Search Results (138)

Insulin resistance (IR) contributes to atherogenic dyslipidemia and elevated ASCVD risk. Apolipoprotein A1 (ApoA1)-associated lipoproteins have diverse anti-atherogenic functions, but it is unclear whether IR drives adverse changes in their proteomic composition. We hypothesized that IR is associated with an atherogenic ApoA1 proteome and that insulin-sensitizing interventions would improve its composition. We studied 861 participants without diabetes (age 47 ± 12 years, 65.5% female). IR was directly measured using the steady-state plasma glucose (SSPG) concentration via the insulin suppression test. ApoA1-associated proteins were quantified by mass spectrometry. A subset underwent interventions for 3 months (N total 108): pioglitazone, PIO n = 38 or weight loss, WL n = 70). Paired t-tests assessed pre- and post-intervention changes. At baseline, several ApoA1-associated proteins significantly correlated with SSPG. Both interventions improved IR (p < 0.01). PIO led to significant increases in 14 ApoA1-associated proteins, including ApoC1–C4, ApoA2, ApoA4, ApoD, ApoE, LCAT, and PON1/3. WL increased several ApoA1-associated proteins, including ApoA4, ApoD, ApoM, and PON1/3. In conclusion, IR is associated with a pro-atherogenic ApoA1 proteome, and both interventions improve this profile. However, PIO has a broader proteomic impact. These findings highlight the potential of targeting the ApoA1 proteome to reduce residual ASCVD risk. Full article

Background: β-lactoglobulin (BLG) is a protein found within whey protein (WP) that is rich in essential amino acids, most notably, leucine (LEU). LEU is considered the most potent EAA in the postprandial stimulation of muscle protein synthesis (MPS), such that suboptimal protein/essential amino acid (EAA) doses containing higher LEU content elicit muscle anabolism comparable to larger protein doses. Our objective was to test the effects of naturally LEU-rich BLG (~10 g protein) versus isonitrogenous whey protein isolate (WPI, ~10 g) on MPS. Methods: Ten healthy young men (26 ± 2 y; 179 ± 2 cm; 81 ± 3 kg) received BLG (1.57 g LEU) or WPI (1.02 g LEU) in a randomised double-blind cross-over fashion. A primed constant intravenous infusion of [1,2 ¹³C₂] LEU was used to determine MPS (isotope ratio mass spectrometry) at baseline and in response to feeding (FED) and feeding-plus-exercise (FED-EX; 6 × 8 unilateral leg extensions; 75% 1-RM). Plasma insulin and EAA’s were quantified. Results: Plasma EAA, branched-chain amino acid (BCAA), and LEU concentrations increased rapidly following both protein supplements but exhibited a significantly greater EAA/BCAA/leucinemia following BLG (p < 0.05 for all). MPS increased significantly in both FED (~52%) and FED-EX (~58%) states, with no significant differences between supplements. Conclusions: Both BLG and WPI effectively stimulated MPS doses in young healthy males, with BLG offering an advantage in EAA/BCAA/LEU bioavailability. It follows that future research should explore the potential of BLG in populations exhibiting anabolic resistance and exercise anabolism deficiency, such as older adults as well as frail and clinical populations, to assess its utility in preserving muscle mass under conditions of suboptimal protein intake. Full article

