Search Results (375)

Endometriosis is increasingly recognized as a chronic systemic disorder extending beyond the classical estrogen-dependent paradigm, integrating metabolic, immune, fibrotic, and nociceptive pathways that sustain lesion persistence and refractory pelvic pain. We propose a mechanistic, translational hypothesis in which tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, may modulate four interconnected pathological axes of refractory endometriosis—Warburg-type metabolic reprogramming with lactate accumulation, peritoneal immune dysfunction, NF-κB/NLRP3/TGF-β1-driven inflammatory–fibrotic remodeling, and persistent nociceptive sensitization—through three convergent molecular nodes: AMPK-associated signaling, GLP-1 receptor activity in peritoneal macrophages and spinal microglia, and the NF-κB/NLRP3/TGF-β1 axis. Particular emphasis is placed on the concept of “peritoneal incretin deficiency”, characterized by reduced peritoneal GLP-1 concentrations and increased expression of incretin-degrading proteases. This concept currently rests on a single, non-replicated case–control study, and the broader mechanistic chain is supported largely by indirect evidence extrapolated from adjacent inflammatory, metabolic, and neuroimmune disease models rather than by endometriosis-specific data. Direct experimental or clinical validation in endometriosis-specific models is currently absent. Accordingly, this article represents a hypothesis-generating framework rather than evidence of established efficacy, or a clinical treatment recommendation, intended to guide future mechanistic and prospective clinical investigation of incretin-based modulation as a potential adjunctive strategy in refractory endometriosis. Full article

Background/Objectives: Given the rising prevalence of overweight and obesity in pediatric populations, identifying effective nutritional interventions for metabolic management is crucial. Beyond their nutritional value, soy and lupin proteins are recognized for their bioactive properties. We formulated two protein-enriched functional beverages and evaluated their impact on the metabolic profile and gut microbiota of adolescent boys with overweight or obesity. Methods: A randomized, double-blind clinical trial was conducted with 30 Mexican male adolescents (12–16 years old). Participants were randomly assigned to consume a functional beverage providing a daily 10 g portion of either soy or lupin protein for 5 weeks. Results: Following the intervention, both groups exhibited significantly attenuated fasting glucose (soy: 93.1 vs. 99.5 mg/dL; lupin: 92.3 vs. 97.9 mg/dL) and C-peptide levels. Consequently, insulin sensitivity, assessed via the HOMA2 index, improved significantly in both cohorts. The soy protein group showed a marked reduction in total cholesterol (–10.4%) and triglycerides (–17.1%). Furthermore, serum levels of plasminogen activator inhibitor-1 (PAI-1) and visfatin were decreased after both interventions. A post-treatment reduction in glucose-dependent insulinotropic polypeptide (GIP) was specifically observed in the lupin group. Regarding the gut microbiota, both protein-based beverage interventions correlated with enhanced 16S rDNA diversity and increased the abundance of the Bacillota phylum and butyryl-CoA transferase-positive bacteria. Conclusions: Our data suggests that the daily consumption of soy or lupin protein-based beverages could exert beneficial metabolic and endocrine effects in adolescent boys with overweight and obesity, potentially mediated by the modulation of the gut microbiome. Full article

