Search Results (1,091)

Mitochondrial dysfunction contributes to female reproductive endocrine disorders and is frequently associated with multisystem symptoms. Insulin resistance (IR) is a common metabolic disorder strongly linked to polycystic ovary syndrome (PCOS), while premature ovarian insufficiency (POI) also impairs fertility. Mitochondrial DNA (mtDNA) deletions and the stress-responsive cytokine growth differentiation factor 15 (GDF-15) have recently emerged as complementary biomarkers of mitochondrial impairment. In this retrospective observational study, we examined reproductive hormones, plasma GDF-15, mtDNA deletions, and clinical symptoms in insulin-resistant women, including those with PCOS or POI. Eighty-one patients were divided into three subgroups: IR-only (n = 49), IR-PCOS (n = 19), and IR-POI (n = 13). IR was defined based on elevated insulin levels during oral glucose tolerance testing (>10 mU/L at 0 min, >50 mU/L at 60 min, >30 mU/L at 120 min) according to national gynecological endocrinology guidelines, acknowledging that IR is not universally accepted as a distinct clinical entity. POI was defined as reduced ovarian reserve before age 40 with anti-Müllerian hormone (AMH) <1.0 ng/mL. Clinical symptoms were assessed using a questionnaire, medical record, and physical examination. MtDNA deletions were detected by long-range PCR, and GDF-15 was measured by ELISA. Free thyroxine (T4) emerged as an independent predictor of GDF-15, suggesting that thyroid function modulates mitochondrial stress signaling in insulin-resistant women. MtDNA deletions and/or elevated GDF-15 correlated with endocrine, gastrointestinal, and neuropsychiatric symptoms, and reduced AMH/FSH ratios indicated impaired ovarian function. Cross-sectional analysis further revealed lower AMH and AMH/FSH ratios in older women with mtDNA deletions, consistent with a trend toward accelerated reproductive aging. Overall, these findings support the role of GDF-15 and mtDNA deletions as complementary biomarkers of mitonuclear stress, with potential relevance for both systemic and reproductive health. Full article

Transcranial direct current stimulation (tDCS) is being explored as an adjunct for diabetes-related symptoms grounded in diabetes-associated alterations in brain networks. We reviewed clinical trials of tDCS conducted in people with diabetes and summarized mechanistic findings relevant to metabolic control. Two reviewers searched PubMed/MEDLINE, Cochrane Library, Google Scholar, Scopus, and ResearchGate for studies published from 1 January 2008 to 31 August 2025. Forty-one records were identified; after screening and full-text assessment, 11 studies met the inclusion criteria. Across predominantly middle-aged adults with long-standing type 2 diabetes, protocols were low-intensity and well-tolerated. The most consistent clinical benefit was analgesia with primary motor cortex stimulation, with randomized comparisons favoring active tDCS over sham. Dorsolateral prefrontal stimulation paired with working-memory training improved cognition and reduced anxiety, while combined motor–prefrontal courses yielded gains in sleep quality and health-related quality of life; a small, randomized study in proliferative diabetic retinopathy reported short-term visual improvements after occipital stimulation. Safety was favorable, and no serious adverse events were reported. Objective metabolic endpoints in diabetic cohorts were scarce; early evidence for insulin-independent improvements in glucose handling and neurometabolic shifts derives mainly from non-diabetic or mixed samples and remains hypothesis-generating. Overall, tDCS appears to be a promising, well-tolerated adjunct for diabetes-related complications. Larger, rigorously sham-controlled trials that align targets with clinical phenotypes and include standardized metabolic outcomes are needed. Full article

Akkermansia muciniphila—a mucus-resident commensal—has emerged as a promising target at the interface of metabolism, barrier function, and immunity. Observational human studies link higher intestinal abundance of A. muciniphila with healthier adiposity and glycemic profiles, while preclinical experiments demonstrate causal benefits on adiposity, insulin resistance, gut-barrier integrity, and inflammatory tone. These effects are attributed to mucus-layer reinforcement, reduced intestinal permeability and endotoxemia, production of short-chain fatty acids, and host signaling by defined bacterial components. In a randomized proof-of-concept trial in overweight/obese insulin-resistant adults, pasteurized A. muciniphila was safe and well-tolerated and improved insulin sensitivity and total cholesterol versus placebo; live cells showed directionally favorable but non-significant trends. A separate multicenter randomized trial of a five-strain consortium that included A. muciniphila improved post-prandial glucose and HbA1c in type 2 diabetes, supporting translational potential while underscoring the need for strain-resolved studies. Evidence for liver and cardiovascular benefits is strong in animals (e.g., MASLD and atherosclerosis models) but remains preliminary in humans. Inter-individual response heterogeneity—potentially influenced by baseline Akkermansia levels and gut-barrier status—highlights the value of personalized, microbiome-guided approaches. Larger, longer clinical studies are now warranted to define optimal dosing and formulation (live vs. pasteurized), durability, safety across populations, and impacts on hard outcomes (clinically meaningful weight change, glycemic endpoints, and cardiometabolic events). Overall, A. muciniphila represents a promising microbial adjunct for metabolic health with a plausible path from postbiotic concepts to clinical application, pending confirmatory trials. Full article

