Oxidized lipoproteins contribute to atherosclerosis and metabolic dysfunction; however, their prognostic significance for major adverse cardiovascular events (MACEs) in patients with type 2 diabetes mellitus (T2DM) and coexisting coronary heart disease (CHD) remains unclear. This multicenter cohort included 3,733 patients with angiographically confirmed T2DM-CHD, followed for 5 years. Baseline circulating oxidized high-density lipoprotein cholesterol (ox-HDL-C), oxidized low-density lipoprotein cholesterol (ox- LDL-C), and oxidized lipoprotein(a) (ox-Lp(a)) were measured, and associations with coronary severity, β-cell function, and MACEs were analyzed using Cox regression, Kaplan-Meier, and restricted cubic spline models. Patients with MACEs had higher baseline ox-HDL-C, ox-LDL-C, and ox-Lp(a), correlating with greater coronary lesion burden and impaired β-cell function. Restricted cubic spline analyses revealed nonlinear, dose-dependent associations, with MACEs risk increasing above thresholds of 19.88 ng/mL (ox-HDL-C), 25.71 ng/mL (ox-LDL-C), and 19.96 μmol/L (ox-Lp(a)), with sexspecific differences observed. In Cox proportional hazards models, individuals in the highest quartile of oxidized lipoproteins had significantly elevated 5-year MACEs risk compared to those in the lowest quartile, and these associations remained robust after adjusting for confounders (ox-HDL-C: adjust hazard ratio [HR], 1.872; 95% confidence interval [CI], 1.408 to 2.489; P<0.001; ox- LDL-C: adjust HR, 2.239; 95% CI, 1.686 to 2.974; P<0.001; ox-Lp(a): adjust HR, 1.917; 95% CI, 1.442 to 2.549; P<0.001). Oxidized lipoproteins are independent predictors of MACEs in patients with T2DM-CHD and reflect vascular and metabolic dysfunction. Incorporating oxidized lipoprotein profiling into clinical risk assessment may improve early identification of high-risk individuals and guide preventive strategies.

Metformin, while central to diabetes management, functions as a highly pleiotropic agent with mechanisms that extend far beyond simple glycemic control. In age-related degenerative diseases, including neurodegenerative disorders, it may modulate mitochondrial function, reduce oxidative stress, and influence longevity-related pathways, suggesting possible anti-aging effects. Emerging evidence also points to anticancer activity, with studies reporting reduced incidence and improved outcomes across several malignancies, potentially through mammalian target of rapamycin (mTOR) inhibition, metabolic reprogramming, and suppression of inflammatory signaling. Furthermore, the 'intestinal glucotonic effect' has been proposed to involve glucose excretion from the circulation into the gut lumen through reactive oxygen species-dependent upregulation and membrane localization of glucose transporter type 1 (GLUT1), an adenosine monophosphate-activated protein kinase (AMPK)-independent process that may contribute to the reprogramming of systemic glucose flux and provides metabolic substrates for the microbiota. Metformin also alters the gut microbiome by increasing the abundance of multiple short-chain fatty acid-producing bacteria and enhancing intestinal barrier function, which may contribute to systemic metabolic and immunologic benefits. Collectively, metformin is a pleiotropic agent with broad effects on aging biology, cancer pathophysiology, host-microbiome interactions, and immunometabolic regulation. Despite decades of clinical use, important gaps remain in understanding how these mechanisms converge to influence outcomes in individuals with diabetes and beyond.

This study assessed the efficacy and safety of HD-6277, a novel oral G protein-coupled receptor 40 (GPR40) agonist in adults with inadequate control of type 2 diabetes mellitus (T2DM). This double-blind, randomized, placebo-controlled phase 2 trial recruited 112 individuals aged 18-75 years with T2DM and glycosylated hemoglobin (HbA1c) levels between 7.0% and 10.0% while on diet and exercise alone for at least 8 weeks before screening. Parallel-group randomized trials of HD-6277 (50 and 100 mg groups vs. placebo) were conducted for 12 weeks. The primary outcome was the change in HbA1c levels from baseline to week 12. Secondary outcomes included changes in HbA1c, fasting plasma glucose (FPG), postprandial glucose, insulin, glycoalbumin, and C-peptide at weeks 4, 8, and 12. At week 12, HD-6277 at 50 and 100 mg demonstrated statistically significant reductions in HbA1c compared to placebo, with least square (LS) mean differences of -0.73% (95% confidence interval [CI], -1.11 to -0.35; P=0.0002) and -0.85% (95% CI, -1.21 to -0.50; P<0.0001), respectively. Both doses also produced clinically meaningful reductions in FPG. Additionally, HD- 6277 at 100 mg significantly increased the insulinogenic index compared to placebo, with an LS mean difference of 1.91 (95% CI, 0.34 to 3.48; P=0.0175). No clinically relevant treatment-related adverse events were observed. HD-6277 at 50 and 100 mg improved glycemic control and was well-tolerated in adults with T2DM inadequately managed with diet and exercise. GPR40 agonists may offer a promising new therapeutic option for T2DM.

Adipose tissue consists predominantly of lipid-filled adipocytes with limited cytoplasmic space, posing challenges for spatial transcriptomic analysis. Spatially-resolved laser-activated cell sorting (SLACS) enables precise isolation of tissue sections, offering a strategy to overcome these challenges. Human visceral adipose tissue (VAT) samples from lean individuals and those with obesity and type 2 diabetes mellitus (Ob-DM) were analyzed. SLACS was used to isolate perivascular (PV) and adipocyte-rich (AD) areas, followed by full-length RNA sequencing to investigate pathways, cellular composition, and post-transcriptional regulation. PV and AD areas exhibited distinct transcriptional patterns. Fibro-inflammatory signatures and vascular remodeling pathways were enriched in the PV, while lipid metabolism and antioxidant pathways were predominant in the AD. Cellular deconvolution suggested area- and disease-specific cell composition. Post-transcriptional modifications, including adenosine-to-inosine (A-to-I) RNA editing and isoform switching in metabolic genes were observed in Ob-DM, suggesting a potential contributor to adipose dysfunction. This study demonstrates the technical feasibility of SLACS-based spatial transcriptomic profiling in human VAT, with exploratory biological findings that warrant validation in larger cohorts.