Journal of Diabetes Investigation最新文献

Aims/introduction: In the SURPASS J-mono trial, tirzepatide demonstrated significant improvements in bodyweight and several metabolic parameters in Japanese participants with type 2 diabetes. This post hoc analysis evaluated the potential relationships between weight loss and metabolic improvements in SURPASS J-mono.

Materials and methods: Metabolic parameter data from tirzepatide-treated participants were analyzed by weight loss subgroups and compared to dulaglutide 0.75 mg. Correlations between changes from baseline to week 52 in weight loss and each metabolic parameter were assessed; Pearson correlation coefficients were derived. Mediation analyses were conducted to evaluate weight loss-associated and -unassociated effects of tirzepatide vs dulaglutide 0.75 mg.

Results: This analysis included 548 participants (tirzepatide: n = 411, dulaglutide: n = 137). Weight loss subgroups showed greater improvement in metabolic parameters with greater bodyweight loss. Significant (P < 0.05) but weak correlations between changes in bodyweight and triglycerides (r = 0.18-0.25), high-density lipoprotein cholesterol (r = -0.37 to -0.29), and systolic blood pressure (r = 0.19-0.41) were observed across treatment groups; in diastolic blood pressure in the tirzepatide 5-mg (r = 0.28), pooled tirzepatide (r = 0.20), and dulaglutide 0.75-mg (r = 0.23) groups; and in fasting serum glucose in the dulaglutide 0.75-mg (r = 0.18) and pooled tirzepatide (r = 0.13) groups. Weight loss was associated with treatment differences between tirzepatide and dulaglutide 0.75 mg to varying degrees across metabolic parameters, with improvements in fasting serum glucose having the lowest association with weight loss (36.6%-43.5%).

Conclusions: In this post hoc analysis, non-glycemic and glycemic parameter improvements appeared differentially associated with weight loss, suggesting both weight loss-associated and -unassociated effects of tirzepatide.

This is an inivitation article for 'JDI updates' series, focusing on the heterogeneity of type 2 diabetes.

Aims: Growth differentiation factor-15 (GDF-15) is an inflammatory cytokine that increases in prediabetes and is known for its anorexigenic effects. This study aims to evaluate the effects of a 12-week exercise program on GDF-15 in individuals with prediabetes.

Materials and methods: In this multicenter, parallel-group, randomized-controlled trial, 64 patients aged 18-60 diagnosed with prediabetes were randomized in a 1:1 ratio into the exercise group (E) and the control group (C). Additionally, 32 patients who were planned to start metformin were included in the metformin group (M). Participants in the exercise group engaged in aerobic exercise at 50-70% of their maximum heart rate for 60 min, 3 days a week. Serum GDF-15 levels were evaluated at the beginning and the end of the 12th week.

Results: The mean age of the 91 participants who completed the study was 46.13 ± 8.52 years, and 23.1% were male. Basal GDF-15 levels were similar among the groups (E = 668.6 ± 415.1, C = 651.8 ± 352.5, M = 603.6 ± 387.2, P = 0.47). At the 12th week, GDF-15 levels were lower in the E compared to the C, while higher in the M compared to the C (E = 383.1 ± 215.6, C = 556.4 ± 285.6, M = 810.8 ± 498.0, P < 0.001). In inter-group comparisons, no significant change was observed in the C between the 0th and 12th weeks, while GDF-15 decreased in the E (P < 0.001) and increased in the M (P < 0.001).

Conclusions: It was determined that in individuals with prediabetes, GDF-15, which serves both as a biomarker of metabolic disorder and has a negative regulatory effect on appetite, decreased with 12 weeks of aerobic exercise and increased with metformin administration.

Aim: To determine the epidemiological characteristics and risk factors for heart failure (HF) among Japanese patients with type 2 diabetes.

