Journal of Diabetes Investigation最新文献

Background: Adolescents with type 1 diabetes (T1D) face premature atherosclerosis, but standard carotid intima-media thickness (IMT) may lack sensitivity for the earliest vascular injuries. Since urinary albumin-to-creatinine ratio (UACR) reflects systemic endothelial dysfunction, we investigated the triple-line pattern (TLP) as a marker of peripheral remodeling and its dose-response relationship with low-grade albuminuria.

Methods: The Subclinical Cardiovascular Disease in Type 1 Diabetes Mellitus (SCVD T1DM) cohort study prospectively recruited 283 adolescents with T1D and 106 age- and sex-matched controls. IMT was measured at the common carotid artery and common femoral artery (CFA) using high-resolution ultrasound. Logistic regression tested categorical UACR thresholds, and restricted cubic spline models evaluated the continuous dose-response association between UACR and TLP.

Results: TLP prevalence was higher in type 1 diabetes than in controls (63.9% vs 49.1%, P = 0.008). While type 1 diabetes was associated with carotid thickening, TLP was linked to structural changes in the lower extremities. TLP-positive participants had greater mean CFA IMT (0.56 ± 0.06 vs 0.44 ± 0.06 mm, P < 0.001). UACR ≥15 mg/g independently predicted TLP (odds ratio 2.83, 95% confidence interval 1.01-7.92, P = 0.048), whereas UACR ≥30 mg/g was not significant. Spline analysis showed no significant nonlinearity (P for nonlinearity = 0.424), with risk increasing above approximately 15 mg/g.

Conclusions: TLP is a prevalent marker of incipient peripheral vascular remodeling in adolescents with type 1 diabetes without macroalbuminuria. A UACR ≥15 mg/g identifies subclinical vascular risk below conventional thresholds, supporting TLP as a potential tool for refined early risk stratification in this population.

Objectives: To evaluate whether glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with improved survival and renal outcomes in patients with rheumatoid arthritis and type 2 diabetes, a population at high cardiometabolic risk.

Materials and methods: We conducted a retrospective cohort study using an active-comparator, new-user design within the TriNetX US Collaborative Network. Adults with rheumatoid arthritis and type 2 diabetes initiating GLP-1 RAs or dipeptidyl peptidase-4 inhibitors (DPP-4is) between 2016 and 2023 were included. The primary outcome was all-cause mortality; secondary outcomes were major adverse cardiovascular events (MACE), major adverse kidney events (MAKE), and all-cause hospitalization. Hazard ratios (HRs) were estimated using Cox regression after 1:1 propensity score matching.

Results: A total of 4,607 patients per group were followed for up to 4 years. GLP-1 RA use was associated with lower all-cause mortality (HR 0.68; 95% confidence intervals (CI), 0.58-0.80), reduced MAKE (HR 0.89; 95% CI, 0.82-0.97), and fewer hospitalizations (HR 0.92; 95% CI, 0.86-0.98), compared with DPP-4is. No significant difference was observed for MACE (HR 0.96; 95% CI, 0.89-1.04). Results were consistent across prespecified subgroups and sensitivity analyses.

Conclusions: In patients with rheumatoid arthritis and type 2 diabetes, GLP-1 RA therapy was associated with 32% lower mortality, 11% fewer kidney events, and 8% fewer hospitalizations vs DPP-4is. These findings support GLP-1 RAs as a promising therapeutic option for this high-risk population.

Background: Diabetic retinopathy (DR) is a microvascular condition resulting from microangiopathy, causing gradual retinal damage and potential blindness. Endothelial-mesenchymal transition (EndMT) serves an important function in DR development. Exploring the molecular mechanism of EndMT in DR is needed.

