Journal of Diabetes Investigation最新文献

Aims/introduction: Patients with type 2 diabetes are at high risk of developing steatotic liver disease (SLD). Weight loss has proven effective in treating metabolic dysfunction-associated steatotic liver disease (MASLD) in obese patients with type 2 diabetes, with sodium-glucose cotransporter 2 (SGLT2) inhibitors showing promising results. However, lean MASLD is more prevalent in Japan, necessitating alternative approaches to body weight reduction.

Materials and methods: We used the J-STEP/LT dataset including up to 3-year treatment data to analyze the effects of the SGLT2 inhibitor tofogliflozin on liver function and treatment safety and conducted a subgroup analysis based on body mass index (BMI; kg/m², <20, 20-<23, 23-<25, 25-<30, and ≥30).

Results: This study included 4,208 participants. Tofogliflozin significantly reduced alanine aminotransferase (ALT) levels in participants with baseline ALT levels >30 U/L across all BMI groups, with median changes of -12, -16, -13, -15, and -15 U/L, respectively (P = 0.9291 for trends). However, median changes in body weight with tofogliflozin were -2.00, -2.75, -2.00, -3.00, and -3.80 kg, respectively (P < 0.0001 for trends), with no significant weight loss observed in the BMI <20 group. ALT levels were also significantly decreased in participants who did not lose weight. Safety assessments according to BMI and age categories revealed no clear differences in the frequency of adverse events.

Conclusions: Tofogliflozin reduced ALT levels without substantial body weight reduction among lean participants. These findings suggest that SGLT2 inhibitors may be a viable treatment option for non-obese patients with type 2 diabetes and SLD.

Aims: This study aimed to delineate the effect of hyperglycemia on the Alu/LINE-1 hypomethylation and in ERK1/2 genes expression in type 2 diabetes with and without cataract.

Methods: This study included 58 diabetic patients without cataracts, 50 diabetic patients with cataracts, and 36 healthy controls. After DNA extraction and bisulfite treatment, LINE-1 and Alu methylation levels were assessed using Real-time MSP. ERK1/2 gene expression was analyzed through real-time PCR. Total antioxidant capacity (TAC), and fasting plasma glucose (FPG) were measured using colorimetric methods. Statistical analysis was performed with SPSS23, setting the significance level at P < 0.05.

Results: The TAC levels were significantly lower for cataract and diabetic groups than controls (259.31 ± 122.99, 312.43 ± 145.46, 372.58 ± 132.95 nanomole of Trolox equivalent) with a significant correlation between FPG and TAC levels in both the cataract and diabetic groups (P < 0.05). Alu and LINE-1 sequences were found to be statistically hypomethylated in diabetic and cataract patients compared to controls. In these groups, TAC levels were directly correlated with Alu methylation (P < 0.05) but not LINE-1. ERK1/2 gene expression was significantly higher in diabetic and cataract patients, showing increases of 2.41-fold and 1.43-fold for ERK1, and 1.27-fold and 1.5 for ERK2, respectively. ERK1 expression correlated significantly with FPG levels. A reverse correlation was observed between TAC levels and ERK1/2 expression.

Conclusions: Our findings indicate that hyperglycemia-induced oxidative stress may alter ERK1/2 gene expression patterns and induce aberrant hypomethylation in Alu and LINE-1 sequences. These aberrant changes may play a contributing role in diabetic complications such as cataracts.

Aims: This study investigated the association between maternal age and early and late gestational diabetes mellitus (GDM).

Methods: In total, 72,270 pregnant women were included in this prospective birth cohort study. Associations between maternal age and early GDM (diagnosed at <24 gestational weeks) and late GDM (diagnosed at ≥24 gestational weeks) were evaluated using a multinomial logistic regression model with possible confounding factors. The reference category was maternal age of 30-34.9 years.

Results: Higher maternal age was associated with higher odds of early and late GDM (P-value for trend <0.0001 and <0.0001, respectively). The adjusted odds ratios (aORs) for early GDM with maternal age of 35-39.9 years and ≥40 were 1.399 (95% confidence interval [CI]: 1.134-1.725) and 2.494 (95% CI: 1.828-3.402), respectively. The aORs for late GDM with maternal age of 35-39 years and ≥40 were 1.603 (95% CI: 1.384-1.857) and 2.276 (95% CI: 1.798-2.881), respectively.

Conclusions: Higher maternal age was associated with an increased risk of GDM regardless of when GDM was diagnosed. The association between maternal age and early GDM was similar to that between maternal age and late GDM.

Aims/introduction: This study examined the effects of high-intensity interval walking training (IWT) compared to moderate-intensity continuous walking training (CWT) on muscle strength, walking ability, and health-related quality of life (QOL) in people with diabetes accompanied by lower extremity weakness.

Materials and methods: People with diabetes accompanied by low isometric knee extensor strength using a simple manual dynamometer (n = 50) were screened and randomly divided into 2 groups: CWT (n = 25) and IWT (n = 25). Both groups were instructed by a physical therapist to perform walking training with the goal of 120 min/week over a 5-month period. The primary outcome, mean change of isometric knee extensor strength, and secondary outcomes, such as gait speed and health-related QOL, were measured at baseline and the end of the intervention.

Results: At the end of the intervention, there was no significant difference in the degree of change in isometric knee extension strength between the two groups. However, there was a significant increase in changes in gait speed and physical QOL in the IWT group (gait speed, P < 0.01; physical QOL, P < 0.05).

Conclusions: The present study showed that IWT for people with diabetes accompanied by lower extremity weakness did not improve knee extension muscle strength compared to CWT but did improve walking ability and physical QOL.

Low-density lipoprotein cholesterol (LDL-C) is known to be a causal substance of atherosclerosis, but its usefulness as a predictive biomarker for atherosclerotic cardiovascular disease (ASCVD) is limited. In patients with type 2 diabetes (T2D), LDL-C concentrations do not markedly increase, while triglycerides (TG) concentrations are usually elevated. Although TG is associated with ASCVD risk, they do not play a direct role in the formation of atheromatous plaques. TG changes the risk of ASCVD in a way that is dependent on LDL-C, and TG is the primary factor in reducing LDL particle size. Small dense (sd)LDL, a potent atherogenic LDL subfraction, best explains the "Atherogenic Duo" of TG and LDL-C. Although hypertriglyceridemia is associated with small-sized LDL, patients with severe hypertriglyceridemia and low LDL-C rarely develop ASCVD. This suggests that quantifying sdLDL is more clinically relevant than measuring LDL size. We developed a full-automated direct sdLDL-C assay, and it was proven that sdLDL-C is a better predictor of ASCVD than LDL-C. The sdLDL-C level is specifically elevated in patients with metabolic syndrome and T2D who have insulin resistance. Due to its clear link to metabolic dysfunction, sdLDL-C could be named "metabolic LDL-C." Insulin resistance/hyperinsulinemia promotes TG production in the liver, causing steatosis and overproduction of VLDL1, a precursor of sdLDL. sdLDL-C is closely associated with steatotic liver disease and chronic kidney disease, which are common complications in T2D. This review focuses on T2D and discusses the clinical significance of sdLDL-C including its composition, pathophysiology, measurements, association with ASCVD, and treatments.

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.