Methods: A retrospective cohort analysis, using J-DREAMS database, was conducted from December 2015 to January 2020 with type 2 diabetes. The primary objectives were to describe patient characteristics stratified by HF history at baseline and new HF events during follow-up. The secondary objectives were to clarify the association between HF history or new HF events and clinical characteristics. The association between renal disease stage and HF was also studied.

Results: Among 18,250 adult patients with type 2 diabetes, 3,613 (19.8%) patients had HF history and the mean age was 68.46 years, predominantly male (66.4%) with 13.32 years of mean duration of type 2 diabetes. Patients with HF history had a higher proportion of patients with nephropathy (51.2%) and coronary heart disease (55.6%) than those without HF history. Coronary heart disease (CHD) and deteriorating renal function were strongly associated with both HF history (CHD adjusted odds ratio [OR]: 7.41, 95% confidence interval [CI]: 6.05-9.08; eGFR G5 stage adjusted OR: 6.56, 95% CI: 2.97-14.49) and new HF events (CHD adjusted OR: 1.63, 95% CI: 1.17-2.29; eGFR G4 stage adjusted OR: 3.42, 95% CI: 1.81-6.47).

Conclusions: Comorbidities, especially CHD and deteriorating renal function, were strongly associated with HF history and new HF events among Japanese patients with type 2 diabetes. The study results suggested the importance of early intervention to treat comorbidities and maintain renal function.

Aim: To elucidate risk factors associated with adverse perinatal outcomes in early-gestational diabetes mellitus (GDM).

Materials and methods: A dataset of 385 early-GDM cases from a prospective cohort was analyzed. Early-GDM was diagnosed if one or more of the following criteria were met: fasting plasma glucose (PG) levels of 92-125 mg/dL, 1-h PG levels ≥180 mg/dL, and 2-h PG levels ≥153 mg/dL during a 75-g oral glucose tolerance test before 20 weeks of gestation. Multivariate analysis was used to examine associations between candidate risk factors and a composite outcome of maternal and neonatal adverse events.

Results: Pre-pregnancy overweight/obesity (pre-pregnancy body mass index [BMI] ≥25.0 kg/m²) was significantly associated with a higher risk of the composite outcome compared with normal weight (pre-pregnancy BMI of 18.5-24.9 kg/m²), an adjusted risk ratio (aRR) of 1.44 (95% confidence interval [CI]: 1.08-1.93), and an adjusted risk difference (aRD) of 13.6% (95% CI: 2.6-24.6%). Compared with fasting PG levels below 92 mg/dL, levels between 95 and 125 mg/dL were associated with a significantly higher risk of the composite outcome, with an aRR and aRD of 1.42 (95% CI: 1.01-1.99) and 12.9% (95% CI: 0.3-25.5%), respectively.

Conclusions: Early-GDM, combined with pre-pregnancy overweight/obesity and/or fasting PG levels of 95-125 mg/dL, is associated with a higher risk of adverse perinatal outcomes and should be prioritized for intervention.

Aim/introduction: Senescence is a key driver of age-related kidney dysfunction, including diabetic kidney disease. Oxidative stress activates cellular senescence, induces abnormal glycolysis, and is associated with pyruvate kinase muscle isoform 2 (PKM2) dysfunction; however, the mechanisms linking PK activation to cellular senescence have not been elucidated. We hypothesized that PKM2 activation by TEPP-46 could suppress oxidative stress-induced renal tubular cell injury and cellular senescence.

Materials and methods: To investigate the effects of PKM2 activation on oxidative stress-induced cellular senescence, we conducted β-galactosidase staining and western blot analysis on human primary renal tubular cells (pRPTECs) treated with hydrogen peroxide with or without TEPP-46. IL-6 levels and glycolytic flux were measured. Cell viability and apoptosis were assessed via the MTS assay and caspase 3 cleavage. For in vivo experiments, we utilized CD-1^db/db mice, a fibrotic type 2 diabetes model, which exhibit kidney fibrosis. After 4 weeks of TEPP-46 intervention, kidney fibrosis and the expression of senescence markers were analyzed.