Background/Objectives: Excessive weight gain is a growing concern among people living with HIV (PWH) receiving integrase strand transfer inhibitor (INSTI)-based regimens as first-line antiretroviral therapy (ART), as it may contribute to multimorbidity. The mechanisms driving weight gain in INSTI users are not fully understood but are thought to be multifactorial. This study examines the plasma metabolome associated with weight gain in PWH on INSTI-based regimens. Methods: We conducted a nested case–control study within the randomized clinical trial MICTLAN (NCT06629480). Sixty-six participants were randomized to receive INSTI-based regimens, either bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) or dolutegravir/abacavir/lamivudine (DTG/ABC/3TC), and followed for 18 months. Weight gain >10% relative to baseline was considered a primary endpoint and used as a criterium to categorize cases (n = 28) and controls (n = 38). Anthropometric and clinical measurements, plasma insulin, and metabolomic profiles were assessed at baseline and 18 months post-ART. Plasma untargeted metabolomics was performed using liquid chromatography–mass spectrometry (LC-MS/MS) to identify metabolomic changes linked to weight gain. Bioinformatic tools, including Partial Least Squares Discriminant Analysis (PLS-DA), volcano plots, and KEGG pathway enrichment analysis, were used to analyze plasma metabolomes and identify significant differential metabolites. Results: Weight gain at 18 months in PWH on INSTI-based ART was associated with insulin resistance, as measured by HOMA-IR (OR 3.23; 95% CI 1.14–9.10; p = 0.023), and visceral adipose tissue thickness > 4 cm (OR 4.50; 95% CI 1.60–13.03; 9.10; p = 0.004), and hypertriglyceridemia (OR 3.9; 95% CI 1.38–10.94; p = 0.008). Baseline HIV RNA viral load >50,000 copies/mL (OR 8.05; 95% CI 2.65–24.43; p = 0.0002) was identified as a baseline predictor of weight gain (aOR 6.58 (1.83–23.58); p = 0.004). In addition, accumulation of circulating medium-chain acylcarnitines, indicative of mitochondrial dysfunction, and insulin resistance were linked to weight gain in PWH on INSTI-based regimens after 18 months of therapy. Conclusions: This metabolomic study identified metabolites reflecting mitochondrial dysfunction, dysregulated lipid metabolism, and altered amino acid metabolism as key mechanisms underlying insulin resistance and weight gain in PWH on INSTI-based ART. Full article

This study aimed to investigate whether knockout of the ApoB48 gene improves lipid metabolism disorders induced by a high-fat diet (HFD) in mice. Clustered regularly interspaced short palindromic repeats–Cas9 gene editing technology was used to knock out the ApoB48 gene in C57BL/6J mice, and genotype identification showed heterozygosity (HE, ApoB48 +/−). Subsequently, eight HE and eight wild-type (WT) mice were fed a HFD for 12 weeks. Fasting blood glucose, and insulin levels were decreased in ApoB48 +/− mice. The intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test showed mild insulin resistance. Moreover, it delayed the development of atherosclerosis and intestinal tissue damage. Differential metabolites such as ceramide, sphingosine, and sphingosine-1-phosphate were identified using liquid chromatography–mass spectrometry, and differentially expressed proteins, including ceramide synthase 6 (CerS6), protein phosphatase 2A (PP2A), and protein kinase B (AKT), were indicated by the Kyoto Encyclopaedia of Genes and Genomes. Therefore, decreased expression of ApoB48 can ameliorate lipid metabolism disorders induced by an HFD, which may be related to the CerS6/PP2A/AKT pathway. This might represent a new approach for exploring methods to treat hyperlipidaemia. Full article

An integrative approach combining network pharmacology, molecular docking, and cellular assays was used to elucidate the potential mechanisms by which the n-butanol extract of Biebersteinia heterostemon ameliorates type 2 diabetes mellitus (T2DM). Chemical constituents of the n-butanol extract were identified via ultra-high-performance liquid chromatography coupled with Q-Exactive Orbitrap mass spectrometry. Active compounds and T2DM-related targets were retrieved from public databases, and intersecting targets were identified. Protein–protein interaction (PPI) networks were constructed using the STRING database, while Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed via the DAVID database. A comprehensive “drug–compound–target–disease–pathway” network was established, and molecular docking was conducted to evaluate binding affinities of key compounds to core targets. Functional validation was performed in insulin-resistant cell models. Network pharmacology analysis identified 37 active constituents within the extract and 222 overlapping targets associated with T2DM. GO enrichment indicated involvement in protein phosphorylation, MAPK cascade activation, and negative regulation of apoptosis. Key signaling pathways included PI3K/AKT and lipid and atherosclerosis pathways. Molecular docking revealed strong binding affinities (binding energies ≤ −9.3 kcal·mol⁻¹) between core compounds—such as cheilanthifoline, glabridin, acetylcorynoline, skullcapflavone II, liquiritigenin, and dinatin—and pivotal targets including GAPDH, AKT1, TNF, SRC, EGFR, and PPARγ. In vitro experiments demonstrated that the extract significantly enhanced glucose uptake and glycogen synthesis in insulin-resistant cells, while suppressing oxidative stress and the expression of pro-inflammatory mediators such as TNF-α, MMP9, and IL-6. Collectively, B. heterostemon shows potential as an effective intervention for T2DM by targeting key molecular pathways, improving insulin sensitivity, and mitigating oxidative stress and inflammation in insulin-resistant cells. Full article

