An established risk factor for ovarian cancer is obesity; epidemiological data show that obese women have a higher incidence and a lower survival rate. PubMed, Scopus, Web of Science, and Google Scholar were searched for pertinent material published between 2010 and 2026 for this narrative review. Reviews, clinical trials, and peer-reviewed research on obesity, ovarian cancer, PI3K/AKT/mTOR, leptin-JAK/STAT3, NF-κB, and associated treatments were included; duplicates and irrelevant publications were eliminated. The pathogenic connection results from adipokine dysregulation, metabolic changes that encourage carcinogenesis, and persistent low-grade inflammation brought on by obesity. Via cytokines, growth factors, and free fatty acids, excess adiposity triggers pro-oncogenic pathways, including PI3K/AKT/mTOR, leptin-JAK/STAT, and NF-κB. Proliferation, angiogenesis, metastasis, and chemoresistance are all fueled by these mechanisms. Through energy provision and extracellular matrix remodeling, adipocyte–tumor interaction in the omentum further increases the likelihood of metastasis. Clinical trials have shown varying degrees of success for pharmacological therapies that target these pathways, including NF-κB modulators, JAK inhibitors, and mTOR inhibitors. Curcumin, oridonin, and genistein are examples of natural substances that show preclinical potential in modifying these signaling cascades. Calorie restriction, low-starch diets, and organized exercise are examples of lifestyle modifications that can enhance metabolic profiles and perhaps affect prognosis. Molecular profiling in precision medicine techniques may improve focused treatment and get past resistance. This study highlights the necessity of multi-modal interventions to address the obesity–ovarian cancer nexus by integrating molecular knowledge, therapeutic techniques, and lifestyle factors.
Type 1 and Type 2 diabetes, despite fundamentally different etiologies, lead to remarkably similar microvascular and macrovascular complications. This shared phenotype is not fully explained by hyperglycemia alone or by differences in insulin exposure. We propose that, at the vascular level, a common state of selective vascular insulin resistance characterized by impaired PI3K/Akt-mediated vasoprotective signaling with relative preservation of MAPK-mediated pro-inflammatory and vasoconstrictive signaling may contribute to these shared vascular outcomes. This Perspective advances a hypothesis-generating conceptual framework intended to integrate existing mechanistic and clinical observations rather than establish a definitive causal model.Prior work has defined selective insulin resistance at the cellular level; here, we propose extending this concept to a disease-level framework that may explain the parallel development of complications in both forms of diabetes. In Type 2 diabetes, metabolic insulin resistance drives this imbalance in the setting of compensatory hyperinsulinemia, whereas in Type 1 diabetes, nonphysiologic peripheral insulin delivery combined with metabolic stress may promote a comparable signaling disturbance. This review synthesizes mechanistic and clinical observations into a unified, testable hypothesis and outlines potential avenues for validation. Rather than replacing established glucotoxic mechanisms, this model suggests that impaired insulin signaling may modify tissue susceptibility to metabolic injury and offers a framework for evaluating therapies aimed at restoring physiologic vascular insulin action.
Aims Gestational diabetes mellitus is a common metabolic complication of pregnancy characterized by impaired insulin signaling and inadequate β-cell adaptation. It is associated with significant maternal and fetal morbidity and long-term cardiometabolic risk. This systematic review aims to elucidate the molecular mechanisms underlying dysregulation of the insulin signaling pathway in GDM and to identify potential therapeutic targets for improved disease management. Methods A PRISMA-guided systematic search of PubMed/MEDLINE, Web of Science, and ScienceDirect databases was conducted for studies published between January 2015 and March 2026. Eligible studies included observational and experimental research focusing on insulin signaling in GDM. After screening 2262 records, 18 studies were included for qualitative synthesis. Study quality was assessed using the Newcastle–Ottawa Scale and Joanna Briggs Institute tools. Results GDM is characterized by disruption of the IRS1/PI3K/AKT signaling axis, resulting in impaired glucose uptake and insulin resistance. Key inhibitory regulators such as DUSP9 and ENPP1 attenuate insulin receptor signaling. Epigenetic modulators, including miRNAs (e.g., miR-770-5p, miR-7) and lncRNAs (e.g., TUG1), play crucial roles in β-cell dysfunction and metabolic regulation. Inflammatory cytokines (TNF-α and IL-6), oxidative stress, adipokine imbalance, and placental dysfunction further exacerbate metabolic dysregulation. Emerging therapies targeting AMPK activation and inflammatory pathways show potential benefits. Conclusion GDM is a multifactorial disorder driven by integrated disturbances in insulin signaling, epigenetic regulation, inflammation, and placental function. Early detection using molecular biomarkers and targeted therapeutic strategies may improve maternal–fetal outcomes and reduce long-term metabolic complications.
