Search Results (154)

Introduction: Previous research has suggested thiazolidinediones (TZDs) may be associated with certain solid tumors. We examined incidence rates over time for patients with solid tumors who received TZD treatment for diabetes. Methods: We identified medication use and diagnosis codes that were aggregated to phecode disease classifications derived from the nationwide Veterans Administration Health Record System from 2000 to 2021. We identified 148,139 patients who had ≥2 diabetes diagnoses and had no previous cancer diagnosis. Among these, 8981 subjects had ≥4 years of TZD exposure. We then identified subjects with ≥2 diagnosis codes for solid tumors including bladder (n = 3987), breast (n = 632), colorectal (n = 5139), esophageal (n = 482), glioma (n = 591), lung (n = 5142), melanoma (n = 1896), pancreatic (n = 726), prostate (n = 11,884), renal (n = 3145), testicular (n = 369), and thyroid (n = 513). We used multivariable Cox proportional hazards regressions to measure associations between TZD use and cancer incidence. TZD use was modeled as a time-varying covariate from the first to last prescription of TZD medication, and analyses were adjusted for age at diabetes diagnosis, self-reported race, self-reported ethnicity, sex, body mass index, and cancer site-specific polygenic risk scores. Results: Long-term (≥4 years) exposure to TZDs was significantly associated with increased risk of developing prostate cancer (HR = 1.24, p < 0.001) and decreased risk of developing lung (HR = 0.58, p < 0.001), bladder (HR = 0.51, p < 0.001), and renal cancer (HR = 0.75, p = 0.003). Conclusions: Decreased risk of developing several solid tumors (lung, bladder, and renal) indicate that TZDs may be strong candidates for drug repurposing strategies to manage these types of cancer. These results warrant replication attempts in external datasets. Full article

Background/Objectives: Signaling mediators of PPARγ influence pathways involved in adipogenesis, lipid storage, inflammation, energy-related processes, and glucose utilization. Recent research indicates that PPARγ coregulators, recruited or released during ligand binding, govern specific gene pathways. It was recently discovered that Gα_q, a heterotrimeric G protein subunit, also signals to PPARγ and may significantly affect adipogenesis and glucose sensitivity. Methods: To explore Gα_q’s role in adipocytes, we generated CRISPR-mediated Gα_q (Gnaq) knockout (Gnaq KO) and scramble control cells from 3T3-L1 preadipocytes. Results: The absence of Gα_q resulted in increased lipid accumulation and elevated serine 273 (but not serine 112) phosphorylation of PPARγ. Gα_q deficiency also decreased mitochondrial abundance and respiration in response to PPARγ ligands such as rosiglitazone, pioglitazone, and troglitazone. RNA sequencing comparing differentiated Gnaq KO and control adipocytes identified over 800 differentially expressed genes, including those associated with enhanced lipid metabolism and reduced inflammation. Corresponding PamGene kinome profiling showed increased serine/threonine kinase activity and decreased phosphotyrosine kinase signaling in Gnaq KO adipocytes. Conclusions: These findings support Gα_q as a regulator of adipocyte function, linking kinase signaling pathways to PPARγ-mediated transcription. This research provides mechanistic insights into targeting Gα_q as a potential treatment for individuals with obesity and metabolic disorders. Full article

Hypertriglyceridemic acute pancreatitis (HTG-AP) progresses rapidly with poor prognosis. Intestinal barrier dysfunction and excessive oxidative stress contribute to its pathogenesis, but specific mediators linking gut injury, oxidative stress and pancreatic damage remain unclear. Here, we identify endogenous phenyllactic acid (PLA) as a critical metabolite regulating intestinal barrier integrity and oxidative homeostasis in HTG-AP. We noted serum PLA, a disease-associated metabolite whose reduction correlates with gut dysbiosis and pancreatic inflammation in HTG-AP. PLA supplementation in HTG-AP mice attenuated intestinal barrier dysfunction and mitigated intestinal oxidative stress, as evidenced by improved gut dysbiosis, reduced reactive oxygen species accumulation, restored superoxide dismutase activity, restored barrier integrity, reduced bacterial translocation to the pancreas, and decreased serum lipopolysaccharide levels, ultimately mitigating pancreatic injury. RNA sequencing of colonic tissue revealed peroxisome proliferator-activated receptor (PPAR) signaling as one of the most significantly altered pathways in HTG-AP. PPARγ expression was markedly reduced in colonic epithelial cells and upregulated upon PLA treatment. Knockdown of colonic epithelial PPARγ via adeno-associated virus abrogated the beneficial effects of PLA on intestinal barrier integrity, oxidative stress and pancreatic injury in HTG-AP mice. The protective effects of PLA were phenocopied by the PPARγ agonist rosiglitazone. Collectively, these findings identified gut microbiota-derived PLA as an endogenously derived metabolite modulating intestinal oxidative stress and barrier function. Using male C57BL/6J mice to establish an HTG-AP model, we further revealed that PLA exerts protective effects against HTG-AP by targeting colonic PPARγ to modulate the gut–pancreas axis, highlighting PLA as a promising candidate for targeted intervention in HTG-AP. Full article