Background: Insulin resistance (IR) is common in overweight or obese individuals. Dysregulation of trace elements such as cobalt (Co) and manganese (Mn) has been associated with obesity and IR markers in individuals with diabetes. However, their role in non-diabetic states is less understood. Objective: This study aimed to analyze the association between serum Co and Mn levels and IR in overweight and obese women without diabetes. Methods: A total of 112 overweight or obese women were evaluated for their anthropometric, metabolic, and biochemical characteristics. To estimate IR, the homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), triglyceride–glucose index (TyG), and triglyceride–glucose–body mass index (TyG-BMI) were calculated. Serum Co and Mn concentrations were quantified by inductively coupled plasma mass spectrometry (ICP-MS). Results: Our results show that 77% of participants exhibited central fat accumulation and a high prevalence of IR. Fasting insulin (FINS), HOMA-IR, and TyG-BMI were significantly higher in obese women, while adiponectin (Adpn) was lower. Moreover, Co was inversely associated with FINS (p = 0.003) and HOMA-IR (p = 0.011), and positively associated with QUICKI (p = 0.011) in obese women. In contrast, serum Mn levels showed negative correlations with fasting glucose (FG) (p = 0.021) and the TyG index (p = 0.048) in overweight women. Conclusions: Co serum levels were positively associated with FG and QUICKI and negatively associated with FINS and HOMA-IR in the obese group. Mn showed negative associations with FG and the TyG index, suggesting that these trace elements may play a role in the IR in people with obesity. Full article

Apolipoprotein A-IV (ApoA-IV) has been implicated in modulating the gut microbiota. However, chronic high-fat diet (HFD) consumption impairs ApoA-IV signaling and disrupts gut microbial balance, contributing to obesity and insulin resistance. This study aimed to investigate the role of ApoA-IV in shaping the gut microbiota and associated metabolic profiles throughout the lifespan of mice exposed to an HFD. Fecal samples were collected from ApoA-IV knockout (KO) and wild-type mice at five time points for microbiota and metabolite profiling using 16S rRNA gene sequencing and gas chromatography–mass spectrometry, respectively. Lifespan was longest in ApoA-IV-KO mice on a normal diet, while the HFD reduced survival across genotypes. Microbiota analysis revealed diet- and age-dependent shifts, including an elevated Firmicutes/Bacteroidota ratio, altered abundance of Akkermansia and reduced Monoglobus in ApoA-IV-KO mice on the HFD. Metabolic profiling showed a stronger impact of diet than genotype, with early and persistent increases in branched-chain amino acids and reductions in short-chain fatty acids (SCFAs). ApoA-IV deficiency modulated lifespan microbial and metabolic changes and shaped distinct responses to dietary stress. Despite age-related convergence in microbiota structure, genotype-specific differences in metabolite profiles and SCFA-producing bacteria correlations persisted into old age, demonstrating the lasting impact of ApoA-IV on host metabolic adaptation. Full article

Astragalus membranaceus (AM), also known as Huangqi in Chinese, refers to the dried root of two Leguminosae species: AM (Fisch.) Bge. and its variety AM (Fisch.) Bge. var. mongholicus (Bge.) Hsiao. In recent years, research on AM has been published in many papers. Its role in treating metabolic syndrome (MetS) has attracted increasing attention. This review summarizes the research progress over the past five years on the chemical constituents of AM and its therapeutic potential in MetS-related diseases. Chemical analyses of AM have gradually expanded from its roots to its stems, leaves, and entire plant. The major compounds isolated from AM include flavonoids, saponins, and polysaccharides. Extraction methods include ultra-performance liquid chromatography coupled with tandem mass spectrometry and in vitro intestinal absorption models combined with high-performance liquid chromatography–photodiode array–tandem mass spectrometry. AM and its active components exert beneficial effects on metabolic disorders such as type 2 diabetes mellitus, non-alcoholic fatty liver disease, obesity, hypertension, and cardiovascular diseases. These effects are achieved mainly through mechanisms such as reducing oxidative stress and inflammation, modulating gut microbiota, regulating lipid metabolism, improving insulin resistance, and protecting pancreatic β-cell function. This review provides a reference for further studies on treatment of MetS of AM. Full article

