Search Results (687)

The enteroendocrine system of the gastrointestinal (GI) tract is the largest endocrine organ in the human body, playing a central role in the regulation of hunger, satiety, digestion, and energy homeostasis. Numerous factors—including dietary components, physical activity, and the gut microbiota—affect the secretion of GI hormones. This study aims to analyze how these factors modulate enteroendocrine function and influence systemic metabolic regulation. This review synthesizes the current scientific literature on the physiology and distribution of enteroendocrine cells and mechanisms of hormone secretion in response to macronutrients, physical activity, and microbial metabolites. Special attention is given to the interactions between gut-derived signals and central nervous system pathways involved in appetite control. Different GI hormones are secreted in specific regions of the digestive tract in response to meal composition and timing. Macronutrients, particularly during absorption, stimulate hormone release, while physical activity influences hormone concentrations, decreasing ghrelin and increasing GLP-1, PYY, and leptin levels. The gut microbiota, through fermentation and metabolite production (e.g., SCFAs and bile acids), modulates enteroendocrine activity. Species such as Akkermansia muciniphila are associated with improved gut barrier integrity and enhanced GLP-1 secretion. These combined effects contribute to appetite regulation and energy balance. Diet composition, physical activity, and gut microbiota are key modulators of gastrointestinal hormone secretion. Their interplay significantly affects appetite regulation and metabolic health. A better understanding of these relationships may support the development of personalized strategies for managing obesity and related disorders. Full article

Background: Low-glycemic index (GI) carbohydrates like isomaltulose (ISO) are known to enhance incretin release and to improve postprandial glucose control at the following meal (an effect known as second meal effect, or SME), which is particularly beneficial for individuals with metabolic syndrome (MetS). This study aimed to assess the most effective preprandial interval of ISO- or saccharose (SUC) snacks (1 h vs. 3 h preload) to enhance prandial incretin responses to a subsequent meal. Methods: In a randomized crossover design, 15 participants with MetS completed four experimental conditions on four non-consecutive days, combining two preload types (ISO or SUC) and two preload timings (Intervention A: 3 h preload; Intervention B: 1 h preload). Specifically, the four conditions were (1) ISO + Intervention A, (2) SUC + Intervention A, (3) ISO + Intervention B, and (4) SUC + Intervention B. The order of conditions was randomized and separated by a 3–7-day washout period to minimize carryover effects. On each study day, participants consumed two mixed meal tests (MMT-1 and MMT-2) with a standardized preload (50 g ISO or SUC) administered either 3 h or 1 h prior to MMT-2. Blood samples were collected over 9 h at 15 predefined time points for analysis of glucose, insulin, C-peptide, and incretin hormones (GLP-1, GIP, and PYY). Results: The unique digestion profile of ISO resulted in a blunted glucose ascent rate (ΔG/Δt: 0.28 vs. 0.53 mmol/L/min for SUC, p < 0.01), paralleled by synonyms PYY elevation over 540 min monitoring, compared with SUC. ISO also led to higher and more sustained GLP-1 and PYY levels, while SUC induced a stronger GIP response. Notably, the timing of ISO consumption significantly influenced PYY secretion, with the 3 h preload showing enhanced PYY responses and a more favorable SME compared to the 1 h preload. Conclusions: ISO, particularly when consumed 3 h before a meal (vs. 1 h), offers significant advantages over SUC by elevating PYY levels, blunting the glucose ascent rate, and sustaining GLP-1 release. This synergy enhances the second meal effect, suggesting ISO’s potential for managing postprandial glycemic excursions in MetS. Full article

