Journal of Diabetes Investigation最新文献

Aims: To assess the extent to which biomedical outcomes and cardiovascular risk profile were improved in the management of Chinese patients with type 2 diabetes enrolled in the metabolic management center (MMC) program.

Materials and methods: We performed propensity score matching of diabetic patients in the MMC program for at least 12 months to those with diabetes under usual primary care, based on age, sex, fasting plasma glucose (FPG) level, and diabetes duration. Difference-in-difference analysis was conducted to compare changes in biomedical outcomes, attainment of treatment targets, and cardiovascular disease (CVD) risk reduction.

Results: Of 557 pairs of diabetic patients matched 1:1 (n = 1,114), the MMC cohort exhibited greater improvements in FPG (-0.84 mmol/L, 95% confidence interval [CI] -1.22 to -0.46, P < 0.001), diastolic blood pressure [BP] (-2.08 mmHg, 95%CI -3.21 to -0.94, P < 0.001), body mass index [BMI] (-0.29 kg/m², 95%CI -0.51 to -0.07, P = 0.009), low-density lipoprotein cholesterol (0.13 mmol/L, 95%CI 0.04-0.23, P = 0.008), high-density lipoprotein cholesterol (0.05 mmol/L, 95%CI 0.01-0.08, P = 0.017), and 10-year CVD risk (Framingham CVD risk, -0.94%, 95%CI -1.71 to -0.17, P = 0.017; atherosclerotic CVD risk, -0.77%, 95%CI -1.34 to -0.20, P = 0.009) when compared to the usual primary care cohort after adjustment for confounders. More patients in the MMC cohort achieved treatment targets with lifestyle modifications than their counterparts under primary care.

Conclusions: Enrolment in the MMC program appears promising in the management of FPG, BP, BMI, lifestyle, and CVD risk in diabetic patients, suggesting the necessity of incorporating the MMC program into routine primary care.

Advanced glycation end-products (AGEs) have been extensively studied because of their close association with the onset and progression of diabetic complications. However, owing to their formation through diverse metabolic pathways, AGEs often reflect a wide range of pathological conditions rather than being specific to diabetic complications. Consequently, identifying an AGE that directly correlates only with diabetic complications remains a challenge. Chronic hyperglycemia not only saturates the glycolytic pathway but also upregulates the polyol pathway, leading to the excessive production of fructose, a highly reactive reducing sugar. Although it has long been understood that fructose-derived AGEs contribute to diabetic complications, their chemical structures remain unidentified. Recent breakthroughs have revealed that glucoselysine (GL) is a primary fructose-specific AGE. Unlike other AGEs, GL is exclusively formed from fructose and not from other reducing sugars, such as glucose or galactose. This specificity provides GL with a distinct advantage in that its production pathway can be traced, making it a reliable indicator of polyol pathway activity. Furthermore, emerging evidence suggests that GL levels correlate with the progression of diabetic complications, including both micro- and macrovascular complications, making it a promising biomarker. GL's potential extends beyond diagnostics, as it may serve as a therapeutic target for managing complications associated with prolonged hyperglycemia and enhanced of polyol pathway. This review focuses on the enhanced polyol pathway and the formation of GL and discusses its biochemical characteristics, clinical significance, and potential as a novel diagnostic marker and therapeutic target in diabetic care.

Objective: To exam the role of miR-92a/KLF2/miR-483 in the pathogenesis of metabolic syndrome.

Methods: In this study, the serum of healthy controls and patients with metabolic syndrome were collected to detect the circulating level of miR-92a and miR-483. In vitro cultured HUVECs, overexpression or suppression of miR-92a, miR-483 or KLF2 to determine the relationship among miR-92a, KLF2 and miR-483. Ang II, ox-LDL, or high glucose treatment were used to mimic the metabolic syndrome. HUVECs or HepG2 cells were treated with Telmisartan, Atorvastatin, or metformin, the miR-483 and its target gene expression was detected. In animal experiment, ob/ob mice were chose to confirm the changes of miR-92a, KLF2, and miR-483.

Results: Compared with the healthy controls, the level of miR-92a was significantly increased, while miR-483 level was remarkably decreased in the patients with metabolic syndrome. In vitro cultured HUVECS, overexpression of miR-92a significantly reduced the expression of miR-483, but overexpression of miR-483 had no effect on miR-92a. Overexpression of KLF2 could downregulate miR-483 level, while inhibition of KLF2 had the opposite effect. When HUVECs and HepG2 were stimulated with Ang II, ox-LDL and high glucose, the expression of miR-483 was significantly decreased and its target genes was increased. Anti-miR-92a could reverse the effect. Furthermore, Telmisartan, Atorvastatin, and Metformin significantly increased miR-483 expression and decreased its target gene expression, which could be reversed by miR-92a mimic. The level of miR-92a was significantly increased in HepG2 cells, which were treated with exosomes derived from endothelial cells with miR-92a overexpression. ob/ob mice showed the similar effects.

Conclusions: Endothelial dysfunction and fatty liver are critically involved in the pathogenesis of metabolic syndrome. MicroRNAs can mediate the cellular communication between vascular endothelial cells (ECs) and distal cell. Serum miR-92a level was higher in metabolic syndrome patients than controls. KLF2 is the target gene of miR-92a, which can increase the production of miR-483, miR-483 acts on its target genes CTGF, ET-1, and β-catenin to protect cell function. EC miR-92a is secreted out of cells into the blood, circulates through the blood to the liver, and continues to exert its biological effects after being absorbed by hepatocytes. LNA-miR-92a administration reversed endothelial cell damage and fatty liver caused by metabolic syndrome by affecting the KLF2/miR-483 pathway.

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 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.

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.