Search Results (1,026)

Microbiome-targeted interventions have shown promise for metabolic health, yet clinical evidence remains inconsistent, particularly across stages of metabolic disease. This study evaluated the metabolic effects, safety, and tolerability of EDC-HHA01, a microbiome-informed, non-pharmacologic intervention, in adults with prediabetes (PD) or Type 2 Diabetes (T2DM). In a randomized, double-blind, placebo-controlled clinical trial, participants received EDC-HHA01 or placebo for six months. The study was adequately powered (≥80%) for the primary endpoint. Outcomes included changes in glycated hemoglobin (HbA1c), indices of insulin resistance, markers of metabolic endotoxemia, safety-related laboratory parameters, and exploratory patient-reported measures. Analyses were stratified by metabolic status and background metformin use. In participants with PD, EDC-HHA01 supplementation was associated with a statistically and clinically meaningful reduction in HbA1c compared with placebo, supported by concordant improvements in fasting insulin, insulin resistance indices, and reductions in endotoxemia markers. In participants with T2DM, changes were directionally similar but attenuated and did not reach statistical significance. The intervention was well tolerated, with no serious adverse events, high adherence, and no clinically relevant adverse changes in renal or lipid parameters. Exploratory patient-reported outcomes indicated favorable acceptability but were not interpreted as efficacy endpoints. EDC-HHA01 was associated with biologically coherent, stage-dependent metabolic effects, most evident in PD. These findings support further investigation of microbiome-informed strategies as metabolic support in early-stage dysregulation. Full article

Background/Objectives: Metformin has been proposed as a potential treatment for hyperprolactinemia irrespective of etiology. Previous studies suggest that vitamin D deficiency attenuates the prolactin-lowering effect of metformin in women. This study examined whether vitamin D status modifies the effects of this agent on prolactin and other anterior pituitary hormones in men with iatrogenic hyperprolactinemia. Methods: Seventy-five adult men with antipsychotic-induced hyperprolactinemia and type 2 diabetes or prediabetes were enrolled. Participants were assigned to three equal groups based on vitamin D status and supplementation: vitamin D-naive men with sufficient levels (group 1), vitamin D-naive men with deficiency (group 2), and men with sufficient vitamin D levels receiving oral supplementation for at least six months (group 3). All participants received metformin (3 g/day) for six months. Plasma 25-hydroxyvitamin D, markers of glucose metabolism, total and monomeric prolactin, TSH, gonadotropins, ACTH, testosterone, and IGF-1 were measured at baseline and after treatment. Results: Baseline characteristics were comparable among groups except for 25-hydroxyvitamin D levels. Seventy participants completed the study. Metformin improved glycemic control and insulin sensitivity in all groups, with greater effects in men with sufficient vitamin D status. Reductions in total and monomeric prolactin were observed only in groups 1 and 3 and were associated with baseline prolactin concentrations and pretreatment 25-hydroxyvitamin D levels. These changes were accompanied by modest increases in LH and testosterone, and improvements in sexual functioning. Vitamin D levels and other hormonal parameters remained unchanged. The magnitude of the metformin effect did not differ between groups 1 and 3. Conclusions: Adequate vitamin D status is necessary for metformin to reduce prolactin levels in men with iatrogenic hyperprolactinemia. Full article

Prediabetes is a critical precursor to type 2 diabetes (T2DM) and cardiometabolic diseases, yet its burden in Oman remains understudied. Leveraging data from Oman’s 2023 National Screening Program, this study quantifies the prevalence of prediabetes and its risk profiles among adults in Muscat Governorate—providing urgent evidence to guide diabetes prevention strategies in the Gulf region. Objectives: To estimate the prevalence of prediabetes and identify associated risk factors among Omani adults screened at primary health centers in Muscat Governorate (2023), given its critical role in preventing type 2 diabetes mellitus (T2DM) progression. Methods: This cross-sectional study analyzed data from Oman’s national screening program. Socio-demographics, clinical parameters (blood pressure, body mass index [BMI]), and laboratory results (fasting glucose, lipids, renal function) were extracted from the Al-Shifa electronic health system and National Screening Register. Multivariable logistic regression was performed using SPSS 30.0 (IBM Corp., Armonk, NY, USA). Results: Among 4862 participants (mean age 43.2 ± 6.3 years; 61.7% female), prevalences were: prediabetes 29.0%, T2DM 5.5%, obesity (BMI 30–40 kg/m²) 35.7%, hypertension 42.0%, hypercholesterolemia 48.8%, and renal involvement 51.8%. Males had significantly higher prediabetes prevalence than females (35.4% vs. 24.7%; adjusted odds ratio [aOR] = 1.43; 95% confidence interval [CI]: 1.21–1.70). Independent risk factors included each 1-year age increase (aOR = 1.05; 95% CI: 1.03–1.08), each 1-unit BMI increase (aOR = 1.03; 95% CI: 1.01–1.05), and family history of diabetes (aOR = 1.28; 95% CI: 1.09–1.50). Conclusions: The high burden of prediabetes and comorbid non-communicable diseases in Oman necessitates urgent public health strategies, including enhanced screening, lifestyle interventions, and gender-specific approaches to curb the T2DM epidemic. Full article