Methods: Human retinal microvascular endothelial cells (HRMECs) were incubated with high glucose (HG) to induce an in vitro DR model. Lentivirus and small-interfering RNAs were used to construct SIRT6 and LIN28A overexpression or knockdown in HRMECs, respectively. AMPK inhibitor, compound C, was used to block AMPK signaling in HRMECs. α-SMA and PECAM1 levels were identified using immunofluorescence. CCK8 and transwell were used to detect cell viability and migration, respectively. The mRNA stability of SIRT6 was analyzed after HRMECs were exposed to actinomycin D. RNA immunoprecipitation was applied to verify the binding relationship between LIN28A and SIRT6 mRNA in HRMECs.

Results: In HG-induced HRMECs, the cells undergo the EndMT process, and SIRT6 levels are downregulated. HG treatment reduced the level of p-AMPK in HRMECs, and compound C reversed the inhibition of SIRT6 overexpression on EndMT in HG-induced HRMECs. By binding to SIRT6 mRNA, LIN28A could enhance SIRT6 mRNA stability. Additionally, LIN28A overexpression inhibited EndMT in HG-induced HRMECs, which was reversed by SIRT6 knockdown.

Conclusion: The stabilization of SIRT6 mRNA by LIN28A activated AMPK signaling, inhibiting the EndMT process in HRMECs caused by HG.

Background/aim: Most patients with proteinuria are considered to have typical diabetic nephropathy (DN). However, when proteinuria occurs without diabetic retinopathy, with hematuria, or persists despite strict glycemic and blood pressure control, it is considered atypical for DN and warrants further evaluation for non-DN via kidney biopsy. Nevertheless, comprehensive information on renal histopathology and prognosis following kidney biopsy remains limited. This study aimed to clarify these issues through a retrospective analysis.

Methods: Among 490 patients who underwent kidney biopsy at Shiga University of Medical Science Hospital between 2013 and 2024, 51 Japanese patients with type 2 diabetes who met at least one criterion for proteinuria atypical for DN were included. Pre- and post-biopsy changes in proteinuria levels and eGFR decline rate, as well as renal histology, were analyzed.

Results: Among the 51 patients, 17 (33.3%) were histologically diagnosed with typical DN, whereas 34 (66.7%) were diagnosed with non-DN, including membranous nephropathy, immunoglobulin A (IgA) nephropathy, renal sclerosis, interstitial nephritis, vasculitis, and others. Compared with the DN group, patients with non-DN were significantly older and had a lower prevalence of diabetic retinopathy. Additionally, the non-DN group showed significant improvements in both proteinuria levels and in the eGFR decline following biopsy and appropriate disease-specific therapy.

Conclusion: A kidney biopsy identified a wide range of kidney diseases as the underlying causes of atypical proteinuria in DN, particularly in elderly patients, thereby improving renal outcomes. These findings underscore the clinical importance of heightened awareness of atypical proteinuria in diabetes management, particularly in aging populations.

Background: Cardiomyopathy is one of the complications of diabetes, among which myocardial fibrosis is the most typical feature. Ubiquitin-specific peptidase 18 (USP18) is a deubiquitinating enzyme. Multiple studies suggest that it may have the potential to protect against myocardial injury under diabetes, but the specific mechanism remains unclear.

Methods: The high glucose (HG) was used to treat neonatal mouse ventricular myocytes (NMVMs) to induce diabetic myocardial injury models, and gene expression was detected by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot. The phenotypes of NMVMs were measured using cell counting kit-8 (CCK-8), the corresponding kits, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and DCFH-DA probe. Besides, cell fibrosis was reflected by immunofluorescence (IF) and Western blot assay. Ubiquitination analysis and Cycloheximide (CHX) experiment were applied to assess protein ubiquitination and degradation, respectively.

Results: USP18 was downregulated in HG-induced NMVMs, and USP18 overexpression promoted viability and inhibited apoptosis of NMVMs exposed to HG. Meanwhile, the inflammation, oxidative stress, and fibrosis of NMVMs impelled by HG were reversed after USP18 upregulation. Mechanically, USP18 stabilized forkhead box C2 (FOXC2) expression by reducing its ubiquitination to participate in regulating NMVM viability, apoptosis, inflammation, oxidative stress, and fibrosis via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway.