Type 2 Diabetes Mellitus (T2DM) represents a significant and escalating global health challenge characterized by chronic hyperglycemia and insulin resistance. Current treatments often fall short, highlighting the urgent need for novel therapeutic strategies. This review focuses on irisin, an exercise-induced myokine, as a promising candidate for both a biomarker and a therapeutic agent in T2DM management. Irisin plays a critical role in metabolic regulation by enhancing insulin sensitivity, promoting the browning of white adipose tissue to increase energy expenditure, and mitigating the chronic low-grade inflammation associated with T2DM. We explore the molecular pathways underlying these effects, including the AMPK/p38 MAPK signaling and modulation of inflammatory cytokines. Furthermore, this review examines the diagnostic potential of irisin, the challenges in its clinical application such as measurement variability, and the potential of integrating AI/ML for improved biomarker analysis. We also discuss preclinical and clinical evidence supporting irisin-based therapies, including recombinant irisin and FNDC5 gene therapy. By addressing current mechanistic disputes and pharmacological hurdles, this review provides a comprehensive overview of irisin's potential to bridge the gap between lifestyle modification and pharmacological intervention, paving the way for a more holistic approach to T2DM management.
Background Obesity promotes vascular injury via dyslipidemia, oxidative stress, inflammation, endothelial dysfunction and apoptosis. Meanwhile methionine methylsulfonium chloride (MMSC) has antioxidant and cytoprotective effects, but its role in obesity-induced vascular injury remains unclear. Methods Twenty-five (25) male Wistar rats were randomly assigned to five groups. Obesity was induced by feeding a high-fat diet for 60 days, while MMSC (50 or 100 mg/kg) or simvastatin (10 mg/kg) was administered concurrently throughout the experimental period. Obesity indices (fasting blood glucose, waist circumference, Lee index, and weight gain), lipid profile (TC, TG, HDL, LDL), and atherogenic indices were assessed. Oxidative stress (SOD, catalase, MDA, GSH, GST), inflammatory (IL-6, TNF-α, NF-κB), apoptotic (cytochrome-c, caspase-3, Bcl-2), vascular tone (endothelin-1, nitric oxide), and VEGF biomarkers were measured, alongside histological evaluation of vascular tissues. Results High-fat diet feeding significantly increased obesity indices, hyperglycemia, dyslipidemia, oxidative stress, inflammation, apoptosis, and endothelial dysfunction, with evident vascular damage. Treatment with 50 and 100 mg/kg of MMSC markedly reduced body weight gain, fasting blood glucose, and obesity indices, improved lipid profile and atherogenic indices, and restored antioxidant status. It also suppressed inflammatory and apoptotic pathways, normalized vascular tone biomarkers, and enhanced VEGF levels. These effects were comparable to simvastatin. Histological findings supported the biochemical results, showing improved vascular structure. Conclusion Methionine methylsulfonium chloride effectively prevented obesity-induced vascular injury through coordinated metabolic, antioxidant, anti-inflammatory, anti-apoptotic, and endothelial-protective mechanisms.
Obesity is the primary upstream driver of metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent chronic liver condition globally, affecting 38% of adults and projected to exceed 55% prevalence by 2040. In obese individuals, visceral adipose tissue dysfunction sustains portal free fatty acid overflow, initiating hepatocellular lipid accumulation, lipotoxicity, and the progressive multicellular inflammatory–fibrotic cascade of metabolic dysfunction-associated steatohepatitis (MASH). The resulting disease burden extends far beyond the liver: MASLD amplifies cardiovascular disease, type 2 diabetes mellitus, and chronic kidney disease risk through shared pathomechanisms of insulin resistance, hepatokine dysregulation, and systemic inflammation. Despite FDA approvals of resmetirom and semaglutide for MASH, conventional pharmacotherapy remains constrained by poor hepatic cell-type specificity and inability to address the full four-cell disease network namely hepatocytes, Kupffer cells, hepatic stellate cells, and liver sinusoidal endothelial cells simultaneously. Nanoformulation-based drug delivery offers a precision alternative. Lipid nanoparticles, polymeric nanoparticles, inorganic carriers, biomimetic extracellular vesicles, and nucleic acid delivery platforms each enable receptor-mediated targeting of specific hepatic cell populations through validated ligand-receptor pairings: GalNAc- ASGPR for hepatocytes, mannose- CD206 for Kupffer cells, pPB/vitamin A- PDGFR-β for hepatic stellate cells, and stabilin ligands for liver sinusoidal endothelial cells. GalNAc-siRNA platforms targeting PNPLA3 and HSD17B13 have entered Phase I/II clinical trials, confirming translational feasibility. Key barriers to broader clinical translation including protein corona-mediated targeting loss, GMP-scale manufacturing constraints, safety characterisation in obese hepatic physiology, regulatory pathway complexity, and global access inequity demand coordinated interdisciplinary resolution; to this end, stimuli-responsive nanocarriers engineered to activate exclusively within the MASLD pathological microenvironment, CRISPR/Cas9-LNP systems targeting high-risk genetic variants such as PNPLA3 I148M, and artificial intelligence-guided formulation design represent the most mechanistically promising strategies to overcome these barriers and define the emerging precision frontier for obesity-associated MASLD.