Background: Type 2 diabetes (T2D), the most common form of diabetes, is associated with a significantly elevated risk of cardiovascular and cerebrovascular complications. However, circulating metabolic signatures that reliably predict the transition to insulin resistance, and are potentially linked to increased vascular risk, remain incompletely characterized. Rodent models, particularly those induced by a high-fat diet (HFD) combined with low-dose streptozotocin (STZ), are widely used to study the progression of T2D. However, the systemic metabolic shifts associated with this model, especially at the plasma level, are poorly defined. Methods: In this study, we performed untargeted liquid chromatography–mass spectrometry (LC-MS)-based metabolomic profiling on plasma samples from control, HFD-only (obese, insulin-sensitive), and HFD + STZ (obese, insulin-resistant) C57BL/6 mice. Results: In the HFD + STZ cohort, plasma profiles showed a global shift toward lipid classes; depletion of aromatic and branched-chain amino acids (BCAAs); accumulation of phenylalanine-derived co-metabolites, consistent with gut–liver axis dysregulation; elevations in glucose, fructose-6-phosphate, and nucleoside catabolites, indicating impaired glucose handling and heightened nucleotide turnover; increased free fatty acids, reflecting membrane remodeling and lipotoxic stress; and higher cAMP, thyroxine, hydrocortisone, and uric acid, consistent with endocrine and redox imbalance. By contrast, HFD-only mice exhibited elevations in aromatic amino acids and BCAAs relative to controls, a pattern compatible with early obesity-associated adaptation while insulin signaling remained partially preserved. KEGG analysis revealed disturbances in carbohydrate metabolism, amino acid degradation, nucleotide turnover, and hormone-related pathways, and HMDB mapping linked these changes to T2D, obesity, heart failure, and renal dysfunction. Conclusion: Collectively, these findings delineate insulin resistance-specific plasma signatures of metabolic inflexibility and inflammatory stress in the HFD + STZ model, distinguishing it from HFD alone and supporting its utility for mechanistic studies and biomarker discovery. Importantly, this plasma metabolomics study shows that insulin-sensitive and insulin-resistant states exhibit distinct variation in circulating metabolites and cardiovascular risk factors, underscoring the translational value of plasma profiling. Full article

Adipose tissue exhibits dynamic metabolic and structural changes in response to environmental stimuli, including temperature fluctuations. While continuous cold exposure has been extensively studied, the molecular effects of prolonged intermittent cold exposure (ICE) remain poorly characterized. Here, we present a proteomic analysis of inguinal white adipose tissue (IWAT) from mice subjected to a 16-week regimen of short-term daily ICE (6 °C for 6 h, 5 days per week) without compensatory caloric intake. Mass spectrometry identified 1108 proteins, with 140 differentially expressed between experimental and control groups. ICE significantly upregulated mitochondrial proteins associated with lipid and carbohydrate catabolism, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and lipogenesis, including LETM1, AIFM1, PHB, PHB2, ACOT2, NDUA9, and ATP5J. These changes reflect enhanced metabolic activity and mitochondrial remodeling. In contrast, proteins linked to oxidative stress, insulin resistance, inflammation, and extracellular matrix remodeling were downregulated, such as HMGB1, FETUA, SERPH1, RPN1, and AOC3. Notably, gamma-synuclein (SYUG), which inhibits lipolysis, was undetectable in ICE-treated samples. Our findings support the hypothesis that ICE promotes thermogenic reprogramming and metabolic rejuvenation in subcutaneous fat through activation of futile cycles and mitochondrial restructuring. This study offers molecular insights into adaptive thermogenesis and presents intermittent cold exposure as a potential strategy to mitigate adipose tissue aging. Full article