Over the last years, incretin receptor agonists—including glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RA) and the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist tirzepatide—have dramatically improved the management of type 2 diabetes, overweight and obesity. However, as the use of incretin receptor agonists continues to increase worldwide, micronutrient deficiencies—including iron deficiency—have emerged as newly recognized adverse effects of these drugs. The present article aims to discuss recent preliminary observational evidence on the potential relationship between incretin receptor agonist-based therapies and the development of iron deficiency and iron deficiency anemia (IDA), as well as the potential mechanisms by which incretin receptor agonists may affect iron homeostasis. Potential mechanisms and factors underlying the development of iron deficiency and IDA in patients treated with incretin receptor agonist-based therapies include inadequate dietary iron intake (due to incretin receptor agonist-mediated reduction in food intake and/or gastrointestinal adverse effects of incretin receptor agonists), low dietary variety, monotonous diets, and changes in food preferences, as well as impairment of intestinal iron absorption (due to delayed gastric emptying, reduced small intestinal motility and/or decreased gastric acid secretion caused by incretin receptor agonists). Moreover, vitamin B2 (riboflavin) deficiency and changes in gut microbiota composition are hypothetical mechanisms that may partly explain iron deficiency in patients treated with incretin receptor agonists, although these hypotheses require confirmation through mechanistic studies. Even though iron deficiency and IDA currently appear to be uncommon adverse effects of incretin receptor agonist-based therapies, clinicians should be aware of the possibility of their occurrence to ensure appropriate prevention and management of these nutritional complications. Nevertheless, future prospective studies are certainly needed to better establish the causal relationship between the initiation of incretin receptor agonist-based therapies and the development of iron deficiency/IDA, as well as the exact mechanisms underlying the potential development of these nutritional complications in patients treated with incretin receptor agonists. Meanwhile, the prescription of incretin receptor agonists should not be unjustifiably restricted by the possible and modest risk of iron deficiency and IDA in patients with one or more approved indications for therapeutic use of these agents. Since no established guidelines currently exist for the prevention and management of iron deficiency and IDA in patients treated with incretin receptor agonists, we herein propose practical strategies to address these possible nutritional complications of incretin receptor agonist-based therapies. These proposed strategies should only be regarded as practical clinical approaches deriving from the existing recommendations for the prevention and management of iron deficiency and IDA, although their cost-effectiveness for the prevention and management of incretin receptor agonist-associated iron deficiency/IDA should be appropriately assessed in future clinical trials. Full article

Insulin resistance (IR) is traditionally viewed within the context of type 2 diabetes. However, it increasingly appears to represent a broader systemic metabolic risk state with potential relevance for carcinogenesis. Chronic hyperinsulinemia can activate insulin-like growth factor-1-dependent pathways, including phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin and mitogen-activated protein kinase signaling, promoting cellular proliferation while limiting apoptosis. At the same time, IR is closely linked to oxidative stress, chronic low-grade inflammation, and epigenetic alterations, together shaping a tumor-promoting microenvironment. Epidemiological studies report consistent associations between IR and increased cancer risk, particularly for endometrial, liver, and colorectal cancers. Yet causality remains uncertain and likely varies by tumor type. Notably, metabolic dysfunction may also occur in individuals with normal body mass index (BMI), underscoring the limitations of BMI-based risk assessment. Unlike previous reviews that primarily focused on individual mechanisms or epidemiological associations, this review examines IR as a systemic metabolic risk state by integrating molecular, epidemiological, biomarker-based, and prevention-oriented perspectives. Particular emphasis is placed on strategies for earlier risk identification using integrated biomarker approaches, including fasting glucose, homeostatic model assessment of insulin resistance, triglyceride-to-high-density lipoprotein ratio, high-sensitivity C-reactive protein, and insulin-like growth factor-1. Emerging tools such as continuous glucose monitoring and hepatokine profiling may further refine risk detection. Sustained lifestyle modification—diet, physical activity, sleep, and stress regulation—remains central to prevention. Pharmacological therapies, including glucagon-like peptide-1 receptor agonists and dual incretin agents, offer additional metabolic benefits, although their long-term impact on cancer risk is still unclear. Therefore, IR is best understood not as an isolated risk factor, but as a systemic metabolic risk state that may influence cancer development, with implications for prevention and early risk stratification. Full article

Dipeptidyl peptidase-4 (DPP-4) is an established therapeutic target in the treatment of type 2 diabetes mellitus (T2DM), primarily due to its role in regulating incretin activity and glucose homeostasis. Although clinically approved DPP-4 inhibitors are widely used, their moderate efficacy has driven the search for novel compounds with improved properties. In this context, natural products have attracted considerable attention as a source of structurally diverse and biologically active molecules. At the same time, molecular docking has emerged as a key computational tool for the identification and evaluation of potential DPP-4 inhibitors. This review summarizes and critically analyzes current molecular docking studies of natural compounds targeting DPP-4. Over 150 studies were evaluated with respect to docking methodologies, selection of protein structures, and validation strategies. The results reveal substantial variability in computational protocols. Frequently used protein structures include ligand-bound DPP-4 models such as 1X70 and 6B1E. Among the investigated compounds, flavonoids represent the most extensively studied class, followed by alkaloids, phenolics, terpenoids, and peptides. Despite numerous reports of favorable binding interactions within the DPP-4 active site, many studies rely solely on docking results without further validation. The limited use of molecular dynamics simulations and experimental assays highlights a significant gap in the current literature. Overall, while molecular docking provides valuable preliminary insights, improved standardization and integration with complementary approaches are essential to enhance the reliability and translational relevance of in silico findings. Full article

