Diabetology International最新文献

Aims: The Japan Diabetes Society revised the diagnostic criteria for slowly progressive insulin-dependent diabetes mellitus (SPIDDM) in 2023. We aimed to clarify the clinical differences between definite and probable SPIDDM using the new criteria in real-world clinical settings in Japan.

Materials and methods: We included data of 190 and 582 patients with definite and probable SPIDDM, respectively, from 24 facilities participating in the Japan Diabetes Clinical Data Management Study Group. Age, sex, body mass index, hemoglobin A1c, and fasting C-peptide levels were extracted from the Computerized Diabetes Care database and analyzed cross-sectionally at the time of registration and at the most recent visit from June to December 2021. Data on pharmacotherapy, macro- and microvascular complications, diabetes duration at the onset of these complications, and drugs concurrently used for hypertension and hyperlipidemia were collected and compared between the two groups.

Results: Collectively, 0.8% and 2.3% of patients with all types of diabetes had definite and probable SPIDDM, respectively. The median age at onset of definite and probable SPIDDM was 41 (interquartile range, 33-52) and 47 (38-57) years; male/female ratio (%), 47.4/52.6 and 60.5/39.5; period until insulin initiation, 41.5 (3.3-126.8) and 78 (12-161) months; and median body mass index at registration; 21.9 (19.4-24.5) and 24.0 (21.1-26.9) kg/m², respectively. The macro- and microvascular complication rates did not differ between the groups.

Conclusions: Patients with definite SPIDDM were predominantly female and had a younger age at onset and shorter period until insulin initiation than those with probable SPIDDM did.

Metallothioneins (MTs) are a cysteine-rich protein that scavenges reactive oxygen species. Hypoxia is involved in the progression of diabetic nephropathy (DN) and aggravates oxidative stress. Hypoxia dramatically induced MT3, whereas induced around twofold increment in MT2, but inhibited MT1 in human renal proximal tubular epithelial cells (HRPTECs). Given that the role of MT3 in DN remains unclear, we explored the involvement of MT3 in DN. Microarray analysis also identified MT3-regulated candidate genes, including ceruloplasmin (CP) and cytochrome b reductase 1 (CYBRD1), as well as FGF-Klotho (KL)-FGFR complexes in HRPTECs. Hypoxia significantly induced MT3 expression through HIF-1-dependent mechanisms, and MT3 small interfering RNA (siRNA) decreased CP, CYBRD1, and KL expression under hypoxic conditions. In humanized MT3-BACTg mice, except HIF-1α, diabetes significantly increased the expression of MT3, CP, CYRBD1, FGFR2, and KL in the renal cortex in MT3-BACTg mice. Diabetic MT3-BACTg mice presented more severely damaged mitochondria in proximal tubules than their wild-type littermates did, accompanied with peritubular capillary obstruction by swollen endothelial cells. Moreover, the proximal tubules-specific overexpression of MT3 in mice (MT3Tg) represented no overlap in the protein expression between MT3 and HIF-1α in diabetic kidney. Accordingly, MT3 siRNA significantly augmented HIF-1α protein and HIF1A in HRPTECs. Finally, MT3 expression in the renal tubulointerstitium was positively correlated with the glomerular filtration rate (GFR) in DN subjects by data from Nephroseq. In conclusion, these results showed that there might be a unique interplay between MT3 and HIF-1α in diabetic kidney of to regulate hypoxia-induced HIF-1α expression.

Supplementary information: The online version contains supplementary material available at 10.1007/s13340-025-00840-y.

Background: Physical activity, including non-exercise activities, is important in the management of obesity in patients with type 2 diabetes mellitus (T2DM). This study aimed to investigate lifestyle factors associated with obesity using detailed measures of physical activity in patients with T2DM.

Methods: This cross-sectional study included 96 outpatients with T2DM (male, 61.5%; median age, 69.5 years). Outpatients self-reported their 24-h physical activity over a period of seven days. In this measure, participants selected one of the various listed activities every 15 min. Obesity indicators were defined by measuring the percent body fat (PBF) and waist-to-hip ratio (WHR); if both exceeded the cutoff values, patients were classified as PBF(+)WHR(+). The association between this outcome measure and physical activity was analyzed.

