Background: Cardiovascular disease (CVD) is the leading cause of mortality in obese patients with type 2 diabetes mellitus (T2DM). Conventional biomarkers often fail to detect early endothelial dysfunction and oxidative stress. Haptoglobin (Hp), an acute-phase protein with antioxidant and hemoglobin-binding properties, may indicate vascular injury. While plasma Hp (pl-Hp) reflects systemic inflammation, urinary Hp (u-Hp) could signal renal and microvascular damage. We hypothesize that elevated u-Hp and altered pl-Hp levels are associated with increased oxidized LDL and may serve as sensitive indicators of early vascular injury, thereby identifying obese patients with T2DM at higher cardiovascular risk. This study aims to investigate the associations between u-Hp, pl-Hp, and oxidized LDL (ox-LDL) in obese patients with T2DM, and to evaluate the potential role of Hp as an early biomarker of cardiovascular risk in this high-risk population. Methods and Results: The study included 57 patients with T2DM (mean age 61 ± 10 years, HbA1c 8.66 ± 1.60%, and BMI 35.15 ± 6.65 kg/m²). Notably, 95% of the patients had hypertension, 82% had dyslipidemia, and 59% had an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m². Pl-Hp and u-Hp concentrations, as well as ox-LDL levels, were assessed using an enzyme-linked immunosorbent assay (ELISA). Correlations and multivariate regression analyses were employed to investigate the associations between Hp, ox-LDL, and clinical cardiovascular risk factors. Pl-Hp was positively correlated with ox-LDL (r = 0.358, p < 0.006) and negatively correlated with C-reactive protein (CRP) (r = −0.364, p < 0.013), while u-Hp correlated positively with HbA1C and apoB levels (r = 0.298, p < 0.030 and r = 0.310, p < 0.021, respectively). Multivariate analysis indicated that pl-Hp, but not u-Hp, was independently associated with ox-LDL (β = 0.536, p < 0.027) after adjusting for potential confounding factors, including age, gender, BMI, HbA1c, liver enzymes, hs-CRP and creatinine. The Stepwise analysis identified IL-6 as the most significant predictor of cardiovascular disease risk, suggesting its pivotal role in subclinical vascular inflammation among obese individuals with T2DM. Furthermore, the significant positive association between pl-Hp and ox-LDL was stronger in patients with declining renal function as expressed by the estimated glomerular filtration rate (eGFR) (eGFR < 30 mL/min/1.73 m²: β = 2.173, p < 0.031 and eGFR 30–59 mL/min/1.73 m²: β = 1.318, p < 0.002). This association also appeared in early and low-normal ranges of serum albumin: creatinine ratio (s-ACR) (s-ACR < 0.2714 mg/mmol: β = 2.304, p < 0.005 and s-ACR 0.2714–0.3649 mg/mmol: β = 1.000, p < 0.041), suggesting that pl-Hp and ox-LDL rise before overt kidney damage. Elevated IL-6 (≥32.93 pg/mL) further strengthened this link (β = 1.037, p < 0.005), highlighting the role of inflammation in amplifying oxidative stress and acute-phase responses. Conclusions: Taken together, these findings emphasize the interconnected contributions of renal impairment, inflammation, and oxidative stress to vascular injury. While these results need to be confirmed in larger prospective longitudinal studies, monitoring pl-Hp levels in conjunction with inflammatory and kidney function markers could be a sensitive and non-invasive way to identify early CVD risk in high-risk groups, such as obese patients with T2DM.

In individuals with type 2 diabetes mellitus (T2DM), elevated levels of both plasma and urinary cystatin C (Cys-C) contribute to increased oxidation, which in turn accelerates the oxidation of low-density lipoprotein (LDL). This process may worsen the development of atherosclerosis and cardiovascular disease by promoting endothelial dysfunction and inflammation. Despite its potential significance, the relationship between Cys-C and oxidized LDL (ox-LDL) in T2DM remains poorly understood. This study investigated the relationship between plasma and urinary Cys-C and ox-LDL levels in T2DM patients. The cohort included 57 patients with T2DM (mean age 61.14 ± 9.99 years; HbA1c 8.66 ± 1.60% and BMI 35.15 ± 6.65 kg/m²). Notably, 95% of the patients had hypertension, 82% had dyslipidemia, 59% had an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m², 14% had coronary artery disease (CAD), and 5% had a history of stroke. Plasma and urinary Cys-C and ox-LDL levels were measured using ELISA. Adipokine and cytokine levels were measured using the multiplex^® MAP Human Adipokine Magnetic Bead Panels. Spearman’s correlation analysis revealed a significant positive correlation of plasma and urinary Cys-C with ox-LDL (r = 0.569, p = 0.0001 and r = 0.485, p = 0.0001, respectively). Multivariable regression analysis indicated that both plasma and urinary Cys-C were independently associated with ox-LDL, after adjusting for confounding factors (β = 0.057, p = 0.0001 and β = 0.486, p = 0.003, respectively). Stepwise linear regression identified TNFα and adiponectin as the strongest predictors of the relationship between urinary Cys-C and ox-LDL (β = 0.382, p = 0.0001; r² = 0.64), while adiponectin alone was the best predictor of the plasma Cys-C and ox-LDL association (β = 0.051, p = 0.005; r² = 0.46). Furthermore, adiponectin partly mediated the relationship between plasma Cys-C and ox-LDL, explaining 18% of the variance in this association. In contrast, TNFα partly mediated the relationship between urinary Cys-C and ox-LDL, accounting for 28% of the variance. This study emphasizes the complex interaction between Cys-C and ox-LDL in T2DM. It highlights the need for additional research involving larger patient cohorts to improve our understanding of the therapeutic potential of plasma and urinary Cys-C in conjunction with ox-LDL for managing complications associated with T2DM.