Diabetes mellitus is largely driven by oxidative stress that disrupts insulin signaling, leading to failure in insulin-mediated glucose absorption. Exploration of natural bioactive compounds is fueled by their promising role in correcting redox imbalance. This study aims to investigate the antidiabetic effect of the methanolic extract of Praecitrullus fistulosus, potentially by transcriptional modulation in streptozotocin–nicotinamide-induced diabetic rats. Male Wistar albino rats (n = 36) were assigned to six groups: normal control; diabetic control; standard drug group; and three treatment groups receiving P. fistulosus extract orally at doses of 200, 400, and 600 mg/kg body weight, respectively, for 30 consecutive days. Diabetes was induced in all groups, except for normal control, by intraperitoneal co-administration of streptozotocin and nicotinamide. Nicotinamide (100 mg/kg) was injected 15 min prior to a single dose of streptozotocin (50 mg/kg). Baseline and endpoint assessments of weight and blood glucose levels were performed. Blood was processed to assess insulin-related indices, lipid profile, and oxidative stress markers. q-PCR and Western blotting were utilized to explore the underlying molecular mechanisms. The diabetic control-group rats exhibited impaired glucose tolerance due to the marked reduction in serum insulin levels, compromised β-cell function, and substantial rise in lipid profile and oxidative stress parameters. Oral administration of P. fistulosus methanolic extract effectively mitigated these alterations in a dose-dependent manner, accompanied by the upregulation of both gene and protein expression involved in the insulin-signaling cascade. Full article

Background/Objective: Aging is associated with a decline in metabolic health, including impaired glucose regulation. Both diet and biological sex impact metabolic health, yet sexual heterogeneity in diet response is understudied. We report on exploratory analyses of sex-specific associations between diet and insulin sensitivity, insulin resistance, and android and intermuscular fat composition in older adults. Methods: This secondary analysis uses baseline data from a previously completed clinical trial (n = 96), the MASTERS study. An oral glucose tolerance test (OGTT) was used to calculate insulin resistance and insulin sensitivity as measures of metabolic function, while dual-energy x-ray absorptiometry and computed tomography were used to assess body composition. Univariate analyses were used to identify sex-specific associations between metabolic health and single nutrients, as well as other dietary components. Feasible solutions algorithm (FSA) modeling was employed to identify food groups that were most associated with insulin sensitivity. Results: In men, greater intakes of vegetable protein (p < 0.0001) and whole grains (p = 0.001) were associated with higher insulin sensitivity, while refined grains (p = 0.003) and conjugated linoleic acids (p < 0.001) were negatively associated. In women, insulin sensitivity was positively associated with alcohol (p < 0.001) and xylitol (p = 0.007). FSA modeling identified whole grains, nuts, and seeds as food groups that predicted higher insulin sensitivity in men, while alcohol remained the strongest predictor in women. Conclusions: Men showed higher insulin sensitivity with plant-based diets, while alcohol intake was the dietary factor most associated with insulin sensitivity in women. The findings of these exploratory analyses support the need for sex-specific clinical trials and dietary guidance for aging populations. Full article

Background: Oral semaglutide is the first oral GLP-1 receptor agonist approved for treating patients with type 2 diabetes mellitus (T2DM). This real-world retrospective study evaluated its effectiveness and tolerability in patients requiring a third-line antidiabetic agent due to poor glucoregulation. Methods: Adult patients with T2DM who were taking oral semaglutide and were monitored at tertiary diabetes centers in Croatia were identified through electronic medical records between October 2022 and December 2024. Patients’ data were included in the analysis if they had been on oral semaglutide for at least six months. Results: A total of 163 patients (72 females and 91 males) were recruited, with 96.9% classified as overweight or obese. Among them, 145 had a BMI greater than 30 (mean BMI: 34.18 ± 4.60). The addition of oral semaglutide to their treatment regimen resulted in significant reductions in BMI, HbA1c, and both postprandial and fasting blood glucose levels, as well as in AST and ALT levels (all p < 0.05). There was also an increase in HDL levels (p = 0.007). The side effects observed were consistent with those previously recognized. Conclusions: This study demonstrates that oral semaglutide is safe and effective for glycemic and extraglycemic management in a real-world setting when used as a third-line agent. The best outcomes in terms of weight and HbA1c reduction can be expected when it is introduced early, ideally within the first five years of diabetes duration, and particularly in patients who are insulin naive. Full article

