Journal of Diabetes Investigation最新文献

Objective: Diabetic foot ulcers (DFU) are one of the most destructive complications of diabetes mellitus. The aim of this study was to link miR-155 and SOX2 with DFU to explore the regulation of wound healing by DFU and its potential mechanism.

Methods: Human keratinocytes (HaCaT) were induced with advanced glycation end products (AGEs) to construct DFU models in vitro. AGE-induced HaCaT cells were subjected to CCK-8 assays, flow cytometry, and wound healing assays to evaluate cell proliferation, apoptosis, and migration capacity, respectively. RT-qPCR and Western blotting were used to determine gene and protein expression levels, respectively. N6-methyladenosine (M6A) levels in total RNA were assessed using an M6A methylation quantification kit.

Results: Our results suggested that the inhibition of miR-155 promoted wound healing in an in vitro DFU model, while the knockdown of HIF-1α reversed this process, and that HIF-1α was a target protein of miR-155. In addition, knockdown of HIF-1α promoted the m6A level of SOX2 mRNA, inhibited the expression of SOX2, and inhibited the activation of the EGFR/MEK/ERK signaling pathway, thus inhibiting the proliferation and migration of HaCaT cells and promoting the apoptosis of HaCaT cells, while overexpression of SOX2 reversed this effect. We also found that METTL3 knockdown had the opposite effect of HIF-1α knockdown.

Conclusions: Inhibition of miR-155 promoted the expression of HIF-1α and attenuated the m6A modification of SOX2 mRNA, thereby promoting the expression of SOX2 and activating the downstream EGFR/MEK/ERK signaling pathway to promote wound healing in an in vitro DFU model.

In both human clinical and animal experimental studies, the altered expression of regulatory RNAs such as miRNAs, lncRNAs, and circRNAs are reported in diabetes and its complications by investigating various samples of serum, plasma, whole blood, and tissues. These identified ncRNAs are candidates for the disease diagnostic markers, prognostic markers, and also therapeutic targets. In the updates, the recently published ncRNAs involved in the onset and progression of DKD are discussed.

This commentary highlights the role of heart rate variability (HRV) indices in predicting diabetic kidney disease (DKD) progression, based on findings from the PERL and ACCORD trials. HRV-derived measures from routine ECGs are shown to be strong predictors of rapid kidney function decline in both type 1 and type 2 diabetes, suggesting their potential utility in identifying individuals at high risk for DKD and guiding early preventive interventions.

Background: This study investigates the gender-specific genetic influence of the single nucleotide polymorphism (SNP) rs1111875 on diabetes risk within the Taiwanese population using data from the Taiwan Biobank. Diabetes mellitus, particularly type 2 diabetes (T2D), is influenced by genetic factors, and the rs1111875 SNP near the hematopoietically expressed homeobox (HHEX) gene has been linked to T2D susceptibility.

Methods: The study included 69,272 participants after excluding those from arsenic-polluted areas and those with incomplete data. Logistic regression models were used for analyses.

Results: The analyses revealed that the CT genotype of rs1111875 was associated with an increased risk of diabetes (OR = 1.092, 95% CI = 1.030-1.157, P = 0.003), as was the TT genotype (OR = 1.280, 95% CI = 1.165-1.407, P < 0.001). The effect was more pronounced in women (CT: OR = 1.118, 95% CI = 1.036-1.207, P = 0.004; TT: OR = 1.404, 95% CI = 1.243-1.585, P < 0.001). Men exhibited a higher overall risk of diabetes (OR = 1.565, 95% CI = 1.445-1.694, P < 0.001) and had a higher prevalence (12.71% vs 7.80%, P < 0.001) compared to women.

Conclusions: The findings underscore the importance of considering gender differences in genetic studies of diabetes and suggest that personalized diabetes management strategies should account for both genetic and gender-specific risk factors. This research contributes to the broader understanding of genetic determinants of diabetes and their interaction with gender, aiming to enhance personalized healthcare strategies for diabetes prevention and treatment.

Objectives: Several studies have reported the potential association between smoking and diabetic nephropathy. However, the studies of non-significant association results were against the association between smoking and diabetic nephropathy. Therefore, the relationship between smoking and diabetic nephropathy was still debated and controversial.

