Polyendocrine metabolic ovarian syndrome (PMOS), previously known as polycystic ovary syndrome, affects 10%-13% of women of reproductive age and remains underdiagnosed despite its substantial health burden. The introduction of the new PMOS nomenclature in 2026 reflects a fundamental shift in understanding the condition as a lifelong endocrine and metabolic disorder with prominent reproductive, psychological, dermatological, and cardiometabolic consequences. Once considered primarily a reproductive disorder, PMOS is now recognized as a multisystem condition. Insulin resistance and compensatory hyperinsulinemia are central pathophysiological mechanisms linking endocrine and metabolic features to reproductive dysfunction. In PMOS, insulin resistance affects 75% of lean and 95% of overweight women. Here we focus on the metabolic features. Recent advances in epidemiology include the first systematic review and meta-analysis examining regional variations in PMOS prevalence. In parallel, contemporary population-based studies of unselected women have confirmed that increased risks of metabolic complications observed in selected clinical cohorts also apply at the population level and have demonstrated increased risk of major adverse cardiovascular events (MACE). These studies report an almost 3-fold increased risk of Type 2 diabetes (OR 2.9) and MACE (HR 1.2-2.5), with cardiovascular risk diverging from approximately 35 years of age. In this review, we summarize recent advances in epidemiology, pathophysiology, metabolic dysfunction, and cardiovascular risk of PMOS, together with their implications for diagnosis and clinical management. Recognizing PMOS as an early-life marker of cardiometabolic disease highlights opportunities for earlier diagnosis, prevention, and individualized risk stratification, supporting integrated, patient-centered care across the life course.

Regulation of skeletal muscle glucose uptake is an effective strategy for reducing postprandial hyperglycemia and improving whole-body glucose homeostasis in the management of type 2 diabetes. The present study investigated that cardamom enhances glucose uptake in skeletal muscle in vitro and improves glucose tolerance in vivo. Bioactivity-guided fractionation of cardamom identified an ethyl acetate fraction (Fr. A) and its subfraction (Fr. A-i) as potent stimulators of glucose uptake in L6 myotubes. Both fractions significantly promoted glucose uptake by enhancing glucose transporter type 4 (GLUT4) translocation to the plasma membrane. Mechanistic investigations revealed activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, accompanied by increased phosphorylation of Akt substrate of 160 kDa (AS160), a key regulator of GLUT4 vesicle trafficking, while no significant changes were observed in insulin receptor substrate-1 (IRS-1) or AMP-activated protein kinase (AMPK) phosphorylation. Fr. A induced a more pronounced effect on AS160 phosphorylation and was therefore selected for further evaluation. The antihyperglycemic potential of Fr. A was assessed in ICR mice using an oral glucose tolerance test. Oral administration of Fr. A (1 and 10 mg/kg body weight) significantly improved glucose tolerance and alleviated postprandial hyperglycemia. Cardamom in skeletal muscle and highlights its potential as a natural therapeutic candidate for the management of postprandial hyperglycemia.

A balanced diet has been associated with a lower risk of total and cardiovascular mortality. One intermediate function linking a balanced diet and lower mortality may be optimal insulin secretion. We examined the association between adherence to the Japanese Food Guide Spinning Top (JFGST) and serum C-peptide concentration, an indicator of basal insulin secretion, in a cross-sectional study in a Japanese population, in whom rice (refined grains) is the staple food. A blood sample was collected in November 2012 and a 12-d weighed food record was collected over the subsequent year. A total of 210 healthy residents aged 35-80 y (83 men, 127 women) were included in the analysis. Multiple regression analysis was performed with log-transformed serum C-peptide concentration as dependent variable and total JFGST score or each score by category of dish as independent variable, with adjustment for age and BMI. In both men and women, total JFGST score was inversely associated with serum C-peptide concentration. Slope in the percentage of differences for every 1-point score addition based the regression coefficients was -2.3% (p<0.001) in men and -1.6% (p<0.001) in women. For specified categories of dishes, scores for grain dishes, snacks and alcoholic beverages, and total energy were inversely associated with serum C-peptide concentrations among men. Among women, in contrast, scores for milk and for fruit were inversely associated with serum C-peptide concentrations. A balanced diet consistent with the JFGST was inversely associated with serum C-peptide concentration among middle-aged Japanese.

