Journal of Diabetes Investigation最新文献

Aims/introduction: COVID-19 containment measures in Japan, characterized by intermittent states of emergency (SE) without strict lockdowns from April 2020 to September 2021, may have significantly impacted lifestyle, weight, and body composition in individuals with diabetes. This study examines changes in glycemic management, body weight, and body composition before, during, and after SE in adults with diabetes.

Materials and methods: This retrospective study included individuals with diabetes aged 20 years or older whose HbA1c and body composition were measured in three periods of pre-SE (April 2019-March 2020), SE (April 2020-September 2021), and post-SE (October 2021-September 2022). Hospitalized individuals were excluded. Participants were divided into subgroups by age (young: <65 years, older: ≥65 years) and gender for analysis.

Results: A total of 673 subjects were analyzed. No significant changes in HbA1c were observed in any period. Body weight remained constant during SE but decreased post-SE. Continuous decreases in skeletal muscle mass were noted in all groups. In the total analysis, body fat mass initially increased during SE but decreased post-SE. However, due to weight loss in the post-SE, the overall body fat percentage rose. Notably, in older males, body fat mass increased during SE and remained unchanged post-SE, resulting in a continuous increase in body fat percentage throughout observational periods.

Conclusion: The study highlights a continuous decline in muscle mass and body weight changes, with body fat percentage fluctuations differing by age and gender. The impact was most significant in older males, underscoring the need for targeted health interventions.

Introduction: We aimed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of orforglipron in Japanese participants with type 2 diabetes.

Materials and methods: This was a double-blind, placebo-controlled, randomized, phase 1 study. In Part A, participants received single doses of orforglipron (2 or 3 mg) or placebo. In Part B, participants received multiple ascending doses of daily oral orforglipron (final target doses: 12, 24, and 45 mg) or placebo for 12 weeks.

Results: Parts A and B enrolled 23 and 60 participants, respectively. The most common treatment-emergent adverse events were gastrointestinal events of mild severity. No severe or serious adverse events were reported. At week 12, median t_max was 5.92-8.00 h, and mean terminal half-life was 51.8-76.1 h. Following multiple ascending doses, orforglipron groups had greater mean reductions from baseline to week 12 in glycemic parameters (fasting glucose: orforglipron 12 mg -64.8 mg/dL, 24 mg -61.1 mg/dL, 45 mg -65.6 mg/dL, placebo 7.4 mg/dL; glycated hemoglobin: orforglipron 12 mg -2.16%, 24 mg -2.17%, 45 mg -2.28%, placebo 0.67%) and body weight (orforglipron 12 mg -2.9 kg, 24 mg -6.3 kg, 45 mg -4.8 kg, placebo 0.3 kg) compared with placebo.

Discussion: In Japanese participants, safety, pharmacokinetic, and pharmacodynamic results were similar to those of previous orforglipron studies. The safety and tolerability of orforglipron were also consistent with those of other glucagon-like peptide-1 receptor agonists. Orforglipron is a potential new treatment option for Japanese patients with type 2 diabetes.

Introduction: Hyperglycemia or diabetes mellitus (DM) is a well-known risk factor for pancreatic cancer, but it is uncertain whether well-controlled glycemic status can affect the pancreatic cancer incidence rate.

Methods: This study used 2,993,519 individuals who underwent four consecutive national annual health screenings between 2009 and 2013. The study participants were divided into three groups: nondiabetes mellitus (non-DM), new-onset DM, and known DM. Each group was further subcategorized based on the fasting blood glucose (FBG) levels and use of antidiabetic medication: well-controlled (<100 mg/dL), moderately controlled (100-125), or poorly controlled (>126).

Results: During a median follow-up of 6.3 years, the incidence rate of pancreatic cancer in the non-DM group significantly increased in the moderately controlled group compared with that in the well-controlled group, regardless of whether the FBG level was recently or initially elevated. However, no dose-response relationship was observed between glucose control status and pancreatic cancer incidence, although the incidence of pancreatic cancer in the new DM and known DM groups was generally higher than that in the non-DM group.

Conclusion: The pancreatic cancer incidence rate in the non-DM group significantly increased in the poorly controlled group. These findings suggest that in populations without DM, maintaining optimal glucose control may be associated with a lower risk of developing pancreatic cancer.

Aims/introduction: Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus and may be linked to renal function decline. However, the prognostic value of point-of-care nerve conduction devices such as DPN-Check® for renal outcomes remains unclear.

Materials and methods: We conducted a single-center retrospective observational study of 403 patients with diabetes (median follow-up 2.9 years) at Tokyo Metropolitan Ohkubo Hospital. DPN was assessed by DPN-Check® (amplitude [AMP] <5 μV or nerve conduction velocity [NCV] <42 m/s) and simplified diagnostic criteria (SDC). The primary outcome was annual eGFR decline, calculated by the linear least squares method; rapid decliners were defined as those with a decline ≥5 mL/min/1.73 m²/year. Multivariate linear and logistic regression analyses were performed to identify independent associations.