Atrial natriuretic peptide (ANP) and oxidized low-density lipoprotein (ox-LDL) play essential roles in the development and progression of vascular complications associated with type 2 diabetes mellitus (T2DM), and both are independently linked to cardiovascular diseases (CVD). However, the relationship between ANP and ox-LDL in patients with T2DM remains unclear as previous studies have primarily focused on circulating levels in various diseases. This study investigated the relationship between ANP and ox-LDL levels in obese individuals with T2DM. The cohort included 57 patients with T2DM (mean age 61.14 ± 9.99 years; HbA1c 8.66 ± 1.60%; BMI 35.15 ± 6.65 kg/m²). Notably, 95% of the patients had hypertension, 82% had dyslipidemia, 59% had an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m², 14% had coronary artery disease (CAD), and 5% had a history of stroke. Plasma concentrations of ANP and ox-LDL were measured using ELISA. Adipokines and cytokines levels were measured using the multiplex^® MAP Human Adipokine Magnetic Beads Spearman’s correlation analysis which revealed a negative correlation between ANP and ox-LDL (r = −0.446, p = 0.001) as well as with the ox-LDL/apoB ratio (r = −0.423, p = 0.001) and ox-LDL/LDLc ratio (r = −0.307, p = 0.038). Multivariable regression analysis indicated that ANP was independently associated with ox-LDL (β = −115.736, p = 0.005). Stepwise linear regression further identified TNFα, leptin, and adiponectin as the strongest predictors influencing the relationship between ANP and ox-LDL levels (β = −64.664, p = 0.0311, and r² = 0.546 for the model). However, these factors did not significantly mediate this association. This study emphasizes the need for further exploration of the complex interaction between ANP and ox-LDL in larger patient populations. This could provide valuable insights into potential therapeutic approaches for managing vascular complications in obese individuals with T2DM.

Background: Glucose handling in hepatocyte-derived cells integrates insulin-responsive AKT signaling with GLUT1-mediated glucose transport, jointly regulating substrate trafficking, glycogen synthesis, and cell survival. MK-2206, a potent allosteric AKT inhibitor, and BAY-876, a highly selective GLUT1 inhibitor, represent targeted approaches to disrupt these processes. However, the consequences of simultaneous inhibition of both nodes in hepatocyte-derived cells remain incompletely understood. Objective: This study aims to evaluate the impact of simultaneous AKT inhibition and GLUT1 blockade on target engagement, cell viability, proliferation, cell death, glucose uptake, and glycogen storage in HepG2 cells. Methods: HepG2 cells were treated with MK-2206, BAY-876, or their combination under basal hyperglycemic and acute insulin-challenged conditions. Multi-model synergy, AKT/GLUT1 pharmacological effects, cell viability, proliferation, cell death, glucose uptake, and glycogen storage were assessed, alongside exploratory molecular docking analyses of both inhibitors against their respective targets. Results: Dual AKT and GLUT1 inhibition produced combination-specific reductions in cell viability and showed a pattern of concurrent antiproliferative effects and increased Annexin V/PI positivity without detectable caspase-3 activation under insulin-challenged conditions. Furthermore, the dual inhibition of AKT signaling and GLUT1-mediated glucose uptake produced combination-specific reductions in basal glycogen content, while glucose uptake reductions showed AKT-dominant patterns without significant combination superiority over MK-2206 alone under either metabolic state. Exploratory molecular docking of MK-2206 and BAY-876 against AKT1 and SLC2A1/GLUT1, respectively, generated computationally predicted binding poses consistent with the established binding modes of these inhibitors. Conclusions: Dual AKT/GLUT1 targeting produces endpoint-specific patterns of pharmacological interaction on insulin-responsive metabolism, proliferation, and cell death in HepG2 hepatocyte-derived cells, distinguishing combination-specific effects from AKT-driven effects. These findings support an endpoint-specific pharmacological framework in which AKT signaling and BAY-876-mediated GLUT1 pharmacological effects jointly influence glucose handling and cell fate in a hepatocyte-derived model.