Background: Recruitment and activation of monocyte-derived macrophages (MoMFs) sustain cholangitis in primary biliary cholangitis (PBC), but whether MoMFs amplify inflammation through ferroptosis remains unclear. We defined ferroptotic programs in MoMFs and evaluated the calpain/ACSL4 axis as a regulatory and therapeutic node. Methods: We analysed a public human liver single-cell RNA sequencing (scRNA-seq) dataset and examined MoMF-associated ACSL4 and 4-hydroxynonenal (4-HNE) signals in CD11b⁺CD68⁺ cells by multiplex immunofluorescence. We used a 2OA–BSA-induced PBC-like mouse model to assess liver injury, inflammation and ferroptosis-related markers and tested Liproxstatin-1 (Lip-1), rosiglitazone (ROSI) or the calpain inhibitor PD150606. Bone marrow-derived macrophages (BMDMs) from control and PBC mice were profiled and challenged with RSL3, with or without Ferrostatin-1 (Fer-1), ROSI or PD150606. Results: MoMFs were expanded in PBC livers and showed the strongest induction of ferroptosis signatures, centered on ACSL4, with enhanced inflammatory crosstalk with cholangiocytes. Human PBC tissues showed increased CD11b⁺CD68⁺ cells positive for ACSL4 or 4-HNE. In PBC-like mice, malondialdehyde (MDA) increased and glutathione (GSH) decreased, and macrophages showed greater colocalization with ferroptosis markers; Lip-1, ROSI or PD150606 improved liver biochemistry, reduced inflammation scores and limited macrophage infiltration. PBC-derived BMDMs upregulated ACSL4 and CAPN1/2 and were more sensitive to RSL3; Fer-1, ROSI or PD150606 attenuated ferroptosis-associated molecular changes. Conclusions: MoMF ferroptosis is prominently engaged in PBC, and our findings implicate a pharmacologically tractable calpain/ACSL4 axis that may contribute to macrophage ferroptotic susceptibility and inflammatory liver injury. Full article

Background/Objectives: Food allergy-induced intestinal inflammation can impair lactose digestion and absorption by damaging the epithelium, leading to secondary lactase deficiency with no effective treatments. The immunometabolism nuclear receptor PPAR-γ regulates gut epithelial function and nutrient absorption. This study aimed to determine whether PPAR-γ activation can preserve lactose digestion and absorption during allergic inflammation and to elucidate the underlying mechanisms. Methods: In an ovalbumin-sensitized Brown Norway rat model of food allergy, animals were treated with either the PPAR-γ agonist rosiglitazone or the antagonist GW9662. Lactose absorption was assessed by in vivo lactose tolerance tests (blood glucose monitoring) and intestinal transit measurements. Jejunal tissues were analyzed for lactase gene expression, lactase enzyme activity, and SGLT1/GLUT2 transporter levels. Results: Allergic rats exhibited reduced weight gain, delayed intestinal transit, and lactose malabsorption (lower blood glucose after lactose challenge), accompanied by sharply decreased jejunal lactase mRNA, enzyme activity, and SGLT1/GLUT2 levels. Rosiglitazone treatment restored intestinal PPAR-γ expression and markedly improved lactose absorption, normalizing the lactose tolerance curve. Rosiglitazone also increased lactase gene expression and enzyme activity, and upregulated SGLT1 levels. In contrast, PPAR-γ inhibition with GW9662 further reduced lactase and transporter levels and failed to improve absorption. Conclusions: PPAR-γ signaling maintains intestinal lactose digestive capacity of rats during allergic inflammation by sustaining lactase production and monosaccharide transporter expression. Our findings verify an immunometabolism mechanism linking nuclear receptor activation to enhanced nutrient absorption and highlight PPAR-γ agonism as a promising therapeutic strategy to alleviate food allergy-associated lactose malabsorption. Full article