Continuous glucose monitoring (CGM) is increasingly applied in adults with non–insulin-treated type 2 diabetes mellitus (T2DM), yet its clinical effectiveness in this population remains underexplored. This systematic review evaluated 32 randomized controlled trials involving 2783 adults comparing CGM with self-monitoring of blood glucose (SMBG). CGM use was associated with a notable increase in Time-in-Range (70–180 mg/dL) of +6.36%, equivalent to approximately 1.5 additional hours per day within target glucose. Glycemic variability improved, with reductions in coefficient of variation and standard deviation, while HbA1c decreased by 0.31–0.70% without elevating hypoglycemia risk. Time-Below-Range (<70 mg/dL) declined by −0.66%, and extreme glucose excursions (TAR>250 mg/dL; TBR<54 mg/dL) were minimal, highlighting the safety profile of CGM. These findings demonstrate that CGM enhances glycemic optimization and stability, supporting its integration as a precision monitoring and behavioral intervention tool for non–insulin-treated T2DM.
Chronic hyperglycemia, insulin resistance, oxidative stress, inflammation, and progressive multi-organ damage are the hallmarks of type 2 diabetes mellitus (T2DM), a complicated metabolic disease. There is a need for safer, multi-target alternatives to current antidiabetic medications because they are frequently constrained by side effects and inadequate defense against long-term problems. Bergenin, a C-glycosylated phenolic glycoside present in numerous medicinal plants, has attracted attention due to its broad pharmacological activity.This narrative review critically summarizes current preclinical and mechanistic evidence regarding the antidiabetic potential of bergenin, including its molecular mechanisms, pharmacokinetics, formulation strategies, and therapeutic relevance in type 2 diabetes mellitus and associated complications. Preclinical studies indicate that bergenin improves glucose homeostasis and insulin sensitivity by protecting pancreatic β-cells, inhibiting the NLRP3 inflammasome, activating the Nrf2 antioxidant pathway, attenuating NF-κB mediated inflammation, and modulating PPAR-ϒ signaling. It also decreases systemic inflammation, oxidative stress, and dyslipidemia. Bergenin also exerts protective effects against diabetic neuropathy, retinopathy, nephropathy, and testicular failure, among other diabetic complications. However, poor oral bioavailability and low aqueous solubility limit its use, despite conclusive evidence from preclinical studies, highlighting the importance of advanced drug-delivery systems for its clinical validation.
Obesity and type 2 diabetes are associated with chronic low-grade inflammation and metabolic abnormalities, in which ceramide accumulation is identified as a core pathogenic factor. Ceramides are bioactive sphingolipids synthesized through both de novo and salvage pathways that repress insulin signaling, induce programmed cell death, and initiate inflammatory cascades. It was reviewed that the gut microbiota is another sphingolipid source, particularly via Bacteroides-derived metabolites, which can modulate host lipid metabolism and immune function. Obesity-associated dysbiosis disrupts sphingolipid production by the gut microbiota, leading to changes in systemic lipids and heightened inflammatory responses induced by ceramides. This ceramide–microbiome-sphingolipid axis contributes to insulin resistance, adipose tissue macrophage activation, and hepatic metabolic stress, linking the ecology of the gut microbiota to diabetic inflammation. In this review, we aim to summarize recent advances in ceramide metabolism, microbial sphingolipid production and their intersection in obesity-associated diabetes. We also addressed the potential of therapeutic interventions (ie, dietary modulation, probiotics, and pharmacological inhibitors) targeting lipid homeostasis to alleviate immunometabolic dysfunction. Deciphering this new axis provides translational chances for biomarker discovery and precision therapies of metabolic disorders.