Results: In the multivariate logistic regression analysis, total physical activities (odds ratio [OR] 0.77, 95% confidence interval [CI] 0.67-0.90) and daily life activities (OR 0.96, 95% CI 0.77-0.96) were each significantly associated with PBF(+)WHR(+). In addition, the results of the analyses of each sub-item of the daily life activities of showed that 'sedentary activities' (OR 1.19, 95% CI 1.03-1.38) and 'standing with some walking' (OR 0.82, 95% CI 0.67-1.00) were each significantly associated with PBF(+)WHR(+).

Conclusion: In patients with T2DM, obesity is associated with physical activity, including non-exercise activities, sedentary behavior, and daily activities involving standing and walking.

Supplementary information: The online version contains supplementary material available at 10.1007/s13340-025-00848-4.

Background: Patients with long-standing type 1 diabetes mellitus (T1DM) often experience severe hypoglycemia (SH); however, the protective and risk factors that influence its occurrence and frequency in the era of advanced diabetes technology remain unclear. This study aimed to investigate the association of impaired awareness of hypoglycemia (IAH) and real-time continuous glucose monitoring (rtCGM) with the incidence and frequency of SH in adults with T1DM.

Methods: This prospective, observational study recruited 311 adults with T1DM (mean age: 50.6 ± 14.7 years; male: 37.9%; diabetes duration: 17.9 ± 11.3 years; mean HbA1c: 7.7 ± 1.0%) from seven diabetes centers across Japan. All participants were aged ≥ 20 years and had been diagnosed with type 1 diabetes for at least 1 year. The primary outcomes were the incidence and frequency of SH, defined as an episode of hypoglycemia necessitating assistance from others. Logistic and Poisson fixed- or random-effects models were selected using the Hausman test and were applied to analyze the data. Data are presented as coefficients with 95% confidence intervals (CIs).

Results: The prevalence of SH was 5.4 (95% CI 3.6-7.7)/100 person-years during the 2-year follow-up period. The logit random-effects model for predicting the occurrence of SH revealed that diabetic peripheral neuropathy (DPN) tended to be associated with an increased risk (coefficient: 2.01, 95% CI - 0.02 to 4.04; P = 0.053), whereas IAH (coefficient: 1.08, 95% CI 0.49 to 1.66; P < 0.001) exhibited a significant association with an increased risk. rtCGM (coefficient: - 1.75, 95% CI - 2.49 to - 1.00; P < 0.001) was associated with a reduced risk. The Poisson random-effects model for predicting the frequency of SH revealed that DPN and the IAH score (coefficient: 0.21, 95% CI 0.06 to 0.35; P = 0.006) exhibited positive associations with an increased frequency of SH, whereas rtCGM (coefficient: - 1.60, 95% CI - 2.84 to - 0.37; P = 0.011) was associated with a reduced frequency of SH.

Conclusion: This panel data analysis demonstrated that IAH was associated with an increased incidence and frequency of SH, whereas rtCGM was associated with a decreased incidence and frequency of SH.

Trial registration: University Hospital Medical Information Network (UMIN) Center: UMIN000039475), approval date: February 13, 2020.

Objective: This study aimed to evaluate the effects of tofogliflozin, a sodium-glucose cotransporter 2 inhibitor, on health issues in patients with type 2 diabetes (T2DM) and overweight or obesity in real-world clinical practice.

Methods: This post-hoc sub-analysis of the UTOPIA trial, a randomized prospective study, included 210 patients (102 in the tofogliflozin group and 108 in the conventional treatment group) with a body mass index of ≥ 25.0 kg/m². The primary outcome was the percentage of patients achieving a weight loss of ≥ 3% at 26 and 104 weeks. Secondary outcomes included improvements in obesity-related health problems.

