Search Results (2,363)

For a few decades, Type 2 Diabetes (T2D) has been recognized as a worldwide public health issue. T2D relies on systemic insulin resistance leading to Beta cell dysfunction. Nowadays, lifestyle modifications, such as improving eating habits and increasing physical activity, represent the first recommendations for managing T2D. Physical exercise, as a structured physical activity, is now considered as a non-pharmacological treatment with a wide range of beneficial effects, especially for people living with T2D. The review intends to summarize the current knowledge of physical exercise benefits in a context of T2D: from “unwanted” adipose tissue reduction to Beta cell health improvement. Moreover, we try to suggest an underlying mechanism explaining physical exercise beneficial effects in the context of T2D focusing on exerkines, molecules secreted in response to physical exercise. With this review, we highlight the beneficial impact of post-exercise secretions on Beta cell health and encourage research to continue in this direction. Identifying new exerkines with beneficial effects in the context of T2D could represent a promising approach for managing metabolic diseases. 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

Chaya leaf has long been used in folk medicine and is gaining scientific interest for its potential role in diabetes management. Recent research indicates that chaya leaf may help to regulate glucose, enhance insulin secretion, and reduce related complications, primarily due to the presence of bioactive compounds such as polyphenols and flavonoids. These compounds are believed to enhance insulin sensitivity and offer protection against oxidative stress, a key contributor to diabetes-related complications. Chaya extracts, particularly methanolic and aqueous forms, have shown anti-diabetic effects in animal models, lowering blood glucose, cholesterol, and triglycerides and reducing inflammation; their bioactive compounds, like quercetin, rutin, and ferulic acid, may enhance the insulin response, reduce inflammation, and improve antioxidant activity. Some studies warn of potential interactions with metformin. This review compiles findings from the past five years, drawing from databases such as PubMed, SciELO, ScienceDirect, Dialnet, Web of Science, and Google Scholar. It highlights chaya’s phytochemical profile, explores proposed anti-diabetic mechanisms, and summarizes evidence from in vivo, in vitro, and clinical studies. The results indicate that adding chaya leaf to the diet may help people with diabetes as a complementary therapy to conventional treatment; nonetheless, further clinical studies are required to comprehend the exact mechanisms and define specific usage instructions. Further investigation into the specific types of compounds present in chaya, their effective dosages, and their safety in human populations is essential to support its integration into medical practice. Full article

Diabetes, a major global healthcare challenge, is characterized by chronic hyperglycemia and significantly exacerbates the severity of systemic complications. Iron, an essential element ubiquitously present in biological systems, is involved in many biological processes facilitating cell proliferation and growth. However, excessive iron accumulation promotes oxidative damage through the Fenton reaction, thereby increasing the incidence of diabetes and worsening diabetic complications. Notably, ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a key mechanism underlying diabetes and diabetic complications. In this review, we provide an update on the current understanding of iron metabolism dysregulation in diabetes risk, and disclose the mechanistic links between iron overload and diabetes evidenced in hereditary hemochromatosis and thalassemia. We particularly highlight iron-mediated oxidative stress as a central nexus impairing glucose metabolism and insulin sensitivity. Furthermore, we discuss the significance of dysmetabolic iron and ferroptosis activation in the progression of diabetes and diabetic complications, as well as the possible application of natural products for iron metabolism regulation and ferroptosis-inhibition-targeted therapeutic strategies to treat diabetes and diabetic complications. Full article

Sarcopenia is a prevalent and disabling complication of chronic kidney disease (CKD), associated with frailty, diminished quality of life, and increased morbidity and mortality. Despite its clinical significance, no pharmacological treatments are currently approved to address muscle wasting in this population. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used in the management of type 2 diabetes and obesity, have shown potential to support muscle mass and function through pleiotropic mechanisms. These include anti-inflammatory and antioxidant actions, improvements in insulin sensitivity and energy metabolism, and mitochondrial support. Given the high burden of sarcopenia in CKD and the frequent overlap with metabolic and cardiovascular comorbidities, GLP-1RAs may offer a novel therapeutic approach. This review examines the biological plausibility and emerging evidence supporting the role of GLP-1RAs in preserving muscle health in CKD, highlighting the need for targeted clinical trials and mechanistic investigations to establish their efficacy in this high-risk group. Full article

