Diabetes, Obesity & Metabolism最新文献

Aims: Randomized controlled trials on sodium-glucose cotransporter 2 (SGLT2) inhibitors have yielded inconsistent findings regarding mortality benefits. It remains unclear whether, and in which subgroups, SGLT2 inhibitors confer survival benefits in older adults with diabetic kidney disease (DKD).

Materials and methods: We emulated a target trial using a nationwide claims and health checkup database in Japan to compare all-cause mortality between SGLT2 and dipeptidyl peptidase-4 (DPP4) inhibitor initiators among 5371 adults aged ≥65 years with DKD. The primary outcome was all-cause mortality. Hazard ratios (HRs) were estimated using propensity score overlap weighting and Cox proportional hazards models in an intention-to-treat analysis. A per-protocol analysis with inverse probability of censoring weighting was conducted as sensitivity analysis. Effect modification by age, body mass index (BMI) and Charlson comorbidity index (CCI) was assessed using restricted cubic spline models.

Results: During a median follow-up of 2.23 (IQR, 1.07-3.49) years, 437 deaths occurred. SGLT2 inhibitor use was associated with significantly lower all-cause mortality than DPP4 inhibitors (HR, 0.51; 95% confidence interval, 0.38-0.70), with consistent results in the per-protocol analysis (HR, 0.50; 95% confidence interval, 0.35-0.73). Survival benefit was evident up to about 80 years of age and among individuals with BMI ≥22 kg/m², irrespective of CCI.

Conclusions: In this target trial emulation study, SGLT2 inhibitors were associated with lower mortality in older adults with DKD, particularly those under 80 years and with BMI ≥22 kg/m². These findings support personalized treatment decisions for this high-risk population in clinical practice.

Background and aims: Methylglyoxal-derived hydroimidazolone (MG-H1), one of the advanced glycation end-products (AGEs), has been a potential biomarker of type 2 diabetes (T2DM), which is strongly related to insulin resistance. However, the relationship between the dynamics of MG-H1 and insulin resistance has not been characterized, and its mechanism on insulin resistance is unknown. In this study, we aimed to investigate the relationship between MG-H1 and insulin resistance in the clinical study of Japanese individuals and identify the molecular mechanisms underlying MG-H1 associated phenomena in vitro.

Methods: We performed the meal tolerance test (MTT) and hyper-insulinemic-euglycemic clamp analysis in 19 patients with T2DM and 19 participants without diabetes (non-DM). We measured their fasting and postprandial MG-H1 using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In addition, we evaluated the effects of MG-H1 on glucose uptake and insulin signalling in C2C12 skeletal myocytes.

Results: The postprandial MG-H1 and the area under the curve (AUC) of MG-H1 in MTTs were significantly negatively correlated with the glucose disposal rate (GDR) in clamp studies both in the T2DM (r = -0.72 [p < 0.001]) and non-DM (r = -0.54 [p < 0.05]) groups. In cultured C2C12 skeletal myocytes, pre-treatment with MG-H1 inhibited insulin-stimulated phosphorylation of Akt and glucose uptake, via the activation of mechanistic target of rapamycin complex 2 (mTORC2).

Conclusions: In clinical study findings revealed that postprandial MG-H1 was a novel marker of insulin resistance in Japanese individuals, and in vitro findings using cultured C2C12 skeletal myocytes suggested that MG-H1 disturbs insulin signalling via the mechanisms of mTORC2 activation.

Background: Effective anti-obesity interventions that preserve lean mass are of increasing clinical significance for optimizing metabolic health. This study investigated whether lorcaserin, a centrally acting weight loss agent, modifies body composition, circulating lipidomic profiles, and muscle-regulating hormones within the myostatin-activin-follistatin-IGF-1 (MAFI) axes.

Methods: Forty-eight adults with obesity were randomized to lorcaserin (10 mg twice daily) or placebo for 6 months in a double-blind trial. Regional body composition, hormones and lipidomics were assessed. Changes were analysed using linear mixed models with fixed effects for time, treatment and interaction. Adjusted deltas and endpoints were compared by analysis of covariance controlling for baseline body mass index. Lipidomic profiles were analysed using principal component and partial least-squares discriminant analyses.

Results: Lorcaserin reduced total body weight (time*treatment, p = 0.004). Adjusted delta and endpoint comparisons showed reductions in total body (p = 0.031) and abdominal fat mass (p = 0.002). Lipidomic assessments revealed primarily lower levels of triglyceride-rich lipoproteins with treatment. No significant changes in MAFI axes components were detected in linear mixed models.

Conclusions: Lorcaserin treatment was associated with greater abdominal fat mass loss, favourable lipid profile changes, while MAFI components remained largely unaffected. Lorcaserin may improve cardiometabolic health primarily through reductions in central adiposity.

Aims: To evaluate the association between longitudinal non-HDL-C exposure and the risks of major adverse cardiovascular events (MACEs) and all-cause mortality in type 2 diabetes patients on lipid-lowering therapy.