The Mediterranean diet (MedDiet) has emerged as a promising dietary strategy for the prevention and management of type 2 diabetes mellitus (T2DM). This narrative review provides a comprehensive synthesis linking the biological pathways of the MedDiet with established clinical evidence. Adherence to this traditional dietary pattern—characterized by a high intake of fiber, complex carbohydrates, antioxidants, and healthy fats—has demonstrated significant benefits in terms of glycemic control, enhanced insulin sensitivity, and overall metabolic health. Mechanistically, the review explains how the MedDiet improves health by modulating key physiological processes, including anti-inflammatory and antioxidant pathways, the regulation of branched-chain amino acid metabolism, the enhancement of short-chain fatty acid production via gut microbiota modulation, and upregulated incretin effects. Importantly, this review explains how the MedDiet complements modern medications, including glucagon-like peptide-1 (GLP-1) receptor agonists and sodium–glucose cotransporter-2 (SGLT-2) inhibitors. By integrating molecular mechanisms with human clinical outcomes, this narrative review addresses multiple aspects of the MedDiet in both the prevention and management of T2DM including glycemic control, weight management, and cardiovascular risk reduction, rendering it a valuable dietary strategy for both the prevention and treatment of this chronic condition. Full article

This paper analyzes the role of cereal products in the diet of individuals with disorders of carbohydrate metabolism, with particular emphasis on their impact on postprandial glycemia and the risk of developing type 2 diabetes (T2D). Cereal products, as the main source of dietary carbohydrates, also provide dietary fiber, minerals, B vitamins, and key bioactive compounds such as β-glucans, arabinoxylans, resistant starch (RS), and polyphenols. These components may reduce the rate of starch digestion and glucose absorption in the small intestine by increasing the viscosity of intestinal contents or by directly inhibiting digestive enzymes such as α-glucosidase. It has been shown that fermentation of these compounds by the gut microbiota leads to the production of short-chain fatty acids (SCFAs), which improve insulin sensitivity and stimulate the secretion of incretin hormones such as GLP-1. A literature review confirms that regular consumption of whole-grain products is associated with a reduced risk of T2D, whereas refining processes and excessive grain fragmentation lead to an increased glycemic index of products. Based on clinical guidelines and a narrative synthesis of the available literature, minimally processed whole-grain products were identified as a fundamental component of dietary therapy for diabetes, which is illustrated by the cereal product pyramid presented in the paper. This review involved a comprehensive literature search in PubMed, Scopus, and Web of Science using relevant keywords. Peer-reviewed articles, reviews, and meta-analyses (mainly 2000–2025) were included based on their relevance. Full article

Diabetes pharmacology has historically been dominated by a glucose-centric framework in which therapeutic efficacy is defined primarily by reduction in blood glucose and glycated haemoglobin (HbA1c). Although this paradigm transformed diabetes from a fatal disease into a chronic manageable condition, persistent cardiovascular, renal, inflammatory, and metabolic complications have exposed the limitations of viewing diabetes principally as a hyperglycaemic disorder. This perspective examines the progressive conceptual transition occurring across modern diabetes therapeutics, beginning with the exhaustion of the traditional glucose-centred model and extending through the emergence of incretin-based therapies, organ-protective pharmacology, immunological intervention, regenerative endocrinology, bioengineering, and AI-enabled closed-loop systems. Drawing on these developments, it argues that contemporary therapeutic advances progressively derive their efficacy from coordinated modulation of interconnected physiological networks rather than solely glucose-lowering effect. On this basis, the article proposes biological systems redesign as a unifying conceptual model for the future of diabetes therapeutics, in which treatment is directed toward the restoration of integrated metabolic and organ-level homeostasis, the preservation of system resilience, and the interception of disease progression across multiple biological scales. Full article