Results: Patients with DPN diagnosed with DPN-Check® had a greater annual eGFR decline than those without (-2.26 vs. -0.81 mL/min/1.73 m²/year, P < 0.001), whereas DPN diagnosed with SDC showed no association. In multivariate analysis, DPN diagnosed with DPN-Check® remained independently associated with faster eGFR decline (standardized β: -0.262, P < 0.001) and with rapid decliner status (odds ratio [OR]: 2.791, 95% confidence interval [CI]: 1.267-6.152, P = 0.011).

Conclusions: DPN diagnosed by DPN-Check® was independently associated with accelerated renal function decline in patients with T2DM, even after adjusting for albuminuria. DPN-Check® may help identify patients at high risk for end-stage kidney disease and guide earlier intervention for both neuropathy and kidney disease.

Aims: Clinical inertia, the failure to intensify treatment despite unmet glycemic goals, is a key factor in poor glycemic management for type 2 diabetes. No studies have defined clinical inertia based on HbA1c trends. In this study, we aimed to assess treatment intensification according to HbA1c trends.

Materials and methods: We analyzed data from the Japan Diabetes Comprehensive Database Project based on an Advanced Electronic Medical Record System (J-DREAMS) between 2016 and 2023. Eligible patients with type 2 diabetes had (1) unchanged prescriptions for the past 90 days; (2) two consecutive consultations within 90 days; and (3) HbA1c levels ≥7%, or ≥7.5%, for patients aged ≥65 years at both consultations. Treatment intensification was defined as an addition or increased dose or switch in antidiabetic medications, inclusive of insulin, at the second consultation. Moreover, factors associated with treatment intensification were assessed.

Results: Of the 5,683 patients, 1,130 (19.9%) received intensified treatment at the second consultation. Intensification occurred more frequently with higher HbA1c levels or worsening HbA1c trends. However, treatments were not intensified in approximately 50% of the patients, with HbA1c levels >8% or a worsening of >1%. Predictive factors included the HbA1c levels at the second consultation, changes in the HbA1c levels between the first and second consultations, the number of oral hypoglycemic medications, and the use of sulfonylureas or glinides.

Conclusions: Physicians should consider HbA1c trends to guide treatment intensification when HbA1c levels exceed target thresholds. Clinical inertia remains an important issue in diabetes management.

Aims/introduction: While treatment for diabetic polyneuropathy (DPN) is still developing, progress has stagnated. The alignment between pathological neurodegeneration in DPN and patients' subjective symptoms is often low, yet these symptoms are frequently used for diagnosis. This reliance has hindered the development of effective drugs to prevent neurodegeneration. This study aims to establish an objective electrophysiological diagnostic method that could support future treatment development and validate its accuracy.

Materials and methods: This retrospective multicenter cohort study involved hospitalized diabetic patients. A total of 314 patients underwent nerve conduction studies using standard electromyography and a simplified nerve conduction testing device (NC-stat/DPNCheck™), along with electrocardiogram-based coefficient of variation of R-R intervals (CV_R-R). Patients with a severity classification of Stage 2 or higher based on electromyography were defined as having DPN. Logistic regression analysis was used to identify significant factors explaining DPN presence, followed by ROC analysis to determine optimal cutoff values for diagnosis.

Results: Significant factors included resting CV_R-R, sural nerve conduction velocity (SNCV), and amplitude of sensory nerve action potential (SNAP). SNCV had the highest area under the curve (AUC = 0.823). The optimal cutoff values were 1.62% for CV_R-R, 46.5 m/s for SNCV, and 10.5 μV for SNAP. Diagnosing DPN based on abnormalities in two or more of these three conditions yielded an accuracy of 79.3%.

Conclusions: The established diagnostic criteria of DPN demonstrate high performance and are expected to be applicable in clinical settings.

A 48-year-old man was referred to our hospital due to hyperglycemia. His casual plasma glucose and glycated hemoglobin A1c were 25.2 mmol/L and 8.7%, respectively. He had undergone bilateral cataract surgery in his 30s. He exhibited a bird-like face contour, gray hair, alopecia, and bilateral calcifications of the Achilles' tendons, suggestive of Werner syndrome (WS). Genetic analysis revealed compound heterozygous mutations in the WRN gene (mutation c. 3139-1G>C, mutation c. 1105C>T), leading to the diagnosis of WS. Adequate glycemic control was not achieved by the treatment with pioglitazone and metformin. Additional administration of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, ameliorated insulin resistance and resulted in an improvement in glycemic control without adverse events. Dapagliflozin may potentially be a choice in treating diabetes associated with WS with an amelioration of insulin resistance.

