [BD] 11.0%, P=0.046; BD -2.6%, P=0.024; BD -0.9%, P=0.027; BD -18.2, P=0.022, respectively). These findings suggest that SIP, with its bolus calculation and CGM integration, is associated with improved glycemic outcomes in adults with intensively insulin-treated diabetes.