Background/Objectives: Gut-derived tryptophan (Trp) metabolites play important roles in metabolic and cardiovascular regulation. Although animal studies suggest their protective effects against metabolic dysfunction, data in adolescents, particularly those with obesity, remain limited. The objective of this study was to evaluate associations between circulating gut-derived Trp metabolites and markers of cardiometabolic, vascular, and platelet health in adolescents with obesity. Methods: Data were analyzed from 28 adolescents (ages 13–18; mean BMI = 36 ± 6.4 kg/m²). Fasting blood was collected to assess lipid profiles using a clinical analyzer and insulin resistance using the homeostatic model assessment for insulin resistance (HOMA-IR). Gut-derived Trp metabolites were measured by UPLC–mass spectrometry, peak oxygen uptake (VO_{2 peak}) by gas exchange during an incremental cycle ergometer test, and body composition by dual-energy X-ray absorptiometry. Platelet spare respiratory capacity (SRC), endothelial function, and liver fat were measured using high-resolution respirometry, flow-mediated dilation (FMD) of the brachial artery, and magnetic resonance imaging respectively. Results: Indole-3-propionic acid was inversely associated with diastolic blood pressure (rho = −0.39, p = 0.047), total cholesterol (rho = −0.55, p = 0.002), and LDL-C (rho = −0.57, p = 0.0014), independent of sex and obesity severity. Indoxyl sulfate was positively correlated with fasting glucose (rho = 0.47, p = 0.012), and adolescents with impaired fasting glucose had 1.6-fold higher IS levels. Indole-3-acetaldehyde declined with age (rho = −0.50, p = 0.007), and Indole-3-acetic acid and indole were higher in Hispanics vs. non-Hispanics. No significant associations were observed between Trp metabolites and FMD, VO₂ peak, or SRC. Conclusions: Gut-derived Trp metabolites, particularly indole-3-propionic and indoxyl sulfate, are associated with markers of cardiometabolic risk in adolescents with obesity. These findings support their potential relevance in early-onset cardiovascular disease risk. Full article

The advancement of modern lifestyles has precipitated excessive consumption of energy-dense foods, driving the escalating global burden of lipid metabolism dysregulation-related pathologies—including obesity, type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), and cardiovascular disorders—which collectively pose a formidable challenge to global public health systems. The almond hull, as a by-product of almond processing, is rich in polyphenolic compounds with demonstrated antioxidant, anti-inflammatory, and lipid-lowering potential, though its precise hypo-lipidemic mechanisms remain elusive. In this study, polyphenols were extracted from almond hulls using 50% ethanol with ultrasound-assisted extraction, followed by preliminary purification via solvent partitioning. The ethyl acetate fraction was analyzed by liquid chromatography–mass spectrometry (LC-MS). Network pharmacology and molecular docking were employed to investigate the interactions between key bioactive constituents (e.g., quercetin, baicalein, and kaempferol) and targets in lipid metabolism-related pathways. Molecular dynamics (MD) simulations further evaluated the stability of the lowest-energy complexes. Results revealed that the ethyl acetate fraction exhibited potent pancreatic lipase inhibitory activity (IC50 = 204.2 µg/mL). At 0.1 mg/mL after 24 h treatment, it significantly reduced free fatty acids (FFAs)-induced intracellular triglyceride accumulation (p < 0.01) and enhanced cellular antioxidant capacity. Network pharmacology and in vitro studies suggest almond hull extract modulates PI3K-AKT signaling and improves insulin resistance, demonstrating lipid-lowering effects. These findings support its potential in functional foods and pharmaceuticals, though further in vivo validation and mechanistic investigations are required. Full article