Creatine supplementation can improve muscle outcomes in older adults, particularly when combined with resistance exercise; however, its efficacy without exercise is less consistent. Guanidinoacetic acid (GAA), the immediate precursor of creatine, may bypass age-related limitations in creatine synthesis and transport and exert distinct effects on muscle energetics and protein metabolism. The main aim of the study was compare the effects of 8 wk of GAA versus creatine supplementation on muscle strength, body composition, and selected protein metabolism biomarkers in older adults. In this randomized, double-blind, exploratory pilot trial, 25 apparently healthy adults aged ≥65 y were assigned to receive GAA (2.0 g/d) or an equimolar dose of creatine monohydrate for 8 wk. Twenty-one participants completed the study (GAA, n=11; creatine, n=10). Handgrip strength, body composition and fluid compartments (via multifrequency bioelectrical impedance analysis), and circulating myostatin, insulin-like growth factor-1, mammalian target of rapamycin, total homocysteine, albumin, and total protein were assessed at baseline and follow-up. Intervention effects were evaluated using repeated-measures ANOVA, and between-group effect sizes for change scores were estimated using Hedges' g with 95% confidence intervals. Handgrip strength increased significantly with GAA (p=0.01) but not with creatine, with a significant time-by-treatment interaction (p=0.04) and a large between-group effect favoring GAA (g=0.91, 95% CI: 0.00 to 1.81). GAA supplementation was associated with significant within-group increases in fat-free mass, body cell mass, muscle mass, and total body water, whereas creatine supplementation did not produce comparable changes. Effect size analyses generally favored GAA for strength, muscle-related indices, and hydration-related compartments, although confidence intervals were wide. Both supplements reduced circulating myostatin, with greater suppression observed with GAA. Creatine supplementation produced a modest reduction in serum albumin that remained within physiological reference ranges. Serum IGF-1 concentrations were below the assay detection limit in most participants, precluding evaluation of the GH-IGF-1 axis. No adverse events were reported, and compliance exceeded 97% in both groups. In this exploratory pilot trial conducted without structured exercise, GAA supplementation was associated with numerically greater improvements in muscle strength and several muscle-related indices compared with creatine; however, these findings are preliminary and hypothesis-generating and require confirmation in adequately powered trials targeting sarcopenia.

Src homology region 2-containing phosphatase 1 (SHP-1), encoded by the protein tyrosine phosphatase non-receptor type 6 (PTPN6), regulates immune and metabolic signaling pathways. Although its functions in immune cells and insulin-responsive tissues are separately established, its integrative function in immunometabolic regulation remains unclear. A damaging variant in the PTPN6 gene (Ala455Thr) was discovered in a French-Canadian family and found to be the cause of early-onset emphysema. Using mice carrying this whole-body human-relevant mutation, we studied immunometabolic phenotypes across aging. Old mutant mice showed decreased body, liver and adipose tissue weights, improved glucose tolerance, and enhanced hepatic insulin sensitivity. Despite improved metabolic parameters, aged mutant mice developed liver abnormalities, including increased fibrosis and aberrant immune cell infiltration. Transcriptomic and histological analyses revealed an age-associated accumulation of intrahepatic B lymphocytes and macrophages, accompanied by increased SHP-1 protein levels and activation of Signal transducer and activator of transcription 3 (STAT3) signaling. Experiments in primary hepatocytes and old hepatocyte-specific Ptpn6 knockout mice suggest that these alterations are driven by immune rather than intrinsic hepatocyte mechanisms. These findings identify SHP-1 as a critical modulator of liver immune homeostasis during aging and demonstrate that immune cell infiltration contributes to age-related hepatic remodeling under SHP-1 deficiency.