Background and Objectives: The management of type 2 diabetes (T2D) extends beyond glycemic control, requiring a more global strategy that includes optimization of body composition, even more so in the context of sarcopenia and visceral adiposity, as they contribute to poor outcomes. Past reviews have typically been focused on weight reduction or glycemic effectiveness, with limited inclusion of new therapies’ effects on muscle and fat distribution. In addition, the emergence of incretin-based therapies and dual agonists such as tirzepatide requires an updated synthesis of their impacts on body composition. This review attempts to bridge the gap by taking a systematic approach to how current blood-glucose lowering therapies affect lean body mass, fat mass, and the risk of sarcopenia in T2D patients. Materials and Methods: Between January 2015 and March 2025, we conducted a narrative review by searching the PubMed, Scopus, and Web of Science databases for English-language articles. The keywords were combinations of the following: “type 2 diabetes,” “lean body mass,” “fat mass,” “body composition,” “sarcopenia,” “GLP-1 receptor agonists,” “SGLT2 inhibitors,” “tirzepatide,” and “antidiabetic pharmacotherapy.” Reference lists were searched manually as well. The highest precedence was assigned to studies that aimed at adult type 2 diabetic subjects and reported body composition results. Inclusion criteria for studies were: (1) type 2 diabetic mellitus adult patients and (2) reporting measures of body composition (e.g., lean body mass, fat mass, or muscle function). We prioritized randomized controlled trials and large observational studies and excluded mixed diabetic populations, non-pharmacological interventions only, and poor reporting of body composition. Results: Metformin was widely found to be weight-neutral with minimal effects on muscle mass. Insulin therapy, being an anabolic hormone, often leads to fat mass accumulation and increases the risk of sarcopenic obesity. Incretin-based therapies induced substantial weight loss, mostly from fat mass. Notable results were observed in studies with tirzepatide, demonstrating superior reduction not only in fat mass, but also in visceral fat. Sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) promote fat loss but are associated with a small yet significant decrease in lean muscle mass. Conclusions: Blood-glucose lowering therapies demonstrated clinically relevant effects on body composition. Treatment should be personalized, balancing glycemic control, cardiovascular, and renal benefits, together with optimal impact on muscle mass along with glycemic, cardiovascular, and renal benefits. Full article

Insulin resistance (IR), a core component in the development of type 2 diabetes mellitus (T2DM), is increasingly recognized for its role in cardiovascular and pulmonary complications. This review explores the relationship between IR, right ventricular dysfunction (RVD), and decreased lung volume in patients with T2DM. Emerging evidence suggests that IR contributes to early structural and functional alterations in the right ventricle, independent of overt cardiovascular disease. The mechanisms involved include oxidative stress, inflammation, dyslipidemia, and obesity—factors commonly found in metabolic syndrome and T2DM. These pathophysiological changes compromise right ventricular contractility, leading to reduced pulmonary perfusion and respiratory capacity. RVD has been associated with chronic lung disease, pulmonary hypertension, and obstructive sleep apnea, all of which are prevalent in the diabetic population. As RVD progresses, it can result in impaired gas exchange, interstitial pulmonary edema, and exercise intolerance—highlighting the importance of early recognition and management. Therapeutic strategies should aim to improve insulin sensitivity and cardiac function through lifestyle interventions, pharmacological agents such as SGLT2 inhibitors and GLP-1/GIP analogs, and routine cardiac monitoring. These approaches may help slow the progression of RVD and its respiratory consequences. Considering the global burden of diabetes and obesity, and the growing incidence of related complications, further research is warranted to clarify the mechanisms linking IR, RVD, and respiratory dysfunction. Understanding this triad will be crucial for developing targeted interventions that improve outcomes and quality of life in affected patients. Full article

The glucagon-like peptide-1 receptor (GLP-1R), which belongs to the class B1 G protein-coupled receptor (GPCR) family, is an important target for treatment of metabolic disorders, including type 2 diabetes and obesity. The growing interest in GLP-1R-based therapies is driven by the development of various functional agonists as well as the huge commercial market. Thus, understanding the structural details of ligand-induced signaling are important for developing improved GLP-1R drugs. Here, we investigated the conformational dynamics of the receptor in complex with a selection of prototypical functional agonists, including CHU-128 (small molecule-biased), danuglipron (small molecule balanced), and Peptide 19 (peptide balanced), which exhibit unique, distinct binding modes and induced helix packing. Furthermore, our all-atom molecular dynamics (MD) simulations revealed atomic feature how different those ligands led to signaling pathway preference. Our findings offer valuable insights into the mechanistic principle of GLP-1R activation, which are helpful for the rational design of next-generation GLP-1R drug molecules. Full article

Nephronophthisis (NPH) is the leading genetic cause of end-stage renal disease in children and young adults, but no effective disease-modifying therapies are currently available. Here, we identify glucagon-like peptide-1 (GLP-1) signaling as a novel therapeutic target for NPH through a systematic drug repurposing screen in zebrafish. By simultaneously depleting nphp1 and nphp4, we developed a robust zebrafish model that reproduces key features of human NPH, including glomerular cyst formation. Our screen revealed that dipeptidyl peptidase-4 (DPP4) inhibitors (Omarigliptin and Linagliptin) and GLP-1 receptor agonists (Semaglutide) significantly reduce cystogenesis in a dose-dependent manner. Genetic analysis demonstrated that GLP-1 receptor signaling is important for maintaining pronephros integrity, with gcgra and gcgrb (GLP-1 receptor genes) playing a particularly important role. Transcriptomic profiling identified adenosine receptor A2ab (adora2ab) as a key downstream effector of GLP-1 signaling, which regulates ciliary morphology and prevents cyst formation. Notably, nphp1/nphp4 double mutant zebrafish exhibited the upregulation of gcgra as a compensatory mechanism, which might explain their resistance to cystogenesis. This compensation was disrupted by the targeted depletion of GLP-1 receptors or the inhibition of adenylate cyclase, resulting in enhanced cyst formation, specifically in the mutant background. Our findings establish a signaling cascade from GLP-1 receptors to adora2ab in terms of regulating ciliary organization and preventing cystogenesis, offering new therapeutic opportunities for NPH through the repurposing of FDA-approved medications with established safety profiles. Full article