Results: At 26 weeks, 46.4% of the tofogliflozin group (95% confidence interval [CI] 36.2-56.8%) achieved a weight loss of 3% of more, significantly higher than 14.4% in the conventional treatment group (95% CI 8.3-22.7%, p < 0.001). At 104 weeks, 62.0% of the tofogliflozin group (95% CI 51.2-71.9%) achieved this outcome compared with 29.3% in the conventional treatment group (95% CI 20.6-39.3%, p < 0.001). The tofogliflozin group also showed greater improvements in glycated hemoglobin, fasting blood glucose, blood pressure, liver indices, high-density lipoprotein-cholesterol, serum uric acid, and quality of life (QOL). Additionally, arterial stiffness progression was significantly reduced (p < 0.05) and the increase in urinary albumin tended to be attenuated (p = 0.056) in the tofogliflozin group.

Conclusions: In Japanese patients with T2DM and obesity, tofogliflozin effectively promotes weight loss and has a positive impact on various obesity-related health problems and QOL. These findings suggest its potential as a therapeutic option for improving both metabolic and cardiovascular health in this population.

Trial registration: UMIN000017607 (https://www.umin.ac.jp/icdr/index.html).

Supplementary information: The online version contains supplementary material available at 10.1007/s13340-025-00845-7.

Diabetic nephropathy (DN) is a significant and major microvascular complication of Type 2 diabetes mellitus (T2DM) with obesity being a major risk factor. Adiponectin is a major adipokine secreted by adipose tissue, encoded by the APM1/ADIPOQ gene. Genetic variation in the ADIPOQ gene has been linked to the development of T2DM and DN. The present study aims to investigate the influence of the rs2241766 and rs17300539 polymorphisms of the APN gene on the risk of DN. A total of 150 participants were grouped as Group I: Control (N = 50), Group II: T2DM (N = 50), and Group III: DN (N = 50). Blood glucose, renal profile, and lipid profile were analyzed and the genetic variants were analyzed using ARMS-PCR. The rs2241766 was significantly associated with an increased risk of developing T2DM in homozygous mutant [OR: 23.40 (2.43-224.64); 0.006], Dominant [3.27 (1.42-7.52); 0.005], recessive [10.75 (1.30-88.47); 0.027] and allelic [3.32 (1.68-6.58); 0.0006] model. Males demonstrated an increased risk but the increase was not statistically significant. The rs2241766 polymorphism was not associated with the development of DN in general and gender subtype. The rs17300539 was not associated with the development of T2DM or DN in the studied population. DN demonstrated significantly lower plasma APN levels and higher oxidative stress (as measured by NOX) compared to healthy controls. The rs2241766 variant enhanced T2DM risk while the rs17300539 polymorphism did not demonstrate any relationship with T2DM development. However, neither the rs2241766 nor the rs17300539 polymorphisms demonstrated any correlation with the onset of DN.

Hyperglycemia is a well-recognized adverse event associated with capivasertib, an oral AKT inhibitor, and may occasionally progress to serious conditions such as diabetic ketoacidosis. We report the case of a 73-year-old woman with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer who developed marked hyperglycemia shortly after initiating capivasertib therapy. Marked hyperglycemia was observed on day 11 of treatment, despite normal baseline levels. Capivasertib was temporarily discontinued, and insulin therapy was initiated. Continuous glucose monitoring revealed transient hyperglycemic episodes occurring exclusively on dosing days, which resolved within approximately 12 h. This pattern suggests a pharmacodynamic correlation and reversible effect of capivasertib on glucose metabolism. Rapid-acting insulin was required only on days when capivasertib was administered. Notably, standard hemoglobin A1c monitoring failed to capture these fluctuations. This case underscores the importance of real-time glucose monitoring and individualized glycemic management during capivasertib therapy, particularly in patients with metabolic risk factors. Early detection and tailored intervention may help prevent severe hyperglycemic complications and facilitate the safe continuation of treatment.