Diabetes is a chronic disease characterized by hyperglycemia. It is associated with a variety of co-morbidities, including depression. This link is likely mediated in part by hyperglycemia-induced increases in inflammation. Given that exercise can benefit diabetes, inflammation, and depression, the aim of this study was to investigate if exercise may treat hyperglycemia-induced neuroinflammation and depressive-like behavior. We used the STZ model of hyperglycemia in male C57BL/6J mice and voluntary wheel running as exercise. To circumvent possible STZ-induced issues with wheel running, we provided mice with wheels for 10 days prior to STZ. Unexpectedly, we observed that 10 days of wheel access was sufficient to blunt development of STZ-induced hyperglycemia as well as most STZ-induced behavioral and inflammatory effects. Mice continued to show mild hyperglycemia, impaired glucose tolerance, and intermediate levels of insulin. No significant behavioral differences were observed. Increases in liver Tnf mRNA expression, but not TNF protein, were noted without changes in Il6 or Il1b. There were no changes in hippocampal Tnf or Il1b. We observed an interesting interaction for Bdnf, such that exercise increased expression in VEH but not STZ mice. This may indicate a neural response to mild hyperglycemia, though additional studies are required to confirm this effect. Overall, these data suggest that 10 days of voluntary exercise is sufficient to blunt STZ-induced hyperglycemia. This model may be useful in investigating the chronic effects of pre-diabetic blood glucose levels on brain health.

A major recent breakthrough in the treatment of type 2 diabetes has been the development of glucagon-like peptide-1 receptor agonists (GLP-1RAs). However, current translational frameworks struggle to predict the clinical outcomes of these drugs from preclinical data. Several challenges contribute to this struggle and are relevant to many drugs: GLP-1RAs act through multi-timescale mechanisms in which short-term effects propagate into long-term changes, no single preclinical system can capture all their effects in humans, and mechanistic extrapolation requires modelling numerous whole-body biological processes. To address this gap, we present a new extrapolation approach, M4 drug discovery, and retrospectively apply it to the GLP-1RA exenatide in a manner that is generalisable to other drugs. The method integrates: multi-level data (cellular to whole-body), multi-timescale data (minutes to months), multi-species data (e.g., rodents to humans), and mechanistic knowledge. In this study, we integrate human cell and animal data with drug-free human studies to successfully predict human pharmacokinetics (cost < χ², p=0.05; 64 < 97) and the outcomes of a 30-week clinical trial (36 < 45). We found that integrating information across the four M4 axes improved predictive performance and physiological relevance: multi-species data inform pharmacokinetics, human cell data provide human population- and donor-specific potency estimates, animal data reveal additional drug effects not observable in cell cultures, and the multi-timescale mathematical modelling enables short-term effects of exenatide and meals to inform long-term changes in insulin sensitivity. This work provides a new framework for translational drug development, supporting safer and more informed preclinical-to-clinical translation.

Semaglutide (SMG) is a glucagon-like peptide-1 receptor agonist with a promising efficacy and safety profile that is widely used for reducing obesity by targeting the appetite control centres in the brain and for type 2 diabetes management by enhancing insulin release and suppressing glucagon secretion. SMG is currently administered subcutaneously that is invasive with reduced patient compliance or orally leading to decreased efficacy owing to first-pass effects. In this study, a nanoparticle (NP) formulation of SMG was developed using a thermoresponsive and biocompatible synthetic polymer, PNPHO (poly(N-isopropylacrylamide-co-(N-acryloxysuccinimide)-co-(polylactide/-hydroxy methacrylate)-co-(oligo (ethylene glycol)), to investigate its potential to enhance nasal mucosal absorption and prolong residence time via the needle-free intranasal (IN) route. The NP formulation was characterized in vitro for physicochemical parameters, stability, mucoadhesion, regional nasal deposition, drug release profile, and cellular permeation, and in vivo for glucose sensitivity and biodistribution. Monodispersed NPs displayed an average size of 26.14 ± 0.19 nm, a negative surface charge with high SMG encapsulation (89%), improved stability against enzymatic degradation and increased permeation across nasal epithelial cells in vitro compared to SMG alone (p < 0.0001). In contrast, it reduced transport across hCMEC/D3 BBB cells. Nasal cast studies revealed greater NP deposition in the turbinates compared to the free drug. In vivo, the NP formulation demonstrated prolonged nasal retention of the formulation within the sinus region along with an improved glucose tolerance with a 24 h dosing regimen, showing an extended period of pharmacological activity that can be utilized for reducing dosing frequency. No detectable brain fluorescence was observed in vivo. Overall, these findings corroborate the potential of IN delivery of thermoresponsive SMG-PNPHO NP formulation with increased efficacy compared to current SMG delivery modes.