Background/Objectives: The transcription factor 7-like 2 (TCF7L2) rs7903146 polymorphism has been strongly associated with type 2 diabetes mellitus (T2DM) in various populations; however, its impact on different ethnic groups is not fully understood. Given the distinct minor allele frequency in Chinese populations, this study aimed to analyze the association of rs7903146 with the risk of T2DM in a Han Chinese cohort and its relationship with relevant clinical parameters. Methods: We conducted a case–control study including 600 patients with type 2 diabetes mellitus (T2DM) and 511 sex-matched non-diabetic controls of Han Chinese descent. The TCF7L2 rs7903146 (C/T) polymorphism was genotyped using a TaqMan™ SNP assay. Clinical parameters, including body mass index (BMI), fasting plasma glucose, hemoglobin A1c, lipid profile, and high-sensitivity C-reactive protein (hs-CRP), were compared between genotypes. Logistic regression analyses were performed under a dominant genetic model (CT/TT vs. CC), adjusting for age, sex, systolic and diastolic blood pressure, BMI, and smoking status. Subgroup analyses were conducted by sex, BMI category, age at diagnosis, and family history of T2DM. Given the exploratory nature of this study and the low frequency of the TT genotype, no formal correction for multiple testing was applied. Results: Frequencies of the CT and TT genotypes were higher in the diabetic group (p = 0.045) and were significantly associated with an increased risk of T2DM under a dominant genetic model (adjusted OR = 2.24, p = 0.025). Individuals with CT/TT genotypes had elevated fasting glucose and hs-CRP levels; these genotypes were also linked to higher BMI in the female T2DM patients. The T allele frequency varied across ethnic groups, being lowest in East Asians and highest in Latin (Brazilian/mixed ancestry) populations. Mechanistically, the T allele may contribute to T2DM via altered TCF7L2 expression, impaired insulin secretion, inflammation, and metabolic dysregulation. Conclusions: The TCF7L2 rs7903146 T allele was associated with an increased risk of T2DM and higher fasting glucose and hs-CRP levels in this Han Chinese cohort. The CT/TT genotypes were also associated with higher BMI in the female T2DM patients. While the findings are consistent with the known effects of this variant in other populations, mechanistic hypotheses such as the involvement of inflammatory or metabolic pathways remain hypothetical and warrant further functional validation. Full article

Insulin resistance is a key driver of metabolic disorders, including type 2 diabetes and non-alcoholic fatty liver disease (NAFLD), progressing to non-alcoholic steatohepatitis (NASH). This study investigated the effects of geniposide (GP) on insulin sensitivity and hepatic fibrosis in a high-fat diet (HFD)-induced NASH model. C57BL/6 mice were fed an HFD for five weeks and subsequently divided into normal chow (NC), HFD, HFD with GP 50 mg/kg (GP50), and HFD with GP 100 mg/kg (GP100) groups. The treatments were administered orally for 12 weeks. GP treatment significantly reduced body weight as well as epididymal fat and liver weights, while no differences were observed in food intake. Improvements in glucose and lipid metabolism were observed in oral glucose tolerance tests, homeostatic model assessment of insulin resistance (HOMA-IR), and blood lipid profiles. Histological analyses revealed that GP suppressed adipocyte hypertrophy and hepatic lipid accumulation and hepatic fibrosis. To further elucidate molecular mechanisms of GP, quantitative real-time polymerase chain reaction (qRT-PCR) analysis was conducted in the liver tissue. GP downregulated expression of inflammatory markers, including F4/80, tumor necrosis factor (TNF)-α, and interleukin (IL)-6. GP treatment modulated genes involved in insulin signaling including Janus kinase 2 (JAK2), insulin receptor (INSR), insulin receptor substrate 2 (IRS-2), and protein kinase B (AKT1) gene expression levels. This suggests GP suppresses inflammation and mitigates insulin resistance by activating the INSR–IRS2–Akt pathway. Additionally, GP enhanced adenosine monophosphate-activated protein kinase (AMPK) expression, suggesting its potential role in improving glucose and lipid metabolism. In conclusion, GP improves insulin resistance, inflammation, and hepatic fibrosis, highlighting its therapeutic potential for NASH and related metabolic disorders. Full article