This study aims to identify distinct sets of genes that can serve as specific biomarkers reflective of biological states distinguishing diabetic nephropathy (DN) or diabetic retinopathy (DR) from healthy individuals, thus providing potential utility for early detection and intervention in diabetic complications. We analyzed two transcriptome datasets (GSE142153 and GSE221521) from the Gene Expression Omnibus, employing the Limma method to identify differentially expressed genes (DEGs) among healthy controls, individuals with DN, and those with DR. Through gene co-regulation mechanisms, we screened for crucial genes related to both DN and DR, and selected candidate biomarkers via functional enrichment analysis, protein-protein interaction network construction, and the integration of machine learning algorithms. Their diagnostic performance was evaluated using receiver operating characteristic curves and dynamic nomogram analysis, and further validated with the GSE154881 and GSE185011 datasets. We identified 48 genes co-regulated by DM and DN, and 171 genes co-regulated by DM and DR. Using protein-protein interaction networks, the top 10 and 18 node genes for DN and DR were screened, respectively, leading to the selection of two biomarkers for DN (HCAR2 and TANK) and three for DR (RHOB, RPL12, and RPS17) through machine learning. Validation results demonstrated the good efficacy of the nomogram, suggesting that these distinct gene sets can serve as specific biomarkers for indicating distinct biological alterations associated with DN and DR.

Supplementary information: The online version contains supplementary material available at 10.1007/s13340-025-00842-w.

Objectives: To investigate whether low skeletal muscle mass predicts insulin resistance (IR) progression in non-obese older adults, and whether its coexistence with abdominal obesity further increases risk.

Methods: This six-year cohort study was part of the Tanno-Sobetsu study, a prospective cohort of 204 community-dwelling Japanese older adults aged ≥ 65 years, enrolled in 2017 and followed through 2023. Participants were classified into four groups based on the presence or absence of low skeletal muscle mass (sex-specific lowest quartile) and abdominal obesity. IR progression was defined as HOMA-IR ≥ 1.73. Participants without IR at baseline were followed for a median of 2.8 years. Cox proportional hazards models were used to estimate adjusted hazard ratios (HR) for IR progression, using the group with neither condition as the reference, with adjustments for age, sex, baseline HOMA-IR, and triglycerides.

Results: During follow-up, 86 participants (42.2%) developed IR. Compared to those with neither condition, low skeletal muscle mass alone was significantly associated with IR progression (HR: 2.11, 95% CI 1.08-4.11, p = 0.029), as was the coexistence of low skeletal muscle mass and abdominal obesity (HRs: 2.09, 95% CI 1.13-3.86, p = 0.019). Abdominal obesity alone was not significantly associated (HR: 1.15, 95% CI 0.61-2.15, p = 0.65).

Conclusions: Low skeletal muscle mass independently predicted IR progression in older adults, even in the absence of abdominal obesity. No additive risk was observed when low muscle mass coexisted with abdominal obesity after adjusting for baseline HOMA-IR. These findings support assessing muscle mass for IR prevention, regardless of abdominal obesity status.

Supplementary information: The online version contains supplementary material available at 10.1007/s13340-025-00843-9.

In the post-SGLT2 inhibitor era, residual renal risk remains a major concern in diabetic kidney disease (DKD). Finerenone, a non-steroidal mineralocorticoid receptor antagonist (MRA), has shown cardiovascular and renal benefits in clinical trials. However, its effectiveness in patients previously treated with other MRAs remains unclear. We retrospectively analyzed 73 patients with DKD who were treated with finerenone at Shimane University Hospital between June 2022 and March 2024. The primary outcome was the change in estimated glomerular filtration rate (eGFR) slope before and after finerenone initiation. The mean eGFR slope significantly improved following finerenone initiation (-7.3 to -0.5 mL/min/1.73 m²/year, P = 0.010). In a sub-analysis of 65 patients with ≥6 months of follow-up, compared to the 1-year pre-treatment period, the decline in eGFR was significantly attenuated (-5.2 to -0.03 mL/min/1.73 m²/year, P = 0.036), accompanied by a significant reduction in the urinary albumin-to-creatinine ratio (UACR). Notably, one-third of patients had switched from other MRAs, most commonly esaxerenone. In this subgroup, a trend toward eGFR preservation was observed, although the reduction in UACR was not observed. In contrast, MRA-naïve patients exhibited significant improvements in both eGFR slope and UACR. No serious cases of hyperkalemic crisis were observed. These findings highlight the favorable renal effects of finerenone, even in high-risk patients previously managed with other MRAs. Finerenone may offer incremental benefit for eGFR preservation and supports its role in comprehensive DKD management.