Spurred by the enormous therapeutic success of glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP1-RAs) against diabetes and obesity, glucagon family receptor pharmacology has garnered a tremendous amount of interest. Glucagon family receptors, e.g., the glucagon receptor itself (GCGR), the GLP-1R, and the glucose-dependent insulinotropic peptide receptor (GIPR), belong to the incretin receptor superfamily, i.e., receptors that increase blood glucose-dependent insulin secretion. All incretin receptors are class B1 G protein-coupled receptors (GPCRs), coupling to the G_s type of heterotrimeric G proteins which activates adenylyl cyclase (AC) to produce cyclic adenosine monophosphate (cAMP). Most GPCRs undergo desensitization, i.e., uncouple from G proteins and internalize, thanks to interactions with the βarrestins (arrestin-2 and -3). Since the βarrestins can also mediate their own G protein-independent signaling, any given GPCR can theoretically signal (predominantly) either via G proteins or βarrestins, i.e., be a G protein- or βarrestin-“biased” receptor, depending on the bound ligand. A plethora of experimental evidence suggests that the GLP-1R does not undergo desensitization in physiologically relevant tissues in vivo, but rather, it produces robust and prolonged cAMP signals. A particular property of constant cycling between the cell membrane and caveolae/lipid rafts of the GLP-1R may underlie its lack of desensitization. In contrast, GIPR signaling is extensively mediated by βarrestins and the GIPR undergoes significant desensitization, internalization, and downregulation, which may explain why both agonists and antagonists of the GIPR exert the same physiological effects. Here, we discuss this evidence and make a case for the GLP-1R being a phenotypically or functionally G_s-selective receptor. We also discuss the implications of this for the development of GLP-1R poly-ligands, which are increasingly pursued for the treatment of obesity and other diseases. Full article

Background/Objectives: Opioid use disorder (OUD) remains a severe health problem globally, resulting in substantial social and economic challenges. While existing medications for managing OUD are proven to be effective, they also present certain challenges. A vaccine offers a promising therapeutic strategy to combat OUD and potentially reduce the risk of overdose death. The TT-6-AmHap heroin conjugate vaccine has effectively reduced heroin-induced pharmacological effects in behavioral assays as well as demonstrated the induction of high titer and high affinity antibody responses in mice and rats. In this GLP study conducted in rabbits, the potential local and systemic toxicity of the TT-6-AmHap heroin vaccine in combination with or without adjuvants ALF43 and Alhydrogel^® (ALFA) was investigated. Methods: Male and female New Zealand White rabbits were administered with vaccines or a saline control intramuscularly at two-week intervals over a 57-day study period. The presence, persistence or reversibility of any toxic effects of the vaccine was determined over a four-week recovery period. Results: Administration of TT-6-AmHap with or without the adjuvants induced high antibody-specific IgG in treatment groups compared to the controls. The study found no TT-6-AmHap-related effects on mortality, physical examinations, dermal Draize observations, body weights, body weight changes, food consumption, ophthalmology, clinical pathology (hematology, coagulation, clinical chemistry, and urinalysis), macroscopic pathology, or organ weights. Conclusions: Under the conditions of this study, these results demonstrate that the TT-6-AmHap vaccine with or without adjuvants was well tolerated, immunogenic, and the effects were not considered adverse in both male and female rabbits. Full article

Background and Objectives: Type 2 diabetes (T2D) is a global health burden with increasing prevalence, necessitating effective management strategies. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as beneficial therapies, promoting both glycemic control and weight loss, yet real-world data on sex differences in response are limited. This study aimed to investigate sex-based differences in glycemic and weight outcomes, as well as adverse effects, in T2D patients treated with GLP-1 RAs at a single diabetes center. Materials and Methods: In this retrospective analysis, 114 patients (58.8% men) with T2D who were initiated on GLP-1 RA therapy between 2015 and 2023 were evaluated. Data on HbA1c, BMI, and adverse events were collected at baseline and 3, 6, and 12 months post-treatment initiation. Results: Our findings indicated a statistically significant HbA1c reduction (from 8.6% at GLP-1 RA initiation to 6.9% at 12 months in men (p < 0.001) and from 8.4% at initiation to 7.0