Tirzepatide and semaglutide are among the most effective incretin-based therapies currently used in type 2 diabetes and obesity. To review direct comparative clinical evidence on tirzepatide versus semaglutide, with emphasis on glycemic efficacy, body-weight reduction, metabolic and mechanistic parameters, and tolerability. PubMed was searched from inception to March 14, 2026, without language or date restrictions, for original human studies directly comparing these agents and secondary pooled, mechanistic, exploratory, or post hoc analyses derived from direct comparative trials. Eleven eligible publications were identified, largely representing three parent comparative settings: SURPASS-2, a 28-week mechanistic phase 1 study, and SURMOUNT-5. Across the available direct comparative literature, tirzepatide generally demonstrated greater metabolic efficacy within the studied dosing and trial frameworks. In type 2 diabetes, it produced larger reductions in HbA1c and body weight, whereas in obesity without diabetes it was associated with greater weight loss and waist-circumference reduction. Mechanistic analyses also favored tirzepatide across several measures of insulin sensitivity, glucose control, and body composition. Secondary and pooled analyses further suggested more frequent achievement of combined glycemic and weight targets and more durable metabolic benefit. Both agents showed the expected incretin-related tolerability profile, with gastrointestinal adverse events predominating. The currently available direct comparative evidence suggests greater metabolic efficacy of tirzepatide, particularly with respect to HbA1c reduction and body-weight loss. However, this conclusion should be interpreted cautiously because the evidence base remains limited, includes multiple overlapping secondary analyses, and is influenced by comparator-dose selection and trial design. Full article

The emergence of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual incretin-based therapies has fundamentally transformed obesity pharmacotherapy, enabling magnitudes of non-surgical weight loss that were previously unattainable. Yet, the clinical success of these treatments cannot be measured in kilograms alone. Total body weight is a composite, tissue-nonspecific endpoint that fails to distinguish between adipose reduction and losses in skeletal muscle mass, strength, and physical function—compartments of direct relevance to metabolic health, functional independence, and long-term resilience. This narrative review builds on and extends existing conceptualizations of weight loss quality by proposing a clinically oriented, multidimensional framework of high-quality weight loss. Within this framework, preferential adiposity reduction is achieved while preserving skeletal muscle mass, neuromuscular function, dietary adequacy, and cardiometabolic health. We examine the physiological and clinical consequences of lean tissue loss during pharmacological energy restriction, with specific attention to phenotypes at greatest risk (i.e., older adults, individuals with sarcopenic obesity, and those with type 2 diabetes). We then evaluate the evidence supporting precision protein nutrition, dietary fiber adequacy, and gastrointestinal tolerability management as nutritional countermeasures, followed by a mechanistic and clinical analysis of resistance training as the primary exercise strategy for preserving lean mass and function. Finally, we discuss body composition monitoring, integrated multidisciplinary care, and unresolved research gaps. The future of obesity treatment lies not in greater weight loss per se, but in achieving better weight loss—defined as metabolically favorable, functionally responsible, and clinically sustainable. Bone health is treated as a further dimension of high-quality weight loss, since pharmacologically driven energy restriction can adversely affect areal bone mineral density and microarchitecture, and adequate protein intake combined with mechanical loading is required to preserve skeletal integrity alongside lean mass. Full article