Dihydroquercetin (DHQ) is a promising object for the development of a treatment for patients with obesity and prediabetes requiring a moderate therapeutic effect. This paper reports a clinical case of DHQ application in a 30-year-old Caucasian male and proposes a molecular mechanism of its anti-obesity effect. DHQ was administrated as a dietary supplement at a dose of 100–200 mg/day during 3 months with treatment interruption for 1 month. The data collected one month before the treatment were used as a control. The molecular aspects were studied via molecular docking with β₃-adrenoceptor (ADRB3, PDB ID: 9IJE) and peroxisome proliferator-activated receptor γ (PPARG, PDB ID: 2ZNO) and molecular dynamic simulation under conditions mimicking a human cellular environment. A pronounced weight decrease up to 0.73 kg/week was observed during DHQ administration. The highest affinity to ADRB3 was observed for the non-ionized H2aH3e-conformation of 2S,3R-DHQ (–8.846 kcal/mol). Molecules with 2S-configuration demonstrate 0.332 kcal/mol higher affinity to PPARG compared to 2R-stereoisomers. The intermolecular complex with cis-DHQ demonstrated higher stability in molecular dynamics simulation. The insights gained from this study may contribute to our understanding of flavonoids not merely as antioxidants but also as active ingredients that selectively interact with receptors. If future investigations confirm these results, they may serve as a foundation for developing a new class of anti-obesity remedies that act via ADRB3. Full article

Background: Young adulthood represents a critical period for the emergence of early metabolic disturbances, potentially influenced by dietary shifts toward convenience and ultra-processed foods. However, evidence linking dietary patterns and cooking practices with objective metabolic biomarkers in Romanian university students remains limited. Methods: This cross-sectional study included 693 students aged 18–24 years at the Victor Babeș University of Medicine and Pharmacy, Romania (June–July 2025). Dietary habits, food preferences, and cooking practices were assessed using a structured online questionnaire, while anthropometric and biochemical data were obtained from university health records. The primary outcome was glycated hemoglobin (HbA1c), a marker of average blood glucose levels over the previous 2–3 months. Prediabetes was defined as HbA1c 5.7–6.4%. Dietary patterns were identified using k-means clustering based on fast-food consumption frequency, main meal of the day, fruit and vegetable intake frequency, and predominant cooking method. Multivariable regression models assessed associations between dietary variables and glycemic or lipid outcomes. Results: Prediabetes prevalence was 21.1% (diabetes: 1.4%). Three dietary patterns were identified: health-conscious (prediabetes 15.4%), mixed (20.0%), and fast-food oriented (27.3%; χ² p = 0.003). Fast-food consumption frequency was independently associated with higher prediabetes risk (OR = 1.78 per category; 95% CI 1.38–2.30; p < 0.001) and higher HbA1c levels (β = 0.147; p < 0.001), while fruit and vegetable intake showed an inverse association with HbA1c (β = −0.109; p < 0.001). A dose–response relationship was observed between fast-food frequency and both HbA1c and prediabetes prevalence (p-trend < 0.001). An interaction between high-temperature cooking methods and frequent fast-food consumption was observed for HbA1c (p = 0.023). BMI and sex were the strongest predictors of lipid outcomes, although fast-food intake was associated with higher triglyceride levels (p = 0.034). Conclusions: Among Romanian university students, dietary patterns characterized by frequent fast-food consumption were associated with higher HbA1c levels and greater prediabetes prevalence. A high-temperature cooking method was associated with higher glycemic levels when combined with frequent fast-food intake. These findings suggest that early dietary behaviors during university years may be relevant for metabolic risk profiles in young adults. Full article