Conclusions: USP18 inhibits the ubiquitination of FOXC2 to stabilize its expression, thereby mediating HG-induced myocardial injury through the JAK/STAT pathway.

Objective: This study analyzed the correlation between serum C1q/TNF-related protein 3 (CTRP3) and cystatin C (CysC) and glucose-lipid metabolism, bone mineral density (BMD), and bone metabolism markers in elderly patients with type 2 diabetes mellitus (T2DM) complicated with osteoporosis (OP).

Methods: A retrospective analysis was conducted on 235 patients with T2DM admitted to Taizhou Municipal Hospital between January 2021 and June 2024. They were categorized into the T2DM group (n = 131) and the T2DM + OP group (n = 104). A healthy control group (n = 95) was established, comprising elderly individuals without diabetes or OP. Serum CTRP3 and CysC were measured. The correlation between serum CTRP3 and CysC levels and relevant metabolism markers and BMD was analyzed. The diagnostic values of serum CTRP3 and CysC were assessed, as well as their role in T2DM + OP.

Results: Serum CTRP3 was lower and CysC was higher in the T2DM + OP group. Serum CTRP3 and CysC levels in the T2DM + OP group were correlated with some indicators of glucose-lipid metabolism and bone metabolism and BMD. The area under the curve (AUC) values of serum CTRP3 and CysC levels in distinguishing T2DM + OP were 0.719 and 0.702 (sensitivity: 60.58%; 61.54%, specificity: 74.05%; 74.05%), respectively, with their combination showing better performance (AUC: 0.773, sensitivity: 76.92%, specificity: 64.89%). Elevated serum CysC (OR: 1.422, 95%CI: 1.161-1.742) and CTRP3 (OR: 0.960, 95%CI: 0.943-0.976) were independent risk and protective factors for T2DM + OP in elderly patients, respectively (all P < 0.05).

Conclusion: CTRP3 and CysC combined detection helps distinguish OP in elderly patients with T2DM.

Aims: To determine the relationship between the neutrophil-to-lymphocyte ratio and enlarged perivascular spaces in patients with type 2 diabetes mellitus.

Materials and methods: Cranial magnetic resonance imaging data from 200 patients with type 2 diabetes mellitus were analyzed to categorize enlarged perivascular spaces in the basal ganglia and centrum semiovale (CSO) by severity. Mild and moderate-to-severe enlarged perivascular spaces groups were compared.

Results: The neutrophil-to-lymphocyte ratio (NLR) was notably elevated in the moderate-to-severe group compared with the mild group, for both basal ganglia (BG) (P < 0.01) and CSO (P < 0.01) enlarged perivascular spaces. Spearman analyses demonstrated strong positive correlations between the NLR and the severity of both BG (r = 0.545, P < 0.001) and CSO (r = 0.440, P < 0.001) enlarged perivascular spaces. Binary logistic regression analysis identified the NLR as an independent risk factor for BG (P < 0.01) and CSO (P < 0.01) enlarged perivascular spaces in patients with type 2 diabetes mellitus. Receiver operating characteristic curve analysis demonstrated that the NLR had an area under the curve of 0.824 for predicting moderate-to-severe BG enlarged perivascular spaces and 0.768 for predicting moderate-to-severe CSO enlarged perivascular spaces.

Conclusions: The NLR independently predicts moderate-to-severe BG and CSO enlarged perivascular spaces in patients with type 2 diabetes mellitus and exhibits diagnostic accuracy for cerebral small vessel disease.

Background: Daily activities require the simultaneous execution of cognitive and motor tasks. Type 2 diabetes mellitus (T2DM) is associated with functional impairments that may compromise dual-task performance, leading to increased dual-task interference.

Objective: To compare dual-task performance and dual-task interference between individuals with T2DM and healthy control subjects.

Methods: This study followed the reporting recommendations of the PRISMA statement. The literature search was conducted in PubMed, Scopus, WoS, LILACS, and PEDro databases. We included studies involving individuals diagnosed with T2DM aged over 18 years, assessed using any dual-task evaluation protocol and compared to healthy control subjects. Methodological quality was independently assessed using the Joanna Briggs Institute checklist and meta-analyses were performed using JAMOVI software.