Background/Objectives: Glucagon-like peptide-1 receptor agonist (GLP-1RA)- and incretin-based therapies are now central to obesity management. Their clinical value, however, should be interpreted beyond total weight loss, because changes in fat mass, lean mass, physical function, and cardiometabolic risk may depend on the accompanying dietary, behavioral, and exercise co-interventions. This systematic review and meta-analysis evaluated GLP-1RA- and incretin-based therapies delivered within lifestyle interventions in adults with overweight or obesity. Methods: The protocol was registered in PROSPERO (CRD420261360837). PubMed/MEDLINE, Web of Science, Scopus, CINAHL, SPORTDiscus, and CENTRAL were searched from inception to the final search dates. Records were deduplicated in Zotero. Risk of bias was assessed using the Cochrane RoB 2 tool. Random-effects meta-analyses were estimated using restricted maximum likelihood with Hartung–Knapp adjustment when pooling was appropriate. Results: Across all database sources, 1651 records were identified. After removing 113 duplicate records and 212 records with an ineligible publication type before screening, 1326 records were screened. Seventy-seven reports were sought for retrieval, five were not retrieved, 72 were assessed at full text, and 48 reports corresponding to 35 independent parent trials or trial clusters were retained for qualitative synthesis. The primary kilogram-scale meta-analysis included eight independent comparisons and showed greater body-weight reduction with GLP-1RA/incretin-based therapy delivered within a lifestyle background than with placebo/control (mean difference [MD] −10.08 kg, 95% confidence interval [CI] −12.76 to −7.39; 95% prediction interval [PI] −17.86 to −2.29; I² = 95.6%). Percentage body-weight change was analyzed separately across 11 independent comparisons and also favored GLP-1RA/incretin-based therapy (MD −9.53 percentage points, 95% CI −11.92 to −7.14; 95% PI −17.58 to −1.48; I² = 95.4%). Conclusions: GLP-1RA- and incretin-based therapies delivered within lifestyle interventions are associated with clinically meaningful reductions in body weight in adults with overweight or obesity. Absolute and relative body-weight change metrics should remain analytically separate. The magnitude of benefit varies across trial contexts, and certainty remains limited by risk-of-bias concerns and considerable heterogeneity. Future trials should standardize the reporting of lifestyle co-interventions, body composition, adherence, physical-function outcomes, and safety monitoring. Full article

Background: With the increasing widespread use of GLP-1 RA and dual GIP/GLP-1 RAs in the treatment of obesity, their safety profile remains a concern for healthcare professionals (HPs). Objective: This study aimed to characterize and evaluate safety data from the EudraVigilance (EV) database for semaglutide (SEM), liraglutide (LIR), and tirzepatide (TIR). Methods: A hierarchical pharmacovigilance approach was applied, integrating SOC- and PT-level analyses with SmPC-based evaluation and both frequentist (ROR, 95% CI) and Bayesian (IC025) disproportionality methods. Within each molecule, reporter type–stratified analyses were performed, while across all molecules, disproportionality analyses were conducted separately in HP reports and in the full database to identify reporting patterns and potential safety signals, including those not described in the SmPCs. Results: Some ADRs, listed in the SmPC of only one or two of the three GLP1-RAs were also reported in the EV database for the other agents whose SmPCs do not specify these ADRs including optic ischemic neuropathy (TIR: 0.28% and LIR: 0.17%), alopecia (LIR: 0.81%), headache (TIR: 2.51%), intestinal obstruction (TIR: 1.55%), angioedema (LIR: 0.19%), hypersensitivity (SEM: 0.58% and LIR: 0.73%), etc. Pancreatitis, in particular, showed a significant but low-magnitude signal, being more frequently reported by HPs compared with non-HPs across all three GLP1-RAs. Additionally, statistically significant signals (IC025 > 0) were observed in both the HPs and full datasets. For example, for SEM vs. TIR, signals were identified for optic ischemic neuropathy (0.17; 0.13), gallbladder disorder (0.09; 0.11), and dysesthesia (0.42; 0.43), respectively. For TIR vs. SEM, signals were observed for injection site erythema (0.05; 0.11), injection site pruritus (0.01; 0.11), and injection site reaction (0.02; 0.08). Conclusions: These findings suggest potential safety signals beyond current SmPC information, emphasizing the need for continuous pharmacovigilance and cautious interpretation of reporting biases. Full article