Background: Elevated prolactin levels are associated with disturbances in female sexual function. While long-term therapy with dopamine agonists has been shown to improve these disturbances, the therapeutic benefits appear to be reduced in the presence of vitamin D deficiency or insufficiency. Therefore, the present study aimed to examine whether vitamin D status modulates the effects of metformin—a medication with less pronounced prolactin-lowering properties—on sexual function and depressive symptoms. Methods: The study cohort comprised three groups of reproductive-age women with drug-induced hyperprolactinemia and prediabetes, matched for age, glycated hemoglobin, and prolactin concentrations. Group I included 25 women with normal vitamin D status who were not receiving vitamin D supplementation. Group II consisted of 25 women with vitamin D deficiency or insufficiency that was adequately corrected through supplementation, while group III included 25 women with untreated vitamin D deficiency or insufficiency. All participants received metformin throughout the six-month study period. Female sexual function and depressive symptoms were assessed before and after metformin therapy using the Female Sexual Function Index (FSFI) and the Beck Depression Inventory-II (BDI-II), respectively. Additional outcome measures included plasma 25-hydroxyvitamin D, fasting plasma glucose, glycated hemoglobin (HbA_1c), the homeostatic model assessment of insulin resistance (HOMA-IR), prolactin, gonadotropins, and sex hormones. Results: Improvements in glucose homeostasis were observed across all groups; however, these changes were more pronounced in groups I and II than in group III. Reductions in prolactin concentrations (total and monomeric), accompanied by increases in gonadotropins, estradiol, and testosterone, were observed exclusively in women with normal vitamin D status. In groups I and II, metformin therapy resulted in significant improvements in total FSFI scores as well as in all individual domain scores. In contrast, in group III, the effects of metformin were limited to increases in the domain scores for lubrication and sexual satisfaction. Improvements in sexual function were positively associated with baseline 25-hydroxyvitamin D levels, reductions in prolactin concentrations, and, to a lesser extent, treatment-related changes in HbA_1c and increases in testosterone. A treatment-induced reduction in total BDI-II scores was observed only among women with normal vitamin D status. Conclusions: Low vitamin D status diminishes the beneficial effects of metformin on sexual function and depressive symptoms in reproductive-age women with iatrogenic hyperprolactinemia. Full article

Diabetes mellitus is projected to affect more than 1.3 billion people worldwide by 2050, with millions remaining undiagnosed or in a prediabetic state. Cardiovascular complications account for nearly half of diabetes-related deaths, highlighting the need for scalable tools capable of identifying metabolic dysregulation before irreversible cardiac damage develops. This review synthesizes current mechanistic, clinical, and computational evidence linking diabetes to cardiac electrophysiological remodeling and examines electrocardiography (ECG) as a non-invasive modality for early detection of dysglycaemia. Chronic hyperglycaemia, insulin resistance, oxidative stress, microvascular dysfunction, and cardiac autonomic neuropathy collectively contribute to measurable ECG alterations, including QT/QTc prolongation, increased QT dispersion, changes in Tp–e indices, and reduced heart rate variability. These changes often precede overt cardiovascular disease and correlate with glycaemic burden and diabetes duration. Recent advances in signal processing and artificial intelligence have expanded the diagnostic potential of ECG. Both classical machine learning approaches and large-scale deep learning models demonstrate that ECG contains latent signatures associated with incident type 2 diabetes and glycaemic status. Despite promising results, heterogeneity in study design, limited representation of prediabetes, and lack of standardized validation frameworks remain major barriers to clinical translation. Prospective, multi-ethnic studies are needed to establish ECG-based screening as a reliable component of early diabetes detection strategies. Full article

Background: Glycated hemoglobin (HbA1c) is widely used for the diagnosis and monitoring of diabetes mellitus; however, its interpretation is largely based on fixed diagnostic thresholds. This study moves beyond describing a glycemic continuum by translating the non-linear HbA1c–microvascular relationship into an individualized risk estimation framework. Methods: In this cross-sectional observational study, adult subjects from a real-world clinical cohort were analyzed using HbA1c as a continuous variable. Associations between HbA1c and metabolic parameters were assessed using correlation analysis. Linear regression was applied to evaluate the relationship between HbA1c and cumulative diabetes-related complication burden. Non-linear associations between HbA1c and the risk of presenting at least one complication were explored using restricted cubic spline logistic regression models. Additional risk estimation analyses focused on the HbA1c gray zone (5.5–6.4%). Results: HbA1c showed a strong continuous association with fasting plasma glucose (ρ = 0.73, p < 0.001) and was positively associated with cumulative complication burden (β = 0.016 per 1% increase in HbA1c, p = 0.009). Non-linear modeling revealed a progressive increase in complication risk beginning below the diagnostic threshold for diabetes, with an inflection of the risk curve within the HbA1c gray zone. Individuals within this interval exhibited a higher prevalence and increased odds of presenting at least one complication compared with lower HbA1c values, although some estimates did not reach statistical significance. Conclusions: HbA1c acts as a continuous and non-linear marker of metabolic stress, with potentially biologically meaningful increases in complication risk emerging below traditional diagnostic thresholds. We demonstrate a non-linear acceleration of microvascular risk within the 5.5–6.4% interval, rather than a simple linear gradient. These findings support the concept of a glycemic risk continuum and highlight the clinical relevance of the HbA1c sub-diagnostic interval for early risk stratification and preventive strategies. Full article