Familial partial lipodystrophy type 3 (FPLD3) is a rare autosomal dominant disorder caused by mutations in peroxisome proliferator-activated receptor gamma(PPARG), which encodes the key adipogenic transcription factor peroxisome proliferator-activated receptor gamma(PPARγ). Clinical diagnosis is challenging due to phenotypic overlap with common metabolic syndromes. We identified a novel PPARG variant in a Chinese family and performed comprehensive functional characterization to elucidate its pathogenic mechanism. The proband, a 15-year-old boy presenting with atypical fat distribution, severe insulin resistance, hypertriglyceridemia, and pancreatitis, underwent clinical evaluation and whole-exome sequencing. The identified variant was confirmed by Sanger sequencing. Its functional impact was assessed through in silico modeling, luciferase reporter assays, protein stability analysis (cycloheximide chase), and evaluation of mitochondrial function (JC-1 staining) and adipocyte gene expression in cellular models. A heterozygous PPARG c.634C>T (p.Arg212Trp, R212W) variant was identified and segregated with the phenotype. Functional studies revealed that the R212W mutant exhibits a partial loss of transcriptional activity (~40% of wild-type) while retaining ligand sensitivity. Crucially, we demonstrated that the mutant protein has significantly reduced stability due to accelerated degradation. In adipocyte models, R212W expression led to impaired mitochondrial membrane potential, depleted cellular ATP levels, and downregulated expression of key metabolic genes (glucose transporter 4[GLUT4], adiponectin[ADIPOQ], fatty acid binding protein 4[FABP4], lipoprotein lipase[LPL], perilipin 1[PLIN1]). These functional deficits were partially rescued by treatment with the PPARγ agonist rosiglitazone. We report a novel pathogenic PPARG R212W variant associated with FPLD3. Our data extend beyond a simple loss-of-function model by establishing a multi-faceted pathogenic mechanism involving protein destabilization, mitochondrial dysfunction, and cellular bioenergetic failure. The partial rescue by rosiglitazone suggests a potential therapeutic avenue. This study underscores the importance of integrating clinical phenotyping with deep functional analysis to diagnose and understand rare monogenic lipodystrophies. Full article

Chemotherapy-induced neuropathic pain (CINP) can be caused by several chemotherapeutic drugs, including paclitaxel, oxaliplatin, and vincristine, which is difficult to treat with several drugs, including antidepressants and anticonvulsants. The patho-mechanisms of CINP are not completely understood. However, they showed oxidative stress, mitochondrial damage, ion channel damage, and immunological dysfunction. Acting as a key regulator of antioxidant responses, nuclear factor erythroid 2-related factor 2 (Nrf2) decreased oxidative stress and mitochondrial damage. In addition, it plays a role in inhibiting nuclear factor kappa B (NF-κB). A systematic, English-only search of MEDLINE (PubMed) was performed for studies on Nrf2, chemotherapy, and neuropathic pain from database inception through 1 December 2024. Several Nrf2 activators, including tempol, oltipraz, rosiglitazone, pristimerin, cannabidiol, daidzein, bardoxolone methyl, curcumin, resveratrol, and mitoquinone, demonstrated analgesic effects in CINP animal models. Furthermore, in clinical studies, curcumin demonstrated significant efficacy in reducing vincristine-induced neuropathy in pediatric leukemia patients, while the combined administration of alpha-lipoic acid with ipidacrin hydrochloride prevented paclitaxel-induced motor neuropathy and improved axonal function in breast cancer patients. Thus, the purposes of our review article were to summarize the analgesic effects of Nrf2 activators and the patho-mechanisms of Nrf2 in CINP animal, and then the consequences for clinical trials were presented. Full article