Introduction: Mean platelet volume (MPV), which reflects platelet size and activity, is known to be elevated in patients with type 2 diabetes mellitus. Although increased MPV has been linked to poor glycemic control and diabetic vascular complications, evidence regarding its association with hard kidney outcomes remains limited. We aimed to investigate the relationship between MPV and kidney events in patients with type 2 diabetes mellitus.

Materials and methods: We retrospectively analyzed longitudinal data from 1,076 Japanese patients with type 2 diabetes mellitus enrolled in the Fukushima Cohort Study. Participants were categorized into quartiles based on baseline MPV levels. The primary endpoint was kidney events, defined as a ≥50% decline in estimated glomerular filtration rate (eGFR) from baseline or progression to end-stage kidney disease requiring kidney replacement therapy. The secondary endpoint was new-onset cardiovascular events.

Results: During a median follow-up of 5.3 years, 97 patients experienced kidney events. The second quartile (Q2) had the lowest incidence of kidney events. Compared with Q2 as the reference, patients in the highest quartile (Q4) had a significantly increased risk of kidney events (adjusted hazard ratio 2.05, 95% confidence interval 1.13-3.72). Higher MPV levels were also significantly associated with an increased risk of cardiovascular events.

Conclusion: Elevated MPV was independently associated with both kidney and cardiovascular events in Japanese patients with type 2 diabetes mellitus. MPV may serve as a simple and useful biomarker for predicting kidney disease progression in this high-risk population.

Aims/introduction: We aimed to explore the association of the triglyceride-glucose (TyG) index and homeostasis model assessment of insulin resistance (HOMA-IR) with subclinical left ventricular function in the general population.

Materials and methods: A total of 2,850 participants with left ventricular ejection fraction ≥50% were recruited from 2017 to 2019 in Danyang. Speckle-tracking echocardiography (Philips CX50) was used to measure global longitudinal strain (GLS). Subclinical left ventricular systolic dysfunction (LVSD) was defined as GLS < 18%.

Results: In univariate analyses, higher TyG index and HOMA--IR were significantly associated with reduced GLS, lower E/A ratio and e', and higher E/e' ratio (P < 0.001). After adjustment for confounders, HOMA-IR remained significantly associated with lower GLS (P = 0.002), whereas the TyG index showed stronger correlations with E/e' ratio (P < 0.01). The inclusion of log-transformed HOMA-IR significantly improved model fit in analyses incorporating GLS and TyG index (P = 0.004) but not in those with E/e' ratio and TyG index (P = 0.65). Conversely, the TyG index enhanced model performance for the E/e'-HOMA-IR association (P < 0.001) but not for GLS-HOMA-IR relationships (P = 1). In addition, participants in the highest versus lowest HOMA-IR quartile demonstrated significantly increased odds ratio of subclinical LVSD (OR = 2.22, 95% CI: 1.26-3.92; P = 0.006), while the TyG index showed no significant association with its prevalence (P = 0.98).

Conclusions: In a community-based population, elevated HOMA-IR demonstrated a robust association with subclinical LVSD, whereas the TyG index exhibited a more pronounced correlation with early diastolic dysfunction.

Aims/introduction: Leukocytes are implicated in the inflammatory cascades of diabetic retinopathy (DR), but their causal roles remain ambiguous. This study employed a two-sample Mendelian randomization (MR) analysis to dissect the causal effects of circulating leukocyte counts on DR risk.

Materials and methods: We utilized summary statistics from large-scale genome-wide association studies (GWAS) for five leukocyte subtypes and DR in European-ancestry populations. The inverse-variance weighted (IVW) method was primary, supported by comprehensive sensitivity analyses including MR-Egger, weighted median, and the MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) test to ensure result robustness.

Results: A total of 2,136 leukocyte-related SNPs were extracted as instrumental variables for causal inference. MR analysis revealed that increased lymphocyte counts are associated with reduced DR risk (IVW OR = 0.93, 95% CI = 0.86-0.99, P = 0.03), while the initial association between higher eosinophil counts and DR risk (IVW OR = 1.11, 95% CI = 1.03-1.19, P < 0.01) was attenuated following correction for outliers. No significant associations were observed for basophil, monocyte, or neutrophil counts. Sensitivity analyses found no evidence of pleiotropy or substantial influence from single SNPs.

Conclusions: Our findings provide genetic evidence supporting a potential causal association between lymphocyte counts and diabetic retinopathy risk, while the association for eosinophil counts was attenuated after correction for outliers. These results highlight the importance of further investigating the physiological role of lymphocytes in diabetic retinopathy to inform effective prevention and treatment strategies.