Journal of Diabetes Investigation最新文献

Ethnic differences in type 2 diabetes risk highlight the need for accurate detection of impaired glucose tolerance (IGT) across all ethnic groups. This study assessed the sensitivity and specificity of HbA1c, fasting plasma glucose (FPG), and 1-h plasma glucose for identifying IGT in 66 Black African (BA) and 77 White European (WE) men. Participants underwent a 75 g oral glucose tolerance test, and diagnostic performance was evaluated using ROC analyses. One-hour glucose showed the highest sensitivity (BA 77.8%, WE 94.1%) and AUC (0.78), whereas FPG 6.1-6.9 mmol/L had the poorest sensitivity (≤7.4%) and lowest AUC (0.49). HbA1c demonstrated ethnic variation: WHO criteria (6.0-6.4%) were more sensitive but less specific in BA than WE men; ADA criteria (5.7-6.4%) showed reduced specificity in BA men. Optimal cut-points differed by ethnicity for all markers. Findings suggest HbA1c and FPG may inadequately detect IGT, while 1-h glucose offers superior diagnostic performance.

Aims/introduction: To investigate the safety of anagliptin/metformin combination tablets by evaluation of lactic acid levels in Japanese patients with type 2 diabetes and moderate renal impairment.

Materials and methods: The participants of type 2 diabetes with creatinine-based eGFR (eGFRcr) of ≥45 and <60 (mL/min/1.73 m²) (Group G3a) received anagliptin/metformin combination LD tablets (anagliptin: 100 mg, metformin hydrochloride: 250 mg/tablet) twice a day for 4 weeks. After 4 weeks, they received anagliptin/metformin combination HD tablets (anagliptin: 100 mg, metformin hydrochloride: 500 mg/tablet) twice daily until after 16 weeks. The participants (Group G3b) with baseline eGFRcr ≥30 and <45 (mL/min/1.73 m²) received anagliptin/metformin combination LD tablets twice daily for 16 weeks. The serum lactic acid levels were examined at weeks 4, 8, and 16 after receiving anagliptin/metformin combination tablets.

Results: The change in serum lactic acid levels from baseline to 16 weeks was -0.09 [-0.28, 0.10] mmol/L (mean [95% confidence intervals]), not exceeding the pre-specified non-inferiority margin (0.7 mmol/L). No significant differences occurred in the change in serum lactic acid levels during all observation periods. Serum lactic acid levels exceeded 2.5 mmol/L in four participants (10.5%) and 5.0 mmol/L in one participant (2.6%) during the observation period. No participant had a plasma metformin exceeding 2.5 μg/mL.

Conclusions: This study demonstrates that the fixed-dose combination of anagliptin and metformin can be used safely in patients with type 2 diabetes complicated by moderate renal dysfunction. The advantage of this fixed-dose combination is also considered to be very large.

Background: Diabetic patients are particularly vulnerable to heat exposure due to impaired thermoregulation and reduced sweating ability. The impact of heat on skin cell function, particularly keratinocytes, is poorly understood. Recent studies highlight the critical role of nitric oxide (NO) in thermoregulation and heat stress responses, but its specific involvement in keratinocyte responses and metabolic profiles remains unexplored.

Objective: This proof-of-concept study investigates the metabolic profiles of HaCat keratinocytes under normal and high-glucose conditions during varied heat exposures.

Methods: We conducted experiments using a metabolomics approach, NO levels assessments, western blot analysis, and evaluations of mitochondrial morphology.

Results: Our findings indicate that acute heat exposure over 90 minutes significantly alters metabolic pathways, particularly amino acid metabolism (including arginine, valine, leucine, and serine), the pyrimidine metabolite uracil, and glycolysis, notably lactate production. Arginine metabolism was uniquely affected by high glucose combined with heat, aligning with previous clinical observations. Furthermore, we discovered that changes in NO production correlated with heat exposure duration, and that NO levels in extracellular vesicles (EVs) from HaCat cells were inversely related to intracellular NO levels. Additionally, we observed alterations in HSP-70 protein expression and mitochondrial morphology, supporting cellular adaptation to thermal stress.