Results: Of the 1,864 articles initially identified, 6 studies met the inclusion criteria, comprising a total of 468 participants. Individuals with T2DM exhibited poorer motor performance during dual-task evaluations, including reduced gait speed (SMD = -0.74 [95%CI: -1.22 to -0.27], P = 0.002) and longer stride times (SMD = 0.34 [95%CI: 0.03 to 0.65], P = 0.039). Additionally, they demonstrated greater dual-task interference in both motor (SMD = -0.67 [95%CI: -1.16 to -0.19], P = 0.006) and cognitive tasks (SMD = -0.33 [95%CI: -0.66 to -0.03], P = 0.033) compared to healthy control subjects.

Conclusion: Individuals with T2DM exhibit poorer dual-task performance and greater dual-task interference. These findings highlight the importance of including DT assessments in the clinical evaluation of individuals with T2DM. However, due to the limited number of studies, further research is warranted.

Introduction: Recent studies have demonstrated that both oral semaglutide and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have beneficial effects on glycemic and weight management as well as providing renal and cardiovascular protection. However, direct comparisons of the effects of these two drugs in clinical practice remain limited.

Materials and methods: This study is a single-center, retrospective, observational study. Patients with type 2 diabetes who were initiated on oral semaglutide or SGLT2is and continued treatment for 6 months or more were retrospectively analyzed and compared.

Results: The semaglutide group (84 patients) and the SGLT2is group (231 patients) showed similar, significant reductions in glycated hemoglobin (HbA1c) (semaglutide: -0.88 ± 0.14%; P < 0.01, and SGLT2is: -0.86 ± 0.06%; P < 0.01, at 6 months), body weight (semaglutide: -2.58 ± 0.37 kg; P < 0.01, and SGLT2is: -2.30 ± 0.18 kg; P < 0.01, at 6 months), and fat mass (semaglutide: -2.20 ± 0.50 kg; P < 0.01, and SGLT2is: -1.93 ± 0.44 kg; P < 0.01, at 6 months), being decreased similarly and significantly in both groups. On the other hand, there was a significant reduction in skeletal muscle mass only in the SGLT2is group (semaglutide: -0.10 ± 0.30 kg; P = 0.74, and SGLT2is: -0.40 ± 0.14 kg; P < 0.01 at 6 months).

Conclusions: While both drugs elicited comparable effects on glycemic management and body weight reduction in patients with type 2 diabetes, caution is needed when using SGLT2is in patients at potential risk for sarcopenia, as they may lead to less favorable changes in skeletal muscle mass compared to oral semaglutide.

Background: Inflammation plays an essential role in the pathogenesis of diabetic nephropathy (DN). Linderalactone (LNL), as a natural sesquiterpene lactone, has been discovered to have anti-inflammatory activation. However, the effects of linderalactone on diabetes-associated renal damage remain unclear.

Methods: This study investigated the effects of LNL on renal function and inflammation in diabetic mice. Renal function, collagen deposition, and fibrosis were assessed. RNA-sequencing was performed to identify molecular pathways affected by LNL. The Dectin1-related pathway was analyzed in kidney tissues and RAW264.7 cells. Dectin1-deficient and Dectin1-overexpressing models were used to confirm the mechanism of LNL.

Results: LNL improved renal function, reduced collagen deposition and fibrosis in diabetic mice without affecting blood glucose levels. RNA-sequencing revealed that LNL primarily impacted the Dectin1 pathway. It inhibited the Dectin1/Syk/CARD9/IRF5/NF-κB pathway, reduced macrophage and neutrophil infiltration, and suppressed inflammatory cytokine expression. Dectin1 knockdown mimicked these effects, while Dectin1 overexpression reversed them.

Conclusions: LNL alleviates DN via suppression of macrophage inflammation by mediating the Dectin1/Syk/CARD9/IRF5/NF-κB signaling pathway, highlighting its potential as a therapeutic agent for diabetes-associated renal injury.