Background: High-density lipoproteins (HDL) exert protective effects on the endothelium, which are impaired in type 2 diabetes (T2D). Although monocyte-derived multipotential cells (MOMCs) can be differentiated into the endothelial lineage, it remains unclear whether HDL glycation, size, and composition could affect MOMCs differentiation. Methods: Twenty normoglycemic (49 years, 35% male), 20 prediabetic (52 years, 35% male), and 20 newly diagnosed T2D participants (51 years, 50% male) were recruited. HDL were isolated from each study group. The size, composition, and early, intermediate, or advanced glycation products of HDL were determined. CD14+ MOMCs were isolated from healthy volunteers and incubated with HDL from each group. Endothelial phenotypic expression was assessed by CD14⁺/KDR⁺ expression. Results: Compared with normoglycemic and prediabetic individuals, T2D patients had higher concentrations of early (4.4, 4.6, vs. 5.2 µmol/mg of protein, respectively; p = 0.049) and advanced (7.7, 8.7, vs. 14.3 µg-BSA-AGEs/mg of protein, respectively; p < 0.02) glycation products in HDL. HDL composition was similar among groups. The CD14+/KDR+ expression in MOMCs incubated with HDL from T2D patients was lower than that observed in prediabetes and normoglycemic individuals (46% vs. 52% and 61%, respectively; p = 0.002). Advanced glycation end products in HDL inversely correlated with CD14+/KDR+ cells (r = −0.418, p = 0.002), adjusting for other HDL characteristics. Conclusions: In T2D patients, increased HDL-advanced glycation impairs the endothelial phenotypic expression of MOMCs, independently of other HDL characteristics. Since advanced glycation leads to greater biological damage, these findings highlight the importance of preserving HDL integrity in T2D patients to support endothelial repair and potentially delay vascular complications. Full article

Background/Objectives: Prediabetes is a metabolic condition involving various phenotypes of glucose metabolism. Prediabetes increases the risk of heart disease, among other conditions. Hence, we employed machine learning tools to characterize phenotypes associated with cardiovascular disease using routine laboratory biomarkers. Methods: We processed laboratory records of over 1,000,000 de-identified individuals, resulting in a sample of 3024 individuals classified as prediabetic (fasting blood glucose 100–125 mg/dL combined with HbA1c 5.7–6.4%). Lipid profile parameters (total cholesterol [TC], HDL-C, LDL-C, and triglycerides) and associated indices (atherogenic index of plasma, Log₁₀(TG/HDL-C), triglyceride–glucose index [TyG], TC/HDL-C, and LDL-C/HDL-C, among others) were analyzed using the k-means algorithm. Two groups emerged based on biomarker concentrations, a pro-atherogenic cluster (P-AC; n = 1113) and a less-atherogenic cluster (L-AC; n = 1911) for cardiovascular disease. Results: We assessed the performance of biomarkers in the P-AC and L-AC clusters using a receiver operating characteristic curve. Triglycerides (area under the curve [AUC] 0.977), AIP (AUC 0.978), and triglyceride–glucose index (AUC 0.974) showed sensitivity and specificity >90%. The TC/HDL-C (AUC 0.903) and LDL-C/HDL-C (AUC 0.865) indices also performed well, with sensitivity and specificity of 80%. Binomial logistic regression applied to the groups generated by k-means using the biomarkers AIP and LDL-C/HDL-C showed an AUC of 0.984 and accuracy above 93%. Conclusions: The k-means algorithm enabled the identification of a P-AC for cardiovascular disease among prediabetics using cost-effective laboratory biomarkers that are widely accessible in laboratories. Individuals classified as P-AC may benefit from differentiated treatment to minimize this factor. Full article