Dietary fats are consumed as mixtures, yet it remains unclear whether fatty acid composition, independent of fat content, dictates human macrophage polarization. We compared two defined mixtures containing identical fatty acids (palmitic, oleic, and linoleic acids) in different ratios: a palmitate-enriched mixture (4:3:3) and an unsaturated fat-dominant mixture (2:4:4). In primary human monocyte-derived macrophages, palmitate enrichment increased CD14+CD11b+HLA-DR+ pro-inflammatory polarization, whereas the unsaturated fat-dominant mixture increased CD14+CD11b+CD163+ anti-inflammatory polarization. Mechanistic studies in THP-1-derived macrophages recapitulated these phenotype shifts and identified a reciprocal nuclear-receptor program: palmitate enrichment induced peroxisome proliferator-activated receptor gamma (PPARγ), together with ER-stress mediators EIF2AK3 and DDIT3, while the unsaturated fat-dominant mixture preferentially induced PPARα and IRF4. Pharmacologic modulation demonstrated functional dependence on PPARγ: GW9662 attenuated palmitate-driven M1-like polarization, whereas rosiglitazone disrupted the protective program under unsaturated fat-dominant conditions. These findings show that fatty acid composition, at equivalent total lipid concentration, is a dominant determinant of human macrophage inflammatory fate and highlight PPARγ as a context-dependent lipid sensor. Full article

Brown adipose tissue (BAT) has emerged as a promising therapeutic target for metabolic disorders such as type 2 diabetes and obesity. To advance research on BAT activation and elucidate the mechanisms underlying adipogenesis, it is crucial to develop a reliable in vitro model. This study aimed to optimize the differentiation of adipose-derived stem cells (ADSCs) into beige adipocytes and to validate the protocol using primary human ADSCs obtained from eight donors. Protocol optimization was first performed with commercial ADSCs, testing more than 30 combinations of adipogenic conditions. Differentiation was assessed by microscopy, Oil Red O staining, and uncoupling protein 1 (UCP1) expression via reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot. Among the key adipogenic factors, rosiglitazone proved more effective than indomethacin. Extending the induction phase from 4 to 8 days and maintaining dexamethasone throughout the culture markedly enhanced differentiation efficiency. Serum concentration above 5% was inhibitory, while optimal conditions were identified as 5 μM rosiglitazone and 20 μg/mL insulin. The optimized protocol successfully induced beige adipogenesis in ADSCs from eight independent donors, though efficiency varied considerably which could be attributed to individual donor variability. These findings provide a robust in vitro model for studying beige fat biology and highlight the relevance of personalized approaches in metabolic research. Full article

Objectives: The repurposing of existing drugs as anticancer agents has attracted attention in cancer drug discovery. This study aimed to examine the anticancer efficacy of rosiglitazone (RSG) against cholangiocarcinoma (CCA) and its underlying mechanisms. Methods: The effect of RSG on the viability of KKU-100 CCA cells was examined. The possible molecular targets were identified using proteomic analysis and verified by a series of cell-based assays. Furthermore, the expression of PPARγ protein in CCA tissues was also assessed. Results: RSG exhibited a cytotoxic effect against KKU-100 cells. Proteomic analysis demonstrated a significant different expression protein pattern of the 100 μM RSG-treated group compared to the control group. Significant alteration of several proteins was found, including the up-regulation of calcium-binding, cytoskeletal, and metabolic proteins, concomitant with the down-regulation of antioxidant enzymes. Detailed analyses revealed that RSG induced apoptosis in CCA cells, accompanied by increased caspase 3/7 activities, reactive oxygen species (ROS) generation, and disruption of mitochondrial function. RSG altered the expressions of annexin A1 and antioxidant enzymes, according to Western blot analysis. GW9662, a PPARγ antagonist, did not affect the viability and apoptosis of KKU-100 cells caused by RSG. Immunohistochemistry analysis revealed that PPARγ expression in CCA patients was associated with sex, but not with other common clinicopathological parameters. Its expression did not correlate with patients’ overall survival time. Conclusions: RSG induced apoptotic cell death in CCA cells, which was accompanied by increased ROS levels and impaired antioxidant defense. Its apoptosis-inducing effect is independent of PPARγ activation. These findings underscore the therapeutic potential of RSG for CCA treatment. Full article