Background/Objectives: Plants and fruits of Physalis philadelphica Lam. Solanacea are commonly used in traditional medicine to improve some illnesses such as diabetes, in North and Central American countries. The aim was to evaluate the effects of aqueous maceration (He-M) and ultrasound-assisted (He-US) extracts of P. philadelphica husk on hyperglycemia, insulin resistance, hepatic steatosis, and oxidative stress in obese rats. Methods: The effects of husk extracts on carbohydrate and lipid absorption were evaluated using oral starch and lipid tolerance tests in healthy male Wistar rats. Obesity was then induced using a high-fructose and saturated fat diet, followed by 16 weeks of extract administration. Results: He-US significantly reduced the postprandial glycemic spike, while both extracts lowered serum triglyceride levels (~50%) following lipid loading, compared with the negative control. In obese rats, both extracts reduced body weight gain (~10%) and lowered fasting glucose levels (22% for He-M and 15% for He-US), compared with the obese control. He-US also reduced insulin levels (~32%), insulin resistance (~53%), and free fatty acids (~52%), while He-M improved hepatic steatosis and reduced liver triglycerides (~26%). Both extracts reduced hepatic nitrite levels, although only He-M significantly decreased lipid peroxidation (~32%). Additionally, both treatments enhanced hepatic antioxidant enzyme activity. Conclusions: Husk extracts exerted beneficial effects on hyperglycemia, insulin resistance, hepatic steatosis, and oxidative stress markers in obese rats. Full article

Obesity has become increasingly prevalent, impacting up to 41 percent of women in the United States between 2021 and 2023, leading to a rise in short- and long-term adverse health events. With regard to reproductive health, obesity is associated with menstrual irregularities, poorer reproductive and obstetric outcomes, and an increased risk of endometrial cancer. Obesity can lead to hyperandrogenism and anovulation, which is consistent with polycystic ovarian syndrome (PCOS). The prevalence of obesity is higher in women with PCOS compared to the general population. Although PCOS increases the risk of obesity, not all women with PCOS are obese, and not all women with obesity develop PCOS. However, individuals with both PCOS and obesity often present with a more extreme phenotype, with increased risk of chronic anovulation, glucose intolerance, dyslipidemia, metabolic syndrome, vitamin D deficiency, and decreased fertility. Therefore, weight loss is the backbone of patient management in women with obesity and PCOS, and is associated with improvement in cardiovascular risk, as well as improvement in menstrual cycles, ovulation, and pregnancy rate. Lifestyle modifications are often the first-line intervention, with data supporting low glycemic index diets, including ketogenic and DASH diets, along with vitamin D supplementation to improve hormonal imbalances, insulin sensitivity, and menstrual cycles in those who do not have normal vitamin D levels. Furthermore, with the recent widespread adoption of newer FDA-approved medications for weight loss, including GLP-1 (glucagon-like peptide) receptor agonists, new data are emerging regarding the impact of PCOS and longer-term cardiovascular risk. The treatment of PCOS requires a personalized approach, with consideration of a patient’s reproductive goals, tolerance of risk, and acceptance of behavioral and financial commitments, as well as consideration of other medical comorbidities. This narrative review explores different weight loss treatment options, comparing lifestyle modifications (including diet, physical activity, mindfulness, stress management, and cognitive behavioral training), weight loss medications, and bariatric surgery and their respective impact on PCOS to assist clinicians in guiding their patients towards an effective, individualized intervention. Full article