Results: In pRPTECs, hydrogen peroxide increased the number of β-galactosidase-positive cells, the expression of senescence markers (p16, p21, p53), and p38 phosphorylation; co-incubation with TEPP-46 suppressed these alterations. Hydrogen peroxide reduced cell viability, induced apoptosis, mesenchymal alterations, and increased lactate production and IL-6 secretion; co-incubation with TEPP-46 or a p38 inhibitor mitigated these effects. In CD-1^db/db mice, TEPP-46 intervention suppressed apoptosis, fibrosis, and tended to reduce the levels of senescence-associated molecules in the kidney.

Conclusions: PKM2 activation could be a molecular target for protection against senescence-associated organ damage, including diabetic kidney disease.

Aims/introduction: Metformin treatment for hyperglycemia in pregnancy (HIP) beneficially improves maternal glucose metabolism and reduces perinatal complications. However, metformin could impede pancreatic β cell development via impaired mitochondrial function. A new anti-diabetes drug imeglimin, developed based on metformin, improves mitochondrial function. Here we examine the effect of imeglimin on β cell differentiation using human induced pluripotent stem cell (iPSC)-derived pancreatic islet-like spheroid (SC-islet) models.

Materials and methods: Human iPSCs are differentiated into SC-islets by three-dimensional culture with and without imeglimin or metformin. Differentiation efficiencies of SC-islets were analyzed by flow cytometry, immunostaining, quantitative PCR, and insulin secretion assay. RNA sequencing and oxygen consumption rate were obtained for further characterization of SC-islets. SC-islets were cultured with proinflammatory cytokines, in part mimicking the uterus environment in HIP.

Results: Metformin perturbed SC-islet differentiation while imeglimin did not alter it. Furthermore, imeglimin enhanced the gene expressions of β cell lineage markers. Maintenance of mitochondrial function and optimization of TGF-β and Wnt signaling were considered potential mechanisms for augmented β cell maturation by imeglimin. In the presence of proinflammatory cytokines, imeglimin ameliorated β cell differentiation impaired by cytokines and metformin.

Conclusions: Imeglimin does not perturb differentiation of SC-islet cells and rather enhances gain in β cell identity gene sets in contrast to metformin. This may lead to the improvement of in vitro β cell differentiation protocols.

Objective: Our study aimed to evaluate the effectiveness of a 3-months digital therapy (DTx) intervention in the real world for the management of blood glucose in 3,902 Chinese patients with type 2 diabetes (T2D) in Lingshui, Hainan.

Methods: Adults with T2D who were capable of using DTx application (app) were enrolled. Fasting blood glucose (FBG), 2-h postprandial blood glucose (2hPBG), and body weight before and after the intervention were collected. Participants recorded blood glucose and body weight at least once weekly, and attended diabetes education program with the app during online follow-up once weekly.

Results: A total of, 3,902 patients with T2D were enrolled, including 46.3% of men, with an average age of 64.3 years. After 3-months of DTx, FBG decreased by 0.52 mmol/L (8.05-7.53, P < 0.001) from baseline, 2hPBG decreased by 1.18 mmol/L (11.95-10.77, P < 0.001), and body weight decreased by 1.50 kg (61.18-59.68, P < 0.001). The median number of glucose self-reports for each patient was three (0, 273) times. Defining participants who finished glucose or weight self-report for once within 7 days as the motivated group (n = 1,013), the motivated group showed significant weight loss after DTx intervention (motivated group vs inactive group, -3.01 kg vs -0.36 kg, P < 0.01). No significant difference was found in FBG and 2hPBG between the two groups.

Conclusions: DTx reveals significant efficacy on glucose and weight control in patients with T2D, which can reduce FBG, PBG, and body weight. Better compliance and motivation with DTx and frequent weight monitoring help achieve better weight control.