Thermogenic adipocytes present a promising therapeutic strategy for metabolic diseases. While murine models have provided valuable insights into thermogenic adipose tissue, their relevance to human physiology is constrained by species-specific differences in tissue distribution and thermogenic capacity. In vitro human models offer a more controlled platform to study adipocyte differentiation, addressing challenges such as limited access to deep fat depots and individual variability. This systematic review summarizes the current literature on human in vitro models for thermogenic adipocyte induction, encompassing 117 studies involving primary human adipocyte progenitors differentiated into thermogenic adipocytes in 2D cultures. Most studies relied on classical adipogenic inducers, including isomethylbutylxanthine, dexamethasone, and insulin, with additional use of triiodothyronine, rosiglitazone, or indomethacin. A few studies incorporated adrenergic stimulation or exposure to lower temperatures to simulate cold exposure. Notably, some studies demonstrated successful differentiation under serum-free, chemically defined conditions, highlighting their potential for reproducibility and translational relevance. A key limitation remains the predominant reliance on gene expression as the primary outcome, with few studies assessing mitochondrial respiration or broader metabolic functions. Moving forward, the development and adoption of standardized, functionally validated protocols will be critical to fully realize the potential of human in vitro thermogenic adipocyte models in metabolic research. Full article

Background/Objectives: Rosiglitazone (RSG), a potent PPARγ agonist for type 2 diabetes mellitus (T2DM), induces adverse adipogenic effects that limit clinical use. We investigated whether emodin (1,3,8-trihydroxy-6-methylanthraquinone, EMO), a natural anthraquinone, mitigates RSG-induced complications while enhancing its insulin-sensitizing benefits in severe obesity. Methods: Male ob/ob mice with established obesity and diabetes were treated for 4 weeks with RSG (10 mg kg⁻¹ day⁻¹), EMO (200 or 400 mg kg⁻¹ day⁻¹) or their combination. Metabolic profiling, organ function, and adipose histology were analyzed. RNA sequencing and mechanistic studies (Western blot, RT-qPCR, luciferase assays) in inguinal subcutaneous adipose tissue (iSAT), epididymal white adipose tissue (eWAT), and 3T3-L1 adipocytes were used to define EMO’s actions. Results: EMO co-treatment dose-dependently reduced RSG-induced weight gain, visceral adiposity (iSAT and eWAT mass, p < 0.05), and ectopic lipid deposition while ameliorating hepatorenal dysfunction. EMO synergistically enhanced RSG’s glucose-lowering effects. Mechanistically, EMO suppressed sterol regulatory element-binding protein 1 (SREBP1)-mediated lipogenesis (Srebp1, Acc, Fasn, Scd1; p < 0.05) and enhanced PPARγ-peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α)-driven thermogenesis via enhanced PPARγ transactivation and nuclear translocation. Thermogenic genes (Ucp1, Ppargc1a, Cidea; p < 0.05) were upregulated, with maximal uncoupling protein 1 (UCP1) induction in iSAT at 400 mg/kg EMO. Conclusions: EMO selectively enhances RSG’s glycemic benefits while attenuating its adipogenic effects in severe obesity by dual PPARγ modulation-inhibiting adipogenic pathways while amplifying thermogenesis. This strategy mitigates RSG’s adverse effects while improving insulin sensitivity, supporting the potential of EMO as a PPARγ adjunct therapy. Full article

Cancer and ageing remain major challenges for humanity, requiring innovative solutions. While the role of mitochondria in cancer and ageing has been extensively studied, peroxisomes have received comparatively little attention in this context. In our study, we investigated the impact of peroxisomes on cancer stemness. We systematically analysed the metabolic differences between MCF-7 cells with low- and high-peroxisome levels. Briefly, MCF-7 cells were stably transduced with GFP- and RFP-fluorescent reporters that were targeted to peroxisomes, by addition of a C-terminal SKL (Serine-Lysine-Leucine) peroxisomal targeting signal. To independently validate our observations, MCF-7 cells were also treated with Rosiglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist that enhances peroxisome levels. Key parameters examined included cancer stemness, levels of reactive oxygen species (ROS), cell division dynamics, autophagy activity, the DNA damage response, susceptibility to ferroptosis, mitochondrial respiration, and aerobic glycolysis in cells with low- and high-peroxisome profiles. Our results demonstrated that elevated peroxisome levels significantly decrease the capacity of breast cancer stem cells (BCSCs) to form mammospheres or colonies, thus reducing their stemness potential. In high-peroxisome cells, Mammosphere formation was reduced by approximately 50%, and colony formation by 80% compared to low-peroxisome cells. This decline in stemness was accompanied by an approximately one-and-a-half-fold increase in ROS levels and a five-fold increase in lipid peroxidation, reflecting increased mitochondrial lipid peroxidation and ferroptosis. Continued research is, however, essential to further validate these findings and to elucidate the underlying mechanisms. Full article