Maternal hyperglycemia during pregnancy poses significant health risks to both mother and fetus. Although gestational diabetes mellitus (GDM) is mainly characterized by insulin resistance, severe hyperglycemia may also result from impaired pancreatic function. This study evaluates the therapeutic potential of pandan (Pandanus amaryllifolius) root and teak (Tectona grandis) leaf extracts in managing streptozotocin (STZ)-induced maternal hyperglycemia in pregnant rats, compared to metformin. Methods: Pregnant rats were administered STZ (60 mg/kg) on gestation day 5. Treatments with metformin (300 mg/kg), pandan extract (low, medium, high doses), and teak extract (low, medium, high doses) were given from gestation day 7 to 21. The key parameters included the maternal blood glucose, insulin levels, pancreatic morphology, fetal and placental outcomes, and gas chromatography/mass spectrometry (GC/MS) phytochemical profiling. GC/MS analysis identified 2,3-butanediol and propanoic acid derivatives as major compounds in pandan, while teak contained catavic acid and methyl copalate. The high-dose pandan extract significantly reduced the maternal blood glucose (p < 0.05), improved the insulin levels and pancreatic mass index, and increased the number of live fetuses, with effects comparable to metformin. The teak extract showed milder improvements. The pandan extract demonstrated dose-dependent antidiabetic potential in this STZ-induced model. Future studies should evaluate these effects in insulin-resistance-based GDM models. Full article

Background/Objectives: Endophytes can produce bioactive metabolites similar to their host plants. CM-YJ44 (Pseudomonas protegens CHA0, 99.24% similarity), an endophyte from Dendrobium officinale, has not yet validated hypoglycemic potential. This study aimed to evaluate its anti-insulin resistance (IR) activity and metabolite profile. Methods: The fermentation broth of CM-YJ44 was separated into three fractions (CM-YJ44-1, -2, and -3) using semi-preparative high-performance liquid chromatography (pre-HPLC). An IR HepG2 cell model was constructed to evaluate their glucose uptake capacity. CM-YJ44-3 was further tested for oxidative stress, inflammatory, and insulin signaling pathway activation. Metabolites in CM-YJ44-3 were preliminarily identified using the Q Exactive Focus LC-MS system (QE), and the dendrobine content was quantified by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). Molecular docking was performed to predict the binding affinities between dendrobine and target proteins. Results: Among the three fractions, CM-YJ44-3 significantly reduced nitric oxide (NO) and reactive oxygen species (ROS) levels in IR cells, enhanced glycogen synthesis, upregulated the activities of pyruvate kinase (PK) and hexokinase (HK), and suppressed the expression of inflammatory factors. Its mechanism of action was mainly through activation of the IRS1/PI3K/Akt/GSK3β/GLUT4 signaling pathway. QE analysis preliminarily identified 24 metabolites in CM-YJ44-3. Quantitative analysis by UPLC-MS/MS showed that the dendrobine content was 78.73 ± 4.29 ng/mL. Molecular docking results indicated that dendrobine exhibited binding energies below −5 kcal/mol with multiple target proteins involved in this signaling pathway, suggesting it may be a key bioactive component responsible for the anti-IR effect. Conclusions: This study provides the first evidence of hypoglycemic bioactive metabolite production by strain CM-YJ44, indicating its potential as a novel microbial candidate for alleviating IR. Full article

Background: Insulin resistance is a key driver of metabolic syndrome and related disorders, yet its underlying metabolic alterations remain incompletely understood. The Triglyceride–Glucose (TyG) index is an emerging, accessible marker for insulin resistance, with growing evidence supporting its clinical utility. This study aimed to characterize the metabolic profiles associated with insulin resistance using the TyG index in a large, population-based cohort, and to identify metabolic pathways potentially implicated in insulin resistance. Methods: Here, we conducted a cross-sectional study using data from the Qatar Biobank, including 1255 participants without diabetes classified as insulin-sensitive or insulin-resistant based on TyG index tertiles. Untargeted serum metabolomics profiling was performed using high-resolution mass spectrometry. Our statistical analyses included orthogonal partial least squares discriminate analysis and linear models. Results: Distinct metabolic signatures differentiated insulin-resistant from insulin-sensitive participants. Phosphatidylethanolamines, phosphatidylinositols, and phosphatidylcholines, were strongly associated with insulin resistance, while plasmalogens and sphingomyelins were consistently linked to insulin sensitivity. Conclusions: Lipid-centric pathways emerge as potential biomarkers and therapeutic targets for the early detection and personalized management of insulin resistance and related metabolic disorders. Longitudinal studies are warranted to validate causal relationships. Full article