In the last 20 years, glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as an important advancement in the pharmacological treatment of type 2 diabetes and obesity. In addition to their defined applications in glucose homeostasis, modern GLP-1 receptor agonists (GLP-1RAs) and new dual/triple incretin agonists have pleiotropic effects, such as cardiovascular protection, renal preservation, neuroprotection, and metabolic remodelling. This review will offer an extensive translational system of the relationship between molecular signaling pathways and therapeutic responses and critically review comparative effectiveness of approved agents (liraglutide, semaglutide, and tirzepatide) in comparison to emerging pipeline drugs. Next-generation delivery systems and formulation strategies (oral peptide technologies with permeation enhancers, nanoparticles, sustained-release depots, transdermal microneedles, and gene-based strategies to overcome bioavailability and adherence barriers) are a major focus. Clinical results of landmark programs such as SUSTAIN, SURPASS and SURMOUNT, show significant enhancements in glycemic control, body weight reduction, and extended cardiometabolic benefits, especially when used with dual agonist therapy. Despite the overall positive safety profile, gastrointestinal adverse events, the durability of treatment, cost-effectiveness, and comparative safety over the long term are still under consideration. This review will demonstrate the ability of GLP-1-based therapies to advance precision endocrinology and future metabolic medicine, by combining mechanistic insights, formulation innovation, and multi-organ therapeutic applications.
Background Non-alcoholic fatty liver disease (NAFLD) clinical phenotypes involve complex interactions between adiposity and diet. A particularly underexplored question is whether dietary quality differs across steatosis severity grades in clinically complex, high-risk cohorts with prevalent T2DM. We hypothesized that specific dietary patterns would be associated with disease severity, independent of anthropometric indices. Methods In this cross-sectional study, 160 adults with confirmed NAFLD were evaluated using structured questionnaires, anthropometric measurements, and a 108-item food frequency questionnaire. Steatosis severity (Grades 1–3) was determined by ultrasonography. Healthy Eating Index-2015 (HEI-2015), Dietary Inflammatory Index (DII), Potential Renal Acid Load (PRAL), and Plant-Based Diet Index (PDI) were computed. Hierarchical binary logistic regression was performed using complete-case analysis (n = 122), adjusting for sex, type 2 diabetes, and total energy intake. Results Body weight, BMI, and waist circumference increased significantly across steatosis grades (p < 0.001). No significant differences were observed in HEI-2015, DII, PRAL, or PDI across groups (p > 0.05), and none showed independent associations with steatosis grade in adjusted models. Dietary quality was uniformly suboptimal across all severity grades. Waist circumference was consistently associated with higher ultrasound-assigned steatosis grades across all models in this selected cohort (OR: 1.10, 95% CI: 1.05–1.16, p < 0.001), accounting for 27% of the variance explained by the base logistic model. Conclusion A key finding is that dietary quality was uniformly suboptimal across all steatosis severity grades, including the mildest stage, supporting consideration of nutritional assessment and intervention from early disease stages regardless of disease severity. In this highly selected clinical cohort with a high burden of metabolic comorbidities, waist circumference demonstrated a consistent independent association with ultrasound-defined steatosis grade. These findings should not be generalized beyond this specific metabolic phenotype.
Obesity is increasingly understood as a systemic immunometabolic disorder rather than only excess adipose accumulation. It disrupts gut microbial ecology, intestinal barrier integrity, immune signaling, and neuroinflammatory balance through the gut-immune-brain axis. Existing literature shows that obesity is associated with microbial dysbiosis, reduced short-chain fatty acids, altered bile acid signaling, metabolic endotoxemia, blood-brain barrier disruption, microglial activation, and inflammasome-mediated inflammation. However, these mechanisms are often reviewed separately, with limited integration of microbial metabolites, epithelial leakage, rare molecular pathways, neurovascular injury, biomaterial delivery, and genome-guided microbiota editing. This review is needed because obesity-related gut-immune-brain dysfunction arises from interacting biological networks rather than a single pathway. The article synthesizes microbiome remodeling, SCFA and bile acid imbalance, tryptophan-kynurenine dysregulation, NLRP3 inflammasome activation, BBB injury, neuroinflammatory cascades, smart biomaterials, CRISPR-guided microbial therapeutics, biomarker stratification, and translational readiness. The review concludes that future obesity therapies should move toward integrated microbiome-biomaterial strategies combining targeted delivery, metabolite restoration, immune control, microbial editing, and long-term safety monitoring. In real-world application, this framework can support personalized treatment design, safer gut-targeted delivery systems, and next-generation therapies for obesity-associated metabolic and neuroimmune complications.