Background/Objectives: Although statins are still the main treatment for dyslipidemia, differences in patient responses, residual cardiovascular risk, and treatment side effects highlight the need for additional methods. Curcumin has attracted considerable interest because of its reported cardioprotective and lipid- and glucose-modulating effects, as well as its ability to influence cellular stress and survival pathways, highlighting its potential relevance to cardiovascular and metabolic disease. This study investigated the effects of atorvastatin (ATO), curcuminoid extract (CUR), and their combination on lipid and glucose metabolism and cell fate in hepatocellular carcinoma-derived cell lines. Methods: Huh-7 cells were treated for 48 h with ATO (10 μM), CUR (20 μM), or their combination (MIX). MTT assays characterized concentration-dependent cytotoxicity and informed concentration selection, and CellTiter-Glo assessed cell viability. ApoB expression and secretion were evaluated by Western blot and ELISA. Lipid accumulation was assessed by Oil Red O microscopy and quantitative analysis. Glucose uptake was measured before and after insulin challenge. Additionally, expression of relevant genes regulating cholesterol, lipoprotein, and glucose metabolism was assessed by qPCR, and apoptosis was examined by Annexin V/PI flow cytometry and Western blotting for apoptotic markers. Results: The ATO-curcuminoid combination markedly reduced ApoB expression and secretion compared with control (p < 0.01). In contrast, the combination significantly increased intracellular lipid accumulation compared with control, ATO, and CUR (p < 0.001). Additionally, CUR and the ATO-curcuminoid combination significantly reduced glucose uptake before and after insulin challenge (p < 0.01; p < 0.001, respectively). Consistent with the impaired glucose uptake, the ATO-curcuminoid combination significantly reduced GLUT2 protein expression compared with control and ATO (p < 0.05 and p < 0.01, respectively). The ATO-curcuminoid combination also significantly increased early and late apoptosis and reduced viable-cell populations (p < 0.05; p < 0.01, respectively). Molecular docking and molecular dynamics simulations revealed that curcuminoids occupied the catalytic domain of HMG-CoA reductase and maintained conserved interactions with key residues, including GLY656, ASN658, and GLY808. Conclusions: ATO-curcuminoid co-treatment suppressed ApoB secretion but was accompanied by increased intracellular lipid accumulation, altered glucose uptake and GLUT2 expression, and apoptosis, indicating a discordant hepatic response. Computational analyses suggested potential interactions between curcuminoids and the catalytic region of HMG-CoA reductase; however, these findings are hypothesis-generating and require direct enzyme-inhibition and kinetic validation.

Diabetes is increasingly recognized as a chronic inflammatory disease marked by systemic metabolic disturbances, with endothelial dysfunction playing a central role in its complications. Hyperglycemia, a hallmark of diabetes, drives endothelial damage by inducing excessive reactive oxygen species (ROS) production, particularly hydrogen peroxide (H₂O₂). This oxidative stress impairs endothelial cells, which are vital for vascular health, leading to severe complications such as diabetic nephropathy, retinopathy, and coronary artery disease—major causes of morbidity and mortality in diabetic patients. Recent studies have highlighted the therapeutic potential of placenta-derived mesenchymal stem cells (pMSCs), in mitigating these complications. pMSCs exhibit anti-inflammatory, antioxidant, and tissue-repair properties, showing promise in reversing endothelial damage in laboratory settings. To explore their efficacy in a more physiologically relevant context, we used a streptozotocin (STZ)-induced diabetic mouse model, which mimics type 1 diabetes by destroying pancreatic beta cells and causing hyperglycemia. pMSCs were administered via intra-peritoneal injections, and their effects on endothelial injury and tissue damage were assessed. Metabolic tests, including glucose tolerance tests (GTTs) and insulin tolerance tests (ITTs) revealed that pMSCs did not restore metabolic homeostasis or improve glucose regulation. However, histopathological kidney, heart, and eye tissue analyses demonstrated significant protective effects. pMSCs preserved glomerular structure in the kidneys, protected cardiac blood vessels, and maintained retinal integrity, suggesting their potential to address diabetes-related tissue injuries. Although these findings underscore the therapeutic potential of pMSCs for diabetic complications, further research is needed to optimize dosing, elucidate molecular mechanisms, and evaluate long-term safety and efficacy. Combining pMSCs with other therapies may enhance their benefits, paving the way for future clinical applications.