Conclusion: This study is the first to demonstrate heat-induced metabolic changes in keratinocytes involving arginine and NO, highlighting their potential as clinical biomarkers for thermal stress adaptation, with implications for both healthy individuals and diabetic patients.

Aims: We sought to compare the MiniMed™ 770G to the 780G insulin pump for glycemic control and quality of life in Japanese adults with T1D over a one-year period.

Methods: Thirty-six adults with T1D who switched from the MiniMed™ 770G to the 780G system were analyzed over 48 weeks using continuous glucose monitoring data, retrospectively. The percentages of time within the target glucose range (70-180 mg/dL), time above 180 mg/dL, and time below 70 mg/dL were compared before and after switching. Quality of life (QOL) scores were also evaluated in 39 patients using a validated questionnaire, prospectively.

Results: After switching to the MiniMed™ 780G, the time within the target glucose range significantly increased from 71.6 ± 12.4% to 76.1 ± 10.2% (P < 0.01), while the time above 180 mg/dL decreased from 25.2 ± 13.4% to 21.0 ± 11.0% (P < 0.01). The time below 70 mg/dL did not differ significantly overall, but nocturnal hypoglycemia decreased from 4.9% to 2.7% (P = 0.02). Glycated hemoglobin improved from 7.2 ± 0.8% to 7.0 ± 0.7% (P < 0.01). Although the total QOL score did not change significantly, the subscales reflecting anxiety and treatment satisfaction improved significantly.

Conclusions: Switching from the MiniMed™ 770G to the 780G system in Japanese adults with T1D improved both glycemic control and treatment-related QOL, supporting the clinical usefulness of the 780G in real-world clinical practice. This study provides the first one-year real-world evidence of MiniMed™ 780G use in Japan.

Aims/introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors enhance circulating levels of biologically intact incretins, yet the relative contribution of glucose-dependent insulinotropic polypeptide (GIP) to their metabolic effects remains incompletely understood. While glucagon-like peptide-1 (GLP-1) has long been emphasized in incretin biology, emerging evidence suggests important physiological roles for GIP. This study investigated whether endogenous GIP signaling is indispensable for the glucose-lowering and anti-obesity effects of DPP-4 inhibition.

Materials and methods: Male Gipr^+/+ and Gipr^-/- mice were treated with anagliptin or linagliptin under normal diet or high-fat diet (HFD) conditions. Glucose tolerance, insulin secretion, incretin levels, body weight, and adiposity were assessed. To confirm GLP-1 pathway integrity, dulaglutide was administered to a subset of animals.

Results: DPP-4 inhibition significantly improved glucose tolerance and attenuated body-weight gain in HFD-fed Gipr^+/+ mice, without affecting food intake. These effects were abolished in Gipr^-/- mice, despite similar elevations in circulating biologically intact GIP and GLP-1. Under normal diet, DPP-4 inhibitors enhanced early-phase insulin secretion and lowered glucose levels in Gipr^+/+ mice, but not in Gipr^-/- mice. Importantly, dulaglutide restored glucose-lowering effects in Gipr^-/- mice, confirming preserved GLP-1 receptor function.

Conclusions: Endogenous GIP signaling is essential for both glucose-lowering and anti-obesity actions of DPP-4 inhibitors in mice. GLP-1 elevation alone is insufficient to compensate for GIP receptor deficiency. These findings refined the mechanistic understanding of DPP-4 inhibitors, highlighted the physiological importance of GIP, and suggested context-dependent metabolic actions of incretins.

Aims: MicroRNA (miRNA) has been confirmed to be related to gene expression regulation and disease progression. However, the role of miR-155-5p in diabetic retinopathy remains unclear.

Materials and methods: The retinal microvascular endothelial cells (RMECs) were treated with high glucose, and then the changes of miR-155-5p, endothelial cell markers (CD31 and VE-cadherin), mesenchymal cell markers (SM22α and α-SMA), and VEGF were detected by RT-qPCR. The apoptotic markers (Bax, Bcl-2, cleaved caspase-3) were detected by Western blotting. Additionally, miRNA inhibitors or small interfering RNA were used to regulate the levels of miR-155-5p and DDAH1. Subsequently, the changes in endothelial-mesenchymal transition markers, oxidative stress markers, and apoptotic proteins were observed. The regulatory relationship between miR-155-5p and DDAH1 was investigated using dual-luciferase reporter assays, RNA immunoprecipitation, and RNA pull-down assays.