Adiponectin and omentin are adipose tissue-derived adipokines implicated in insulin sensitivity and cardiometabolic regulation. Their behavior across different stages of dysglycemia, as well as in relation to visceral adiposity and cardiometabolic phenotypes, remains incompletely understood. In this cross-sectional study, circulating adiponectin and omentin levels were evaluated in individuals with prediabetes (PreDM, n = 100) and newly diagnosed type 2 diabetes mellitus (T2DM, n = 128). Associations with insulin resistance-related indices, including the triglyceride–glucose (TyG) index and TyG-derived composites, the visceral adiposity index (VAI), cardiometabolic phenotypes, and cardiovascular risk categories, were assessed using correlation and multivariable regression analyses. Discriminatory performance for metabolically unhealthy obesity was evaluated using receiver operating characteristic (ROC) curve analysis. Both adiponectin and omentin levels were lower in T2DM compared with PreDM (22.05 vs. 30.30 and 25.72 vs. 38.84, p < 0.0001 for both). In PreDMs, omentin showed a significant inverse correlation with the TyG index (weak correlation, ρ = −0.197, p = 0.050), whereas adiponectin demonstrated only weak trends. In multivariable models, VAI and male sex were independent predictors of circulating omentin levels, whereas fasting insulin was not. In contrast, adiponectin did not retain independent associations with metabolic or visceral adiposity indices. In T2DM, adipokine–metabolic associations were largely absent. Neither adipokine differed substantially across cardiometabolic phenotypes or cardiovascular risk categories. ROC analyses revealed modest overall discriminatory performance for metabolically obese phenotypes, with poor discrimination after stratification by glycemic status (area under the ROC curve (AUC) of 0.704 for adiponectin and 0.710 for omentin, and AUC of 0.431 for adiponectin and 0.461 for omentin, respectively). Circulating adipokines appear to exhibit stage-dependent relationships with metabolic dysfunction, being more informative in PreDM than in established T2DM. Omentin may reflect visceral adiposity-related metabolic alterations in early dysglycemia, whereas adiponectin shows limited independent associations. Overall, these findings suggest that adipokines have limited diagnostic or cardiovascular risk-stratification utility when considered in isolation and may be better interpreted within multimarker cardiometabolic assessment frameworks. Full article

Background: Abelmoschus esculentus L. (okra) has shown potential efficacy in animal models of metabolic disorders; however, evidence from clinical studies emanates from trials with a small sample size, and the findings remain contradictory. This study aims to evaluate the impact of okra on glycemia and insulin resistance in individuals with type 2 diabetes (T2D) and prediabetes. Method: A literature search was conducted on PubMed, Scopus, ScienceDirect, and Web of Science, including manual screening of references. Abelmoschus esculentus, okra, Hibiscus esculentus, lady’s finger, and diabetes were used as potential keywords and adjusted for each database. A meta-analysis web tool was used to analyze the data, with results reported as the mean difference (MD) or standardized mean difference (SMD), along with 95% confidence intervals (CI). Results: Nineteen clinical studies conducted in patients with T2D and prediabetes were analyzed. The evidence revealed that, compared to the control group, okra significantly reduced fasting blood glucose (SMD = −0.70 (95% CI, −1.03 to −0.36), p < 0.0001) and glycated hemoglobin (MD = −0.77%, 95%CI (−1.36 to −0.18), p = 0.0102. Furthermore, it reduced the homeostatic model assessment of insulin resistance (HOMA-IR) levels, MD = −0.61, 95% CI (−1.07, −0.15), p < 0.0097. However, no significant effect was observed on insulin (p = 0.5823). Conclusions: The evidence gathered in this study suggests that okra may have the potential to regulate glycemia in individuals with T2D and prediabetes. However, the effect on insulin resistance remains controversial, as only HOMA-IR was improved. Full article