Two previously undescribed highly oxygenated cembrane-type diterpenes, namely sarcocraol A (1) and sarcocraol B (2), along with five known compounds (3–7), have been isolated from the soft coral Sarcophyton crassocaule collected off Ximao Island in the South China Sea. Their structures were determined through comprehensive spectroscopic analysis, QM-NMR calculations, TDDFT-ECD computation, X-ray diffraction analysis, and by comparison with literature data. Plausible biosynthetic pathways for these compounds were also proposed. All compounds were evaluated for peroxisome proliferator-activated receptors (PPARs) transcriptional activity using luciferase assay. The bioassay results demonstrated that compound 1 exhibits selective PPAR-γ agonistic activity. Furthermore, it promoted glucose uptake in HepG2 cells by 1.18-, 1.45-, and 1.90-fold at concentrations of 2.5, 5, and 10 μM, respectively, whereas rosiglitazone (10 μM) produced a 2.47-fold increase over the induced control. Compound 1 at 10 μM induced mild lipid accumulation in 3T3-L1 cells, showing a 1.63-fold increase relative to the control, which was much lower than the 3.28-fold increase observed in rosiglitazone (10 μM) group indicating its potential antidiabetic properties. These findings suggested that compound 1 could be a promising lead for the development of antidiabetic agents. Full article

Background/Objectives: Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder characterized by insulin resistance, impaired insulin secretion, and chronic hyperglycemia. Recent studies have identified microRNAs (miRNAs), a class of small non-coding RNAs that regulate gene expression at the post-transcriptional level, as modulators of pathways involved in T2DM pathophysiology. Dysregulated miRNA expression has been detected in various samples collected from patients with T2DM, implicating these molecules in disease onset and progression. Methods: We systematically searched PubMed, Scopus, and Web of Science for studies published from the earliest available records to 18 August 2025 using the following Boolean search terms: “miRNA AND gliclazide”, “miRNA AND glibenclamide”, “miRNA AND gliquidone”, “miRNA AND glimepiride”, “mirRNA AND metformin”, “miRNA AND pioglitazone”, “miRNA AND rosiglitazone”, “miRNA AND sitagliptin”, “miRNA AND vildagliptin”, “miRNA AND alogliptin”, “miRNA and saxagliptin”, “miRNA AND linagliptin”, “miRNA AND liraglutide”, “miRNA and dulaglutide”, “miRNA AND semaglutide”, “miRNA AND tirzepatide”, “miRNA AND lixisenatide”, “miRNA AND empagliflozin”, “miRNA AND dapagliflozin”, miRNA AND insulin glargine”, “miRNA AND insulin detemir”, “miRNA AND insulin degludec”, “miRNA AND insulin aspart”, “miRNA AND insulin glulisine”, and “miRNA AND insulin lispro”. Additionally, gray literature was searched in ClinicalTrials.gov, the EU Clinical Trials Register (EudraCT), and the ISRCTN Registry to identify unpublished studies. Studies were eligible for inclusion if they were clinical interventional studies assessing the impact of currently available antidiabetic treatments on miRNA expression. Only articles published in English were considered. The risk of bias was evaluated using the RoB2 (Risk of Bias 2) and ROBINS-I (Risk Of Bias In Non-randomized Studies—of Interventions) tools. Study characteristics and major findings were tabulated. Results: A total of 1263 manuscripts was identified initially. After removing duplicates, 726 articles remained for further screening. Ultimately, 17 manuscripts reporting interventional clinical trials on the effects of antidiabetic treatment on miRNA were included, encompassing a total of 1093 patients. Key findings included treatment-associated changes in miRNA expression and their potential utility for the prediction of clinical outcomes. Conclusions: Current evidence supports the hypothesis that antidiabetic treatments modulate miRNA expression, with some findings showing predictive value for metabolic outcomes. However, the available data remain limited and of low grade of certainty, and further large-scale clinical studies are needed to provide deeper insights into these associations. Full article