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists have transformed obesity treatment, producing substantial weight loss during active therapy. However, real-world effectiveness may be limited by gastrointestinal adverse events, reduced dietary intake, fat-free mass loss as part of total weight reduction, and weight regain after discontinuation. Methods: This narrative review synthesizes current pharmacological, nutritional, gastrointestinal, body-composition, and implementation evidence to propose an evidence-informed nutrition-first framework for patients receiving incretin-based therapy for obesity. Results: We translate pharmacologic mechanisms into practical dietary strategies, including protein prioritization, structured meal patterns, hydration and fiber management, symptom-targeted interventions, resistance-training support, and maintenance planning. Because direct trials of structured nutrition interventions in GLP-1RA- or dual incretin-treated populations remain limited, several recommendations are extrapolated from the broader obesity, caloric restriction, body-composition, gastrointestinal, and expert-consensus literature. Conclusions: Integrating structured nutrition care into pharmacotherapy pathways may help address meal-related symptom burden, support protein and fluid adequacy, identify patients at higher nutritional or body-composition risk, and prepare patients for long-term weight-management behaviors. Embedding practical nutrition management within multidisciplinary obesity care may help translate pharmacologic efficacy into durable, patient-centered outcomes. Full article

Background: Effective postprandial glycemic regulation is essential for preventing metabolic disorders such as type 2 diabetes. While pharmacological interventions like GLP-1 (Glucagon-Like Peptide-1) receptor agonists are effective, dietary strategies using low-digestible carbohydrates (LDCs) may offer a sustainable and complementary approach. Methods: Two human physiological investigations were conducted to evaluate the acute metabolic responses to allulose, 1-kestose, resistant maltodextrin (RD), and fructo-oligosaccharide powder (FOP), administered both in isolation and in conjunction with a reference meal (RM). Results: In Study 1, all tested LDCs elicited minimal plasma glucose responses when consumed alone. In Study 2, distinct metabolic benefits were observed depending on the type of LDCs. Allulose exhibited the strongest effects, significantly reducing postprandial glucose and insulin levels while increasing plasma GLP-1 concentrations. 1-Kestose exhibited significantly lower plasma glucose and insulin incremental area under the curve (iAUC) compared to RM alone, indicating improved glycemic regulation. RD significantly enhanced subjective satiety between 30 and 180 min post-consumption. These findings highlight that each LDC exerts unique physiological effects. Conclusions: Collectively, these results demonstrate that acute LDCs consumption distinctly regulates metabolic responses, supporting their application as functional ingredients in targeted nutritional strategies for managing glycemic and metabolic health. Full article

Diabetic peripheral neuropathy (DPN) remains a leading cause of disability in diabetes, yet current care is largely symptomatic and does not directly address early neurovascular-immune pathology. This narrative review synthesizes clinical, redox, vascular, and immunological evidence into a peripheral nerve neurovascular unit (PNVU)/blood–nerve barrier (BNB)-centered framework for DPN. First, the review outlines the diagnostic and translational endpoint landscape of DPN, emphasizing that commonly used clinical, neurophysiological, small-fiber, and imaging-based tools capture important disease domains but do not directly assess early BNB dysfunction. It then reviews the anatomical and functional basis of the PNVU and BNB, including endoneurial microvascular endothelial cells, pericytes, basement membrane components, immune cells, and tight-junction proteins. Next, it discusses how chronic hyperglycemia and dyslipidemia drive metabolic-to-vascular coupling, redox imbalance, antioxidant defense failure, advanced glycation end products (AGEs), receptor for AGEs (RAGE), and nuclear factor-κB (NF-κB) signaling, endothelial activation, leukocyte recruitment, macrophage polarization, and junctional disassembly, culminating in increased BNB permeability and exposure of peripheral nerves to pro-inflammatory and neurotoxic mediators. Finally, it evaluates incretin-based therapies—including glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors, DPP-4is), and emerging multi-agonists—as potential modulators of oxidative and inflammatory stress within this framework. Although semaglutide and related agents show mechanistic plausibility and preclinical promise, direct evidence for incretin-mediated BNB stabilization in human DPN remains limited. By reframing DPN as a redox-driven neurovascular-immune disorder, this review highlights barrier-focused biomarkers, translational endpoints, and hypothesis-generating therapeutic opportunities that require clinical validation. Full article