Type 2 diabetes mellitus and prediabetes often develop silently and may remain undiagnosed for years. This is particularly relevant in regions where laboratory-based screening is not always readily accessible. Against this background, the present work explores whether multilead electrocardiography can provide physiologically meaningful markers potentially associated with disturbances in glucose metabolism. We developed and tested an upgraded wearable 12-lead ECG system capable of synchronized multichannel recording under controlled conditions. ECG signals were acquired in sitting and standing positions, with a sampling frequency of 500 Hz and a recording duration of one minute per posture. The hardware architecture included a high resolution analog front-end and wireless data transmission; the accompanying software provided acquisition control, preprocessing, visualization, and data storage within a unified framework. Signal processing focused on the extraction of rhythm-related and morphological parameters, with particular attention to ventricular repolarization indices. QT interval, heart rate–corrected QT (QTc), and QT dispersion (QTd) were calculated across leads, as these parameters are known to reflect heterogeneity of repolarization and autonomic influences on myocardial electrophysiology. The analysis was structured to ensure reproducible boundary detection and systematic feature formation rather than isolated parameter measurement. The study had a pilot character and included a limited and unbalanced sample (healthy n = 10; prediabetes n = 1; T2DM n = 1). For this reason, the results are presented descriptively and should be regarded as preliminary observations. In representative cases, differences in QT-related indices were noted between categories of glycemic status; however, the potential influence of age, sex, and other confounders cannot be excluded. A pilot expert comparison of T-wave end detection demonstrated close agreement between the automated algorithm and cardiologist assessment (mean Δ$T_{end}$ approximately −1 to −2 ms; MAE 10–24 ms). Diagnostic performance metrics such as ROC/AUC, sensitivity, and specificity were not calculated at this stage, as validation in a larger cohort with biochemical confirmation (HbA1c, OGTT) is required. The study demonstrates the technical feasibility of combining synchronized 12-lead wearable acquisition with structured multilead repolarization analysis. The proposed system should therefore be considered a research platform intended to support further clinical validation and methodological development rather than a finished screening solution. Full article

Background: Hydroxytyrosol (HT) is a phenolic compound found in extra virgin olive oil that modulates oxidative and inflammatory status. However, clinical trials evaluating HT as a stand-alone supplement remain scarce, and its underlying mechanisms and pathway modulation are not yet fully understood. This study aimed to investigate the metabolic effects of HT supplementation in individuals with overweight and prediabetes using an untargeted metabolomics approach. Methods: An untargeted liquid chromatography–mass spectrometry (LC–MS)-based metabolomics analysis was performed on serum samples from 49 participants with overweight and prediabetes enrolled in a randomized controlled trial. Participants received either HT (15 mg/day for 16 weeks; n = 24) or placebo (n = 25). Global metabolomic profiling was used to compare metabolic changes between the two groups. Results: HT supplementation induced a distinct metabolic profile compared with placebo. Participants in the HT group showed reduced levels of nitrogenous base derivatives and arachidonic acid, together with increased concentrations of phosphatidylcholines, lysophosphatidylcholines and sphingomyelins. These alterations suggest modulation of two key metabolic pathways including purine degradation and arachidonic acid metabolism. Conclusions: These findings provide mechanistic insights into the biological effects of HT and support the integration of metabolomics and multi-omics approaches in future clinical studies to validate these pathways in larger populations. Full article

Background/Objectives: Obesity and prediabetes are overlapping global epidemics. This systematic review synthesises evidence on gene-diet interactions in adults with obesity, prediabetes, or related cardiometabolic risks. It evaluates Mediterranean and DASH dietary patterns, macronutrient quality, and energy restriction across both single-variant and polygenic score approaches. Methods: PubMed was searched for English language papers published in the last 5 years (last run: 31 October 2025). Fewer than 200 studies were retained after excluding those lacking explicit statistical testing for gene-diet interactions or relevant endpoints. Results: Evidence supports restricting saturated fat and preserving carbohydrate quality as general baseline targets, with associations heterogeneous by genotype. Effect modification was observed: healthy dietary patterns were associated with lower risk in high polygenic-risk strata (OR~0.53) but little or no benefit in low-risk groups. TCF7L2 variants were associated with macronutrient thresholds (e.g., protein > 18%, carbohydrate < 48%) affecting visceral adiposity, while APOA2 variants showed genotype-dependent inflammation, including paradoxical increases in markers with higher dietary antioxidant capacity. Interpretation was limited by underpowered interaction tests, multiplicity, and uneven ancestry representation (e.g., unique SLC16A11 and CREBRF signals). Conclusions: While anti-inflammatory dietary substitutions improve biomarkers irrespective of some variants (e.g., TCF7L2), genotype-informed nutrition appears to yield the largest absolute risk reduction in high-risk populations. Clinical implementation should therefore combine baseline diet-quality guidance with targeted strategies for genotype-specific response patterns (e.g., APOA2 antioxidant heterogeneity and TCF7L2 carbohydrate thresholds), rather than rely on uniform recommendations alone. Future progress requires preregistered, genotype-stratified trials and locally trained polygenic scores to address ancestry-specific genetic architecture. Full article