Objectives: Although angiopoietin-like 4 (ANGPTL4) is highly associated with glucose hemostasis and lipid metabolism, the relationships between the serum ANGPTL4 level, glucose status and hepatic steatosis remain unclear. Therefore, this study aimed to quantify the independent effects of glucose intolerance and hepatic steatosis on circulating ANGPTL4 concentrations. Methods: A total of 348 age- and sex-matched participants with normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and newly diagnosed diabetes (NDD) with or without hepatic steatosis were recruited for this cross-sectional study. Serum ANGPTL4 levels were measured, and multivariate linear regression analysis was used to evaluate the relationship between ANGPTL4, glycemic status and hepatic steatosis. Results: Compared with NGT, both IGT and NDD were associated with significantly higher serum ANGPTL4 concentrations, irrespective of hepatic steatosis status. Serum ANGPTL4 did not differ by the presence versus absence of hepatic steatosis. In multiple regression analysis, body mass index, homeostasis model assessment of insulin resistance, NGT vs. IGT, and NGT vs. NDD were independently associated with ANGPTL4 levels after adjustment for cardiovascular risk factors and adiponectin, whereas hepatic steatosis was not. Conclusions: Elevated serum ANGPTL4 concentrations were independently associated with prediabetes and diabetes, irrespective of hepatic steatosis. Full article

Background/Objectives: The objective of this study was to assess the diagnostic accuracy of the Triglyceride-Glucose (TyG) index for screening gestational diabetes mellitus (GDM) at 24–28 weeks of gestation, to determine its optimal diagnostic threshold, and to compare its predictive performance with conventional lipid ratios (LDL/HDL, TG/HDL, and TC/HDL). Materials and Methods: We retrospectively analyzed 440 pregnant women with singleton pregnancies who underwent a 75 g oral glucose tolerance test (OGTT) between January and July 2025. The TyG index and lipid ratios were calculated, and their associations with GDM were evaluated. Subgroup analyses were conducted to assess the efficacy of the TyG index in predicting GDM, using logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs), and receiver operating characteristic (ROC) curve analysis along with restricted cubic spline modeling to evaluate diagnostic performance and determine the optimal cutoff value. Results: The overall prevalence of GDM, as defined by the IADPSG (International Association of the Diabetes and Pregnancy Study Groups) criteria, was 22.7%. The median TyG index was significantly higher in the GDM group compared with the non-GDM group (9.1 vs. 8.9, p = 0.001). The TyG index was a significant predictor of GDM (p < 0.05), with each one-unit increase associated with significantly higher odds of GDM (OR = 12.29), after adjusting for covariates. ROC analysis demonstrated an AUC of 0.716 (95% CI: 0.627–0.793, p < 0.001) for the TyG index, and the optimal cut-off value was identified as 9.35, yielding a sensitivity of 38.5% and a specificity of 96.5% and a negative predictive value of 83.7%. Subgroup analyses indicated that the TyG index had limited discriminative ability for predicting GDM in both the post-load and insulin-requiring groups. Among conventional lipid ratios, TG/HDL demonstrated the highest predictive performance (AUC = 0.587), while LDL/HDL (AUC = 0.483) and TC/HDL (AUC = 0.509) demonstrated low predictive accuracy. Compared with conventional lipid ratios, the TyG index demonstrated superior predictive performance. Conclusions: A higher TyG index was positively associated with the development of GDM and showed better predictive ability than conventional lipid ratios. However, its low sensitivity limits its use as a standalone diagnostic tool, suggesting it may be most useful when combined with other clinical parameters. Full article

Background/Objectives: Dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetic agents that regulate blood glucose by preventing the degradation of active incretin hormones. Although clinically effective, this drug class is associated with adverse effects, creating the need for new molecular scaffolds with improved safety and efficacy. Methods: We evaluated the antihyperglycemic activity of β-aminohydrazine and β-amino-N-acylhydrazone derivatives (LASSBio-2123, 2125, 2129, and 2130) using a combined in vivo and in silico approach. Male C57BL/6 mice underwent glucose tolerance tests (GTT) and dexamethasone-induced insulin resistance protocols. Hepatic and skeletal muscle glycogen levels, as well as GLUT4 mRNA expression, were quantified. In silico studies included ADMET predictions and molecular docking analyses against aldose reductase and glucokinase enzymes. MTT was performed on the pancreatic cell line MIN6 (Mus musculus). Results: Among the compounds tested, LASSBio-2129 demonstrated the most promising profile, with favorable ADMET parameters, metabolic stability, and high docking affinity for aldose reductase and glucokinase. In vivo, LASSBio-2129 (10 mg/kg, i.p.) reduced blood glucose, increased hepatic and muscle glycogen storage, and upregulated GLUT4 mRNA expression in skeletal muscle. Additionally, LASSBio-2129 improved insulin sensitivity in the dexamethasone-induced insulin resistance model, with effects comparable to sitagliptin. Conclusions: The combined pharmacological, docking, and ADMET analyses identified LASSBio-2129 as aldose reductase inhibitor candidate and glucokinase activator. Its ability to improve glucose tolerance, enhance glycogen storage, and increase GLUT4 expression highlights its potential as a promising molecule for the treatment of type 2 diabetes mellitus. Full article