Type 2 diabetes (T2D) is a complex metabolic disease characterized by chronic hyperglycemia due to insulin resistance and inadequate insulin secretion. Beyond the classically implicated organs, emerging evidence highlights the gut as a central player in T2D pathophysiology through its interactions with metabolic organs. The gut hosts trillions of microbes and enteroendocrine cells that influence inflammation, energy homeostasis, and hormone regulation. Disruptions in gut homeostasis (dysbiosis and increased permeability) have been linked to obesity, insulin resistance, and β-cell dysfunction, suggesting multifaceted “Gut-X axes” contribute to T2D development. We aimed to comprehensively review the evidence for gut-mediated crosstalk with the pancreas, endocrine system, liver, and kidneys in T2D. Key molecular mechanisms (incretins, bile acids, short-chain fatty acids, endotoxins, etc.) were examined to construct an integrated model of how gut-derived signals modulate metabolic and inflammatory pathways across organs. We also discuss clinical implications of targeting Gut-X axes and identify knowledge gaps and future research directions. A literature search (2015–2025) was conducted in PubMed, Scopus, and Web of Science, following PRISMA guidelines (Preferred Reporting Items for Systematic Reviews). Over 150 high-impact publications (original research and review articles from Nature, Cell, Gut, Diabetologia, Lancet Diabetes & Endocrinology, etc.) were screened. Data on gut microbiota, enteroendocrine hormones, inflammatory mediators, and organ-specific outcomes in T2D were extracted. The GRADE framework was used informally to prioritize high-quality evidence (e.g., human trials and meta-analyses) in formulating conclusions. T2D involves perturbations in multiple Gut-X axes. This review first outlines gut homeostasis and T2D pathogenesis, then dissects each axis: (1) Gut–Pancreas Axis: how incretin hormones (GLP-1 and GIP) and microbial metabolites affect insulin/glucagon secretion and β-cell health; (2) Gut–Endocrine Axis: enteroendocrine signals (e.g., PYY and ghrelin) and neural pathways that link the gut with appetite regulation, adipose tissue, and systemic metabolism; (3) Gut–Liver Axis: the role of microbiota-modified bile acids (FXR/TGR5 pathways) and bacterial endotoxins in non-alcoholic fatty liver disease (NAFLD) and hepatic insulin resistance; (4) Gut–Kidney Axis: how gut-derived toxins and nutrient handling intersect with diabetic kidney disease and how incretin-based and SGLT2 inhibitor therapies leverage gut–kidney communication. Shared mechanisms (microbial SCFAs improving insulin sensitivity, LPS driving inflammation via TLR4, and aryl hydrocarbon receptor ligands modulating immunity) are synthesized into a unified model. An integrated understanding of Gut-X axes reveals new opportunities for treating and preventing T2D. Modulating the gut microbiome and its metabolites (through diet, pharmaceuticals, or microbiota therapies) can improve glycemic control and ameliorate complications by simultaneously influencing pancreatic islet function, hepatic metabolism, and systemic inflammation. However, translating these insights into clinical practice requires addressing gaps with robust human studies. This review provides a state-of-the-art synthesis for researchers and clinicians, underlining the gut as a nexus for multi-organ metabolic regulation in T2D and a fertile target for next-generation therapies. Full article

Pituitary pars intermedia dysfunction (PPID) is a common, slowly progressive, neurodegenerative disorder of the older horse. Oxidative damage to the hypothalamic periventricular neurons results in loss of dopaminergic inhibition of the pars intermedia region of the pituitary gland. Consequently, there is increased production of the pro-opiomelanocortin (POMC)-derived hormones normally produced by this region, as well as initial melanocyte hypertrophy and hyperplasia, followed by adenomatous change. Clinical signs that are highly suggestive of the disease are generalised and regional hypertrichosis and delayed/abnormal coat shedding. Numerous clinical signs provide a moderate clinical suspicion, including hyperhidrosis, abnormal fat distribution/regional adiposity, epaxial muscle atrophy/loss of topline, laminitis, weight loss, recurrent infections, behavioural changes/lethargy, polyuria and polydipsia, a pot-bellied appearance, bulging supraorbital fat pads, reduced wound healing, lordosis and infertility. In all animals, a diagnosis of PPID is made based on the signalment, clinical signs and results of further diagnostic tests, with age being a crucial factor to consider. Currently recommended further diagnostic tests are measurement of basal adrenocorticotrophic hormone (ACTH) concentrations (all year) and evaluation of the ACTH response to thyrotrophin-releasing hormone (TRH) using seasonally adjusted references intervals (non-autumn). Animals should also be tested for insulin dysregulation, as laminitis risk in PPID is associated with hyperinsulinaemia. PPID can be managed but not cured; it is a lifelong condition. The individual clinical signs can be managed, e.g., clipping the excessive haircoat and providing unrestricted access to water for individuals with polydipsia. Alternatively, pharmacological management can be employed, and the dopamine-2 receptor agonist pergolide is licensed/approved for the treatment of equine PPID. This should be prescribed in combination with dietary recommendations based on the body condition score and insulin sensitivity status of the individual animal. Full article