Materials and methods: This post hoc analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial included patients with type 2 diabetes who had non-HDL-C measured at baseline and four subsequent visits over 24 months. Longitudinal exposure was assessed using cumulative load, variability (standard deviation) and trajectory (slope). Outcomes were MACEs and all-cause mortality. Cox proportional hazard models were used to obtain hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: Among 4673 participants with a median follow-up of 7.5 years, 695 MACEs and 842 deaths occurred. After adjusting for baseline and mean non-HDL-C levels, the highest quartile of cumulative load (HR, 1.81; 95% CI, 1.41-2.32), variability (HR, 1.27; 95% CI, 1.00-1.60) and the most rapidly increasing slope (HR, 1.26; 95% CI, 1.02-1.56) were each associated with increased risks of MACEs, compared to the lowest quartile. The association with all-cause mortality followed a similar pattern, except for the non-HDL-C slope. Stratified analyses showed that cumulative load and variability were associated with MACEs among participants with baseline non-HDL-C < 130 mg/dL, and with all-cause mortality among those with baseline ≥130 mg/dL. No significant associations with slope were observed within strata of baseline non-HDL-C.

Conclusions: Longitudinal non-HDL-C exposure showed associations with both MACEs and mortality, independent of baseline non-HDL-C, underscoring the need for sustained and stable non-HDL-C control over time.

Metabolic and bariatric surgery (MBS) is the most effective treatment for severe obesity. It usually results in spectacular weight loss, associated with improvements of obesity-associated comorbidities. The mechanisms underlying these benefits are not fully understood but could involve a postoperative activation of the enzyme 5' AMP-activated protein kinase (AMPK). Hence, as AMPK is largely expressed in insulin-sensitive cells, it acts as a key regulator of cardio-metabolic homeostasis, and its activity is down-regulated in tissues from obese, insulin resistant patients. This narrative review aims to summarise the available clinical data regarding changes in AMPK activity following MBS and to discuss the potential relevance of these changes in postoperative physiology. The eight studies reporting specifically changes in AMPK activity following MBS in humans were analysed. They all showed increases in AMPK activity in tissues or blood cells, with effects observed as early as 3 months and persisting beyond 12 months post-surgery. However, the data does not allow us to conclude on (i) the potential specificity of effects depending on the surgery procedure, (ii) the mechanisms involved in the AMPK activation, and (iii) its role in postoperative metabolic outcomes, highlighting that further investigations are warranted to address these issues. Understanding AMPK changes in postoperative physiology could establish its relevance as a potential prognostic marker of surgery metabolic outcomes and as a new target to improve the benefits of MBS. More generally, it may provide insights into the development of novel therapeutic strategies for obesity and associated comorbidities.

Aims: To evaluate the cardiovascular efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in Asian, Black or African American, and White populations, and to assess whether the magnitude of cardiovascular risk reduction differs across these populations.

Materials and methods: PubMed and EMBASE were searched to 11 November 2025 for randomized placebo-controlled GLP-1RA trials in adults with type 2 diabetes or overweight/obesity that reported race-stratified major adverse cardiovascular events (MACE; cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke). Hazard ratios (HRs) for MACE were extracted for Asian, Black or African American, and White populations. Random-effects meta-analyses were used to obtain pooled HRs and ratios of HRs (RHRs) comparing treatment effects between populations.

Results: Nine trials, including the recent SOUL trial, were included, comprising 8164 Asian, 4036 Black or African American, and 62 503 White participants. GLP-1RAs reduced MACE risk in Asian (HR 0.73; 95% CI 0.63-0.85; p < 0.001) and White populations (HR 0.86; 95% CI 0.81-0.91; p < 0.001). In Black or African American populations, the effect was similar to that in White populations (HR 0.88; 95% CI 0.67-1.15; p = 0.34) but did not reach statistical significance. The pooled RHR for Asian versus White populations was 0.84 (95% CI 0.71-0.98; p = 0.027), indicating a significantly greater risk reduction in Asian populations. The RHR for Asian versus Black or African American populations was 0.81 (95% CI 0.57-1.16; p = 0.25), with point estimates favouring Asian populations.

Conclusions: GLP-1RAs reduced MACE risk across populations, with greater relative risk reduction in Asian populations and broadly similar benefits in Black or African American and White populations.

Aims: Emerging evidence suggests that indole-3-propionic acid (IPA), a gut microbiota-derived tryptophan metabolite, confers metabolic benefits in type 2 diabetes (T2D). However, its direct role in preserving pancreatic β-cell function and the underlying molecular mechanisms remains largely undefined. This study aimed to investigate the role and underlying mechanisms of IPA in preserving β-cell function and alleviating endoplasmic reticulum (ER) stress under diabetogenic conditions.

Materials and methods: High-fat diet-fed and db/db mice were treated with IPA via oral gavage. Glucose homeostasis, islet morphology, and insulin secretion were evaluated. In vitro studies in MIN6 cells and isolated islets assessed IPA's effects on ER stress, insulin secretion, and apoptosis. Proteomics, molecular docking, luciferase reporter assays, and gene expression analyses were conducted to identify key molecular targets.

Results: IPA significantly preserved islet architecture and enhanced insulin secretion. Proteomic analysis revealed downregulation of ER stress pathways and upregulation of SGPP1 upon IPA treatment. SGPP1 was essential for IPA-mediated suppression of ER stress and β-cell apoptosis through direct interaction with HSPA5. IPA stabilized and activated the transcription factor FOXA1, which in turn transcriptionally upregulated SGPP1 expression.

Conclusion: IPA protects pancreatic β-cells by activating the FOXA1-SGPP1-HSPA5 signalling pathway, thereby alleviating ER stress and enhancing β-cell survival.