Results: After culturing RMECs with high glucose, the level of miR-155-5p increased. After the miR-155-5p level was reduced, the levels of CD31 and VE-cadherin increased, while the levels of SM22α, α-SMA and VEGF decreased. Additionally, the downregulation of miR-155-5p significantly inhibited the increase in ROS and Malondialdehyde (MDA) levels as well as cell apoptosis. DDAH1 is the downstream target of miR-155-5p. The downregulation of DDAH1 significantly weakened the inhibitory effects of miR-155-5p downregulation on endothelial-mesenchymal transition, oxidative stress, and cell apoptosis.

Conclusions: In diabetic retinopathy, miR-155-5p affects the endothelial-mesenchymal transition process and oxidative stress levels of RMECs through DDAH1 and reduces cell apoptosis induced by high glucose.

Background: Diabetic peripheral neuropathy (DPN), a complication of diabetes, is characterized by complex pathophysiology, high global morbidity, and limited early diagnostic tools. MicroRNAs (miRNAs) have emerged as potential regulators in DPN.

Aims: This study aimed to investigate miR-210-3p as a diagnostic biomarker for DPN and elucidate its molecular mechanisms in disease progression.

Methods: A total of 72 type 2 diabetes patients, 75 DPN patients, and 70 healthy controls were enrolled. Serum miR-210-3p expression was measured by RT-qPCR, and its diagnostic value was evaluated using ROC curve analysis. Multivariate logistic regression identified risk factors for DPN in type 2 diabetes patients. In vitro, a high-glucose (HG) induced RSC96 Schwann cell model was established to explore miR-210-3p function. Dual-luciferase reporter experiments demonstrated that miR-210-3p directly targets BDNF. Additionally, CCK-8 assays measured proliferation, flow cytometry analyzed apoptosis, and transwell chambers quantified cell migration.

Results: Serum levels of miR-210-3p were markedly elevated in DPN patients compared with both type 2 diabetes subjects and healthy controls (P < 0.001). The diagnostic performance was robust, achieving an AUC of 0.830 (sensitivity 72.0%; specificity 80.6%). Multivariate analysis confirmed miR-210-3p, fasting blood glucose, and glycated hemoglobin A1c as independent DPN risk factors. MiR-210-3p negatively regulated BDNF, and the miR-210-3p inhibitor reversed HG-induced Schwann cell dysfunction, while BDNF knockdown abrogated this protective effect.

Conclusions: MiR-210-3p serves as a potential diagnostic biomarker for DPN and regulates Schwann cell function via targeting BDNF, providing novel insights into DPN pathogenesis and therapeutic targets.

Aims: Several studies have suggested diabetes to possibly be associated with muscle atrophy, that is, so-called sarcopenia, in seniors. The association between grip strength and disease states has not yet been examined in a large-scale general population study. Therefore, we conducted a large-scale analysis of the relationship between grip strength and glucose tolerance in Japanese subjects aged ≥65 years receiving health check-ups.

Methods: We collected data from 22,717 subjects who underwent medical check-ups. After excluding subjects who did not meet the criteria, data from 15,529 subjects who underwent the grip strength measurement were analyzed. The subjects were divided into three groups according to anthropometric and biochemical data, including glucose tolerance status. Baseline characteristics, including grip strength, were compared among the three groups. Regression analysis was performed to investigate the association between grip strength and glucose tolerance status.

Results: For males, median grip strength was significantly lower in the group with diabetes (36.0 kg) than in those with prediabetes (37.0 kg) or normal glucose tolerance (37.3 kg). According to logistic regression analysis, higher grip strength was associated with lower odds of diabetes (OR = 0.959, 95% CI: 0.949-0.968 vs normal, OR = 0.968, 95% CI: 0.957-0.979 vs prediabetes) or prediabetes (OR = 0.990, 95% CI: 0.981-0.999 vs normal) for males, while not reaching statistical significance for females.

Conclusions: Diabetes is associated with lower grip strength in Japanese males aged ≥65 years.