The pregnane X receptor (PXR), a ligand-activated nuclear receptor, plays a central role in regulating the metabolism of both endogenous substances and xenobiotics. In recent years, increasing evidence has highlighted its involvement in chronic diseases, particularly metabolic disorders and cancer. PXR modulates drug-metabolizing enzymes, transporters, inflammatory factors, lipid metabolism, and immune-related pathways, contributing to the maintenance of hepatic–intestinal barrier homeostasis, energy metabolism, and inflammatory responses. Specifically, in type 2 diabetes mellitus (T2DM), PXR influences disease progression by regulating glucose metabolism and insulin sensitivity. In obesity, it affects adipogenesis and inflammatory processes. In atherosclerosis (AS), PXR exerts protective effects through cholesterol metabolism and anti-inflammatory actions. In metabolic dysfunction-associated steatotic liver disease (MASLD), it is closely associated with lipid synthesis, oxidative stress, and gut microbiota balance. Moreover, PXR plays dual roles in various cancers, including hepatocellular carcinoma, colorectal cancer, and breast cancer. Currently, PXR-targeted strategies, such as small molecule agonists and antagonists, represent promising therapeutic avenues for treating metabolic diseases and cancer. This review comprehensively summarizes the structural features, signaling pathways, and gene regulatory functions of PXR, as well as its role in metabolic diseases and cancer, providing insights into its therapeutic potential and future drug development challenges. Full article

Microbial metabolites offer a multitude of mechanisms for alleviating diabetes, particularly type 2 diabetes (T2D). However, the metabolites of yeasts recognised as safe remain under-explored and are receiving less attention in the treatment of T2D. In addition to the recognised probiotic status of certain yeasts, their genetic feature is responsible for many of the effects observed. Branched and non-branched short-chain fatty acids, bioactive peptides, carotenoids, and polysaccharides (β-glucans, mannans, and peptides derived from them) have vital properties that modulate intestinal permeability, soothe inflammation, and directly influence insulin sensitivity. Their action mechanism ranges from hepatic lipogenesis via the induction of hormone-sensitive lipase and the inhibition of α-glucosidase or DPP-IV to promoting the secretion of GLP-1 (Glucagon-Like Peptide-1) and GIP (Gastric Inhibitory Polypeptide), orchestrating immune modulation, and nourishing the gut microbiota. The richness of the yeast metabolome suggests that a concentrated fermentate could be developed to potentiate the functional effects in vitro in the treatment of T2D. The purpose of this review is to take stock of the current state of knowledge of probiotic yeast metabolites and outline their potential for the treatment of diabetes via the development of food supplements or nutraceuticals. Full article

Autonomic dysfunction of the stomach typically manifests as delayed gastric emptying or gastroparesis and is seen in individuals with both type 1 and 2 diabetes. However, impaired gastric motility is only modestly associated with the presence of upper gastrointestinal symptoms, and the diagnosis of gastroparesis essentially requires a formal measurement of gastric emptying, ideally employing a sensitive and precise technique such as scintigraphy. There is a bidirectional relationship between gastric emptying and glycemia: insulin-induced hypoglycemia accelerates, while acute elevations in blood glucose may delay gastric emptying. On the other hand, relatively more rapid emptying is associated with a higher initial rise in postprandial glucose. The management of gastroparesis requires an individualized approach, integrating dietary modifications, nutritional supplementation, pharmacological therapies, and, in severe cases, advanced interventions including gastrojejunostomy and gastric electrical stimulation. This review provides an overview of the pathophysiology and diagnosis of autonomic neuropathy of the diabetic stomach and discusses current clinical management strategies. Full article