Previous studies examining the association between serum Asprosin levels and metabolic syndrome (MetS) have produced inconsistent findings. The roles of general and abdominal obesity, and insulin resistance in this relationship remain unclear. Methods A cross-sectional study was performed to assess the association between Asprosin and metabolic syndrome in 146 participants with metabolic statuses ranging from normal blood glucose to type 2 diabetes. Asprosin concentrations were measured using an enzyme-linked immunosorbent assay (ELISA). Results No statistically significant difference in asprosin levels was observed between males and females. Among all participants, those with metabolic syndrome, representing 53% of the cohort, exhibited elevated Asprosin concentrations (P = 0.006 in women and p < 0.01 in men). Logistic regression analysis demonstrated that Asprosin significantly predicted elevated fasting blood glucose (P < 0.001),increased triglyceride levels (P < 0.05) and redused HDL cholesterol (P = 0.05 in both sexes after adjusting for age. Furthermore, Asprosin was associated with increased waist circumference in men. When metabolic syndrome was analyzed as a single condition, Asprosin remained a significant predictor in both men and women after adjusting for age, diabetes status, total cholesterol, and waist circumference (Odd Ratio (OR),3.48; 95% confidence interval [CI] 2.46 to 6.71; p = 0.001) for women and OR,3.22%:95%CI, 2.40 to 6.23for men. However, this association lost statistical significance after adjustment for the homeostasis model assessment of insulin resistance (HOMA-IR) in women (P = 0,072). In men, significance was also lost following adjustment for HOMA-IR (P = 0.083) Conclusion Asprosin is associated with specific components of metabolic syndrome rather than all aspects. It serves as an independent marker for metabolic syndrome, distinct from obesity. This relationship appears to be closely linked to insulin resistance, although causality cannot be inferred from the present cross-sectional design.
Purpose of Review Obesity and type 2 diabetes mellitus (T2DM) represent converging global epidemics demanding more targeted prevention strategies than population-averaged dietary guidelines can deliver. This review synthesises current evidence on gene-diet interactions as the molecular foundation of precision nutrition for T2DM prevention, critically evaluating how genetic stratification at key susceptibility loci particularly FTO, MC4R, PPARG, and TCF7L2 can inform individualised dietary intervention in high-risk populations. Recent Findings Large-scale GWAS meta-analyses have identified over 500 BMI-associated loci, and polygenic risk scores demonstrate robust independent associations with T2DM incidence across diverse populations. FTO risk allele carriers exhibit amplified adiposity under high-fat dietary exposures, while Mediterranean and higher-protein patterns substantially attenuate this disadvantage. PPARG Pro12Ala carriers demonstrate genotype-dependent lipid benefits from omega-3 supplementation, and TCF7L2 T allele carriers face markedly greater T2DM risk under high-glycaemic-load conditions while achieving greater glycaemic benefit from structured dietary intervention. Evidence from PREDIMED-Plus, POUNDS Lost, and Food4Me confirms dietary quality reduces T2DM risk equivalently across polygenic risk strata, though prospective genotype-concordant dietary assignment trials have not yet demonstrated superiority over standard approaches. Multi-omics integration and artificial intelligence-driven optimisation exemplified by the NIH Nutrition for Precision Health trial and a landmark 2025 phase III AI-powered diabetes prevention RCT represent the emerging translational frontier. Summary Gene-diet interactions at key susceptibility loci are biologically robust and clinically meaningful. Translating these findings equitably into scalable T2DM prevention requires purpose-designed phase III trials, cross-ancestry genomic research, multi-omics integration, and structural investment in equitable implementation across diverse populations globally.
Obesity is a complex, multifactorial metabolic disorder characterised by excessive adipose tissue accumulation, contributing to serious comorbidities including type 2 diabetes mellitus, cardiovascular disease, and chronic systemic inflammation. Conventional therapeutic approaches encompassing lifestyle modification, pharmacotherapy, and bariatric surgery remain limited by poor long-term adherence, systemic side effects, and insufficient tissue specificity. Nanotechnology has emerged as a transformative strategy to overcome these limitations, enabling targeted, controlled, and efficient delivery of therapeutic agents directly to adipose tissue. This review provides a comprehensive and critically integrated overview of nano-enabled therapeutic strategies for obesity, with particular emphasis on adipose tissue-targeted modulation and metabolic reprogramming. The biology of white, brown, and beige adipocytes is first examined to establish a mechanistic framework for therapeutic targeting. Subsequently, major nanocarrier platforms including lipid-based systems, polymeric nanoparticles, inorganic nanomaterials, biomimetic carriers, and stimuli-responsive smart nanocarriers are critically evaluated alongside active and passive targeting strategies. The roles of nanocarriers in delivering small-molecule drugs, gene-based therapeutics, nutraceuticals, and combination regimens are discussed. Safety considerations, translational barriers, and future directions including precision nanomedicine and artificial intelligence integration are also addressed.