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, also known as gliflozins, are a class of antidiabetic agents that act independently of insulin by promoting renal glucose excretion. They modulate glucose reabsorption in proximal renal tubules. Initially, they were used for the treatment of type 2 diabetes mellitus (T2DM); however, numerous pleiotropic benefits beyond glycemic control were observed. Large clinical trials confirmed their efficacy in reducing cardiovascular mortality, heart failure hospitalizations, and progression of chronic kidney disease. SGLT2 inhibitors reduce oxidative stress and inflammation and induce favorable metabolic adaptations, including lowering ketosis and upregulation of erythropoiesis. They also exert protective effects on hepatic and cognitive function. Additionally, SGLT2 inhibitors lower serum uric acid and reduce adipose tissue mass, which usually results in weight loss. Although generally well-tolerated, they are associated with increased risk of urogenital infections, euglycemic ketoacidosis, and a potentially enlarged amputation risk. Current guidelines worldwide recommend their use not only for T2DM but also for heart failure and chronic kidney disease, marking a paradigm shift toward organ-protective therapies. This review provides a comprehensive synthesis of current evidence on the mechanisms, clinical benefits, and safety profile of SGLT2 inhibitors, highlighting their expanding role in cardiometabolic and multisystem disease management. Full article

Background/Objectives: Gestational Diabetes Mellitus (GDM) is a global health issue with immediate and long-term maternal–fetal complications. Current diagnostic approaches, such as the Oral Glucose Tolerance Test (OGTT), have limitations in accessibility, sensitivity, and timing. This study aimed to identify key nodes and structural interactions associated with GDM using graph theory and network analysis to improve early predictive strategies. Methods: A literature review inspired by PRISMA guidelines (2004–2025) identified 44 clinically relevant factors. A directed graph was constructed using Python (version 3.10.12), and centrality metrics (closeness, betweenness, eigenvector), k-core decomposition, and a Minimum Dominating Set (MDS) were computed. The MDS, derived using an integer linear programming model, was used to determine the smallest subset of nodes with systemic dominance across the network. Results: The MDS included 20 nodes, with seven showing a high out-degree (≥4), notably Apo A1, vitamin D, vitamin D deficiency, and sedentary lifestyle. Vitamin D exhibited 15 outgoing edges, connecting directly to protective factors like HDL and inversely to risk factors such as smoking and obesity. Sedentary behavior also showed high structural influence. Closeness centrality highlighted triglycerides, insulin resistance, uric acid, fasting plasma glucose, and HDL as nodes with strong predictive potential, based on their high closeness and multiple incoming connections. Conclusions: Vitamin D and sedentary behavior emerged as structurally dominant nodes in the GDM network. Alongside metabolically relevant nodes with high closeness centrality, these findings support the utility of graph-based network analysis for early detection and targeted clinical interventions in maternal health. Full article

Background/Objectives: The classification of patients with diabetes into phenotypes with distinct risks and therapeutic needs is crucial for individualized care. We recently introduced a clustering model for gestational diabetes mellitus (GDM). This study aims to further characterize the proposed clusters and to identify cluster-specific differences in glucometabolic parameters during early pregnancy in an independent cohort. The metabolic profiles and dietary habits of GDM clusters will be compared with those of a normal glucose-tolerant (NGT) control group. Methods: 1088 women (195 who developed GDM and 893 who remained NGT) underwent a broad risk evaluation at early pregnancy. GDM patients were further categorized into the three proposed GDM subtypes (CL1 to CL3). Results: Among GDM patients, 7.7% were classified as CL1, 35.9% as CL2, and 56.4% as CL3. CL1 showed higher age, pregestational BMI, and increased glucose concentrations both at fasting and during the diagnostic oral glucose tolerance test. CL2 was characterized by elevated BMI and fasting glucose, while CL3 showed higher glucose concentrations after the oral glucose load, with BMI levels comparable to NGT mothers. Women in the CL1 group exhibited impaired insulin sensitivity and β-cell function at early pregnancy and showed elevated lipid levels. Compared to NGT women, a positive family history of diabetes was more prevalent in CL1 and CL3, but not in CL2. Dietary patterns were similar across all groups. Conclusions: Our study showed distinct alterations in glucometabolic parameters already at early pregnancy among GDM subtypes. Patients in CL1 exhibited the most unfavorable risk constellation and could benefit from lifestyle changes and nutrition therapy in early pregnancy, despite showing similar dietary patterns as the NGT group. Full article

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