(1) Background: Following the discovery of the adipokine/hormone asprosin, a substantial amount of research has provided evidence for its role in the regulation of glucose homeostasis, as well as appetite, and insulin sensitivity. Its levels are dysregulated in certain disease states, including breast cancer. To date, little is known about its role in endometrial cancer (EC). The present study investigated the effects of asprosin on the transcriptome of the Ishikawa and NOU-1 EC cell lines, and assessed the expression of asprosin’s candidate receptors (TLR4, PTPRD, and OR4M1) in health and disease. (2) Methods: tissue culture, RNA extraction, RNA sequencing, reverse transcription-quantitative PCR, gene enrichment and in silico analyses were used for this study. (3) Results: TLR4 and PTPRD were significantly downregulated in EC when compared to healthy controls. TLR4 appeared to have a prognostic role in terms of overall survival (OS) in EC patients (i.e., higher expression, better OS). RNA sequencing revealed that asprosin affected 289 differentially expressed genes (DEGs) in Ishikawa cells and 307 DEGs in NOU-1 cells. Pathway enrichment included apoptosis, glycolysis, hypoxia, and PI3K/AKT/ mTOR/NOTCH signalling for Ishikawa-treated cells. In NOU-1, enriched processes included inflammatory response, epithelial-mesenchymal transition, reactive oxygen species pathways, and interferon gamma responses. Other signalling pathways included mTORC1, DNA repair, and p53, amongst others. (4) Conclusions: These findings underscore the importance of understanding receptor dynamics and signalling pathways in the context of asprosin’s role in EC, and provide evidence for a potential role of TLR4 as a diagnostic biomarker. Full article

Type 2 diabetes (T2D), a growing global health concern, is closely linked to obesity and sedentary behavior. Central to its development are insulin resistance and impaired glucose metabolism in peripheral tissues, particularly skeletal muscle, which plays a key role in energy expenditure, glucose uptake, and insulin sensitivity. Notably, increased accumulation of lipid metabolites in skeletal muscle is observed both in endurance exercise—associated with improved insulin sensitivity—and in high-fat diets that induce insulin resistance. The review examines the contrasting metabolic adaptations of skeletal muscle to these opposing conditions and highlights the key signaling molecules involved. The focus then shifts to the role of the stress kinase p38α mitogen-activated protein kinase (MAPK) in skeletal muscle adaptation to overnutrition and endurance exercise. p38α enhances mitochondrial oxidative capacity and regulates nutrient utilization, both critical for maintaining metabolic homeostasis. During exercise, it cooperates with AMP-activated protein kinase (AMPK) to boost glucose uptake and fatty acid oxidation, key mechanisms for improving insulin sensitivity. The co-activation of p38α and AMPK in skeletal muscle emerges as a promising therapeutic avenue to combat insulin resistance and T2D. The review explores strategies for selectively enhancing p38α activity in skeletal muscle. In conclusion, it advocates a comprehensive approach to T2D prevention and treatment, combining established caloric intake-reducing therapies, such as GLP-1 receptor agonists, with interventions aimed at increasing energy expenditure via activation of p38α and AMPK signaling pathways. Full article

Per- and polyfluoroalkyl substances (PFASs) are widespread in the environment, bioaccumulate in humans, and lead to disease and organ injury, such as liver steatosis. However, we lack a clear understanding of how these chemicals cause organ-level toxicity. Here, we aimed to analyze PFAS-induced metabolic perturbations in male and female rat livers by combining a genome-scale metabolic model (GEM) and toxicogenomics. The combined approach overcomes the limitations of the individual methods by taking into account the interaction between multiple genes for metabolic reactions and using gene expression to constrain the predicted mechanistic possibilities. We obtained transcriptomic data from an acute exposure study, where male and female rats received a daily PFAS dose for five consecutive days, followed by liver transcriptome measurement. We integrated the transcriptome expression data with a rat GEM to computationally predict the metabolic activity in each rat’s liver, compare it between the control and PFAS-exposed rats, and predict the benchmark dose (BMD) at which each chemical induced metabolic changes. Overall, our results suggest that PFAS-induced metabolic changes occurred primarily within the lipid and amino acid pathways and were similar between the sexes but varied in the extent of change per dose based on sex and PFAS type. Specifically, we identified that PFASs affect fatty acid-related pathways (biosynthesis, oxidation, and sphingolipid metabolism), energy metabolism, protein metabolism, and inflammatory and inositol metabolite pools, which have been associated with fatty liver and/or insulin resistance. Based on these results, we hypothesize that PFAS exposure induces changes in liver metabolism and makes the organ sensitive to metabolic diseases in both sexes. Furthermore, we conclude that male rats are more sensitive to PFAS-induced metabolic aberrations in the liver than female rats. This combined approach using GEM-based predictions and BMD analysis can help develop mechanistic hypotheses regarding how toxicant exposure leads to metabolic disruptions and how these effects may differ between the sexes, thereby assisting in the metabolic risk assessment of toxicants. Full article