Growing public interest in incretin-based therapies for weight loss has been accompanied by increasing availability of research peptides purchasable online. Products may be used without medical assessment or counselling regarding adverse effects, sick-day management or appropriate follow-up. In addition, composition, purity and dosing accuracy may be uncertain. Retatrutide is a novel triple agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 and glucagon receptors currently being investigated for obesity and type 2 diabetes mellitus, but has no established role in type 1 diabetes mellitus. We report a man in his mid-30s with longstanding type 1 diabetes mellitus who presented with severe vomiting, diarrhoea, hyperglycaemia, ketonaemia and acute kidney injury shortly after self-administering an online-purchased product marketed as retatrutide for weight loss. His partner, who had taken the same preparation, also developed gastrointestinal symptoms. Both had also consumed a potential foodborne source of infection. In type 1 diabetes mellitus, where patients remain dependent on exogenous insulin to suppress ketogenesis, gastrointestinal illness may rapidly precipitate ketosis when insulin is omitted and oral intake is reduced. Although diabetic ketoacidosis did not develop, peak ketonaemia reached 4.3 mmol/L in the setting of dehydration and insulin omission, requiring intravenous insulin and fluid replacement. During recovery, recurrent hypoglycaemia required intravenous dextrose and insulin dose adjustment, highlighting challenges of glycaemic management in acutely unwell patients exposed to agents with incretin and glucagon receptor activity. Stool culture subsequently grew Shigella flexneri, introducing diagnostic uncertainty regarding the relative contributions of gastrointestinal infection and retatrutide exposure, and complicating counselling regarding future retatrutide use. While causation cannot be established, the temporal relationship, similar symptoms in another exposed individual, and recognised gastrointestinal adverse-effect profile of retatrutide suggest that exposure may have contributed to symptom severity or amplified the metabolic consequences of infection. This case highlights diagnostic and management challenges created by unregulated research peptides obtained outside healthcare pathways, particularly in patients with type 1 diabetes mellitus where evidence to guide management is limited and clinicians in non-specialist settings may be unfamiliar with these agents. As access expands through online vendors and social media, clinicians should routinely enquire about prescribed and non-prescribed agents when assessing unexplained illness or metabolic decompensation.

Recent studies have shown that adipose tissue (AT) secretes elevated levels of extracellular vesicles (EVs) in obesity, and these EVs play roles in metabolic diseases. The inhibition of calpains has anti-inflammatory and anti-fibrotic effects on AT in mice and reduces EV secretion in some cell types in vitro. However, its effects on human AT and adipocyte EV secretion remain unexplored. This study aimed to investigate calpeptin's effects on EV-mediated communication and adipocyte function, offering potential insights into therapeutic approaches for metabolic diseases. Human Simpson Golabi Behmel Syndrome (SGBS) preadipocytes were differentiated and treated with calpeptin. EVs were isolated by standard ultracentrifugation, and studied by nanoparticle tracking analysis, electron microscopy, and mass spectrometry. Diverse analyses, including RNA-sequencing, liquid chromatography-mass spectrometry (LC-MS), and confocal microscopy were utilized to study calpeptin's effects on SGBS cells. AT samples from bariatric surgery patients were cultured ex vivo to assess calpeptin's effects on primary AT. We demonstrated for the first time that calpeptin reduces EV secretion in human SGBS adipocytes. Proteomic analyses revealed that calpeptin alters the abundances of proteins related to EV secretory pathways. While reduced EV secretion was accompanied by anti-inflammatory effects, calpeptin also altered insulin signalling pathways and reduced adiponectin expression, suggesting negative effects on adipocyte metabolism. Indeed, LC-MS analyses of cells and EVs revealed that calpeptin altered proteins-both in cells and EVs-that are associated with stress responses. Notably, calpeptin upregulated HO-1 in vitro and in ex vivo AT cultures, indicating induced oxidative stress in adipocytes and AT. While calpeptin shows anti-inflammatory promise in human SGBS adipocytes, its adverse effects on insulin signalling, adiponectin expression, and signs of oxidative stress raise concerns about its therapeutic potential against obesity-related pathologies in humans. Our results highlight the need to understand the broader impact of calpeptin on adipocyte metabolism.