Methods: Prospective cohort studies were included in the current meta-analysis. The tobacco smoking (current smokers or former smokers) and non-smoking groups in the enrolled studies were compared for the hazard ratio (HR) of diabetic nephropathy. Fifteen studies with 221,821 subjects were included in this meta-analysis. Subgroup analysis of the type 1 diabetes and type 2 diabetes groups was also performed individually to investigate the effects of different types of diabetes on the relationship between smoking and diabetic nephropathy.

Results: Current smoking was significantly associated with a greater log HR of diabetic nephropathy [1.44 (1.22-1.70), Z = 4.39]. In addition, former smoking was significantly associated with diabetic nephropathy [log HR = 1.04 (1.03-1.05), Z = 8.02]. The individual subgroup analysis of type 1 diabetes and type 2 diabetes subjects showed that smoking might be both significantly associated with greater log HRs of diabetic nephropathy.

Discussion: Current and former smoking might be the risk factors for diabetic nephropathy in the current meta-analytic results. The phenomenon of such significant associations were discovered in type 1 and 2 diabetes.

Introduction: An increased rate of gastrointestinal (GI) symptoms is reported in patients with type 2 diabetes receiving imeglimin plus metformin vs monotherapy or in combination with other antidiabetic drugs. This post-hoc analysis explored GI symptom incidence, risk factors for their occurrence, and the impact on therapeutic efficacy during imeglimin and metformin combination therapy.

Materials and methods: Data were derived from the 52-week, open-label, phase 3 TIMES-2 trial in Japanese type 2 diabetes patients. Patients in the imeglimin plus metformin group were divided into two subgroups based on the presence of GI symptoms and diarrhea, with efficacy and safety assessed. Factors associated with their occurrence were explored using multivariate logistic regression analysis.

Results: Of 64 patients analyzed, GI symptoms and diarrhea occurred in 40.6% (n = 26) and 17.2% (n = 11) of patients, respectively. Metformin dose and patient age did not significantly affect their incidence. Events occurred more frequently within the first 4 months of treatment. Approximately half resolved within 1 week, and most were mild. Type 2 diabetes duration <5 years was significantly associated with diarrhea (odds ratio = 5.979; P = 0.039). Significant hypoglycemic effects were observed from baseline, irrespective of GI symptoms or diarrhea. However, the degree of HbA1c improvement tended to be greater in patients with GI symptoms and diarrhea.

Conclusions: Increased awareness regarding the potential for GI symptoms, including diarrhea, during imeglimin plus metformin combination therapy is warranted. This data will provide clinicians with useful information regarding symptomatic treatment when it occurs and help determine whether to continue treatment administration and is expected to improve patient adherence.

Aims/introduction: Fatty acid-binding protein (FABP) 4, which acts as an adipokine secreted by adipocytes, macrophages, and capillary endothelial cells, is expressed in injured glomerular cells. It has been reported that urinary (U-) FABP4 is associated with renal dysfunction and proteinuria in several glomerular kidney diseases. However, the clinical significance of U-FABP4 in diabetic kidney disease (DKD) remains undetermined.

Materials and methods: Immunohistological analyses of FABP4 and FABP1 (liver-type FABP), an established biomarker for impaired proximal tubules, were performed in the kidneys of patients with DKD and nonobese diabetic mice (KK-Ta/Akita mice). The associations between U-FABP4 and U-FABP1 with kidney function and metabolic indices were also investigated in patients with type 1 diabetes (n = 57, mean age: 61 years) and patients with type 2 diabetes (n = 608, mean age: 65 years).

Results: In both patients with diabetes and diabetic mice, FABP4 was expressed in injured glomeruli with increased markers of endoplasmic reticulum stress in addition to peritubular capillaries, whereas FABP1 was mainly expressed in proximal tubules. Levels of U-FABP4 and U-FABP1 were independently associated with each other, and both levels were independently associated with estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) after adjustment of age, sex, type of diabetes, duration of diabetes, and systolic blood pressure in patients with diabetes.

Conclusions: Urinary level of FABP4 derived from injured glomeruli with increased endoplasmic reticulum stress is independently associated with eGFR and UACR, suggesting a promising biomarker for glomerular damage in patients with diabetes.

Objective: To explore and validate the association between the oxidative balance and prevalence of diabetic kidney disease (DKD) and mortality in patients with diabetes.

Study design: A large and representative sample from the National Health and Nutrition Examination Survey (NHANES) from 2013 to 2016 was analyzed to study the potential association between Oxidative Balance Score (OBS) and prognosis of DKD in adult diabetic patients. Weighted multivariate logistic regression analysis was conducted to examine the relationship between OBS and DKD risk. Subgroup analysis, sensitivity analysis, and mediation effect analysis were conducted to explore the effect of the covariates and assess the robustness of the findings. Mendelian randomization (MR) was employed to evaluate the correlated relationship between mitochondrial reactive oxygen species (ROS) levels and DKD at the genetic level.

Result: The highest OBS quartile showed the most significant negative correlation with DKD compared to the lowest OBS quartile (OR = 0.62, 95% CI 0.41-0.92, P = 0.017). Higher OBS was associated with a reduced risk of DKD (OR = 0.96; 95% CI = 0.93, 0.98; P < 0.001) and mortality (P = 0.021 by log-rank) in diabetic patients. This association remained robust even after excluding individual OBS components. Subgroup analysis revealed the interaction of metabolic syndrome on OBS was significant. Mediation analyses revealed that OBS's effect on DKD was independent of blood uric acid and cholesterol. Restricted cubic spline (RCS) analysis indicated a typical L-shaped relationship between OBS and DKD risk. The physical activity was identified as the core variable predicting DKD risk by two machine learning algorithms. MR showed a potential correlated relationship between ROS and microalbuminuria in DKD.

Conclusions: The high level of oxidative balance score was negatively correlated with the risk of DKD and mortality in diabetic patients.

This review highlights the significance of the Japan Diabetes Complications Study (JDCS), one of the earliest large-scale studies of people with type 2 diabetes outside Europe and the United States, in understanding type 2 diabetes mellitus among East Asian populations, particularly in Japan. Historically, large-scale clinical studies on type 2 diabetes mellitus have predominantly focused on Western populations, despite East Asians comprising the largest proportion of diabetic patients globally. The JDCS, which was initiated in 1996, enrolled 2,033 Japanese type 2 diabetes mellitus patients. It aimed to evaluate the effects of intensive lifestyle interventions on diabetic complications. The study demonstrated that lifestyle-focused interventions significantly reduced the risk of stroke and other complications compared to conventional treatment. Key findings of its sub-analyses include the unique characteristics of Japanese patients with type 2 diabetes mellitus, such as their lower body mass index (BMI) compared to Western counterparts and a stronger association between even modest BMI increases and beta cell dysfunction. Additionally, the JDCS provided insights into the risk factors for nephropathy, retinopathy, and macrovascular complications, emphasizing the importance of controlling blood pressure, glycemia, and lifestyle factors. The study also explored the impact of diet, exercise, and mental health on diabetic outcomes, revealing the protective effects of physical activity and a balanced diet, while highlighting the risks associated with high salt intake and depression. A risk prediction model tailored to Japanese patients was also developed. Overall, this study made a significant contribution to the evidence-based management of type 2 diabetes mellitus in East Asia.

Background: The relationship between the systemic immune-inflammatory index (SII) and the prognosis of cardiovascular disease (CVD) patients with diabetes or prediabetes remains uncertain. This study investigated the association between baseline SII and all-cause and cardiovascular mortality in American adults with CVD and diabetes or prediabetes.

Methods: Our survey included 4,060 adults with cardiovascular disease and diabetes or prediabetes from the National Health and Nutrition Examination Survey (1998-2020). Using restricted cubic splines (RCS) based on Cox regression models and a two-piecewise Cox proportional hazards model for both sides of the inflection point, we elucidated the nonlinear relationship between baseline SII and mortality. Mediation analysis was used to explore the indirect impact of SII on mortality through eGFR.

Results: In the median 129 months of follow-up, 620 people died from cardiovascular causes and 1,800 from all causes. In the CVD population with diabetes or prediabetes, SII showed a U-shaped relationship with all-cause mortality. The association between SII and CVD mortality was nonlinear and J-shaped. Stratified and interaction analysis confirmed the stability of the core results. Notably, eGFR partially mediated the association between SII and both all-cause and cardiovascular mortality by 9.4% and 6.9%, respectively.

Conclusions: SII revealed a U-shaped relationship with all-cause mortality (inflection point: lnSII = 6) and a J-shaped association with CVD mortality (inflection point: lnSII = 5.73) in CVD patients with diabetes or prediabetes among American patients. Thus, assessing the SII index may offer valuable insights into risk assessment and prognosis in patients with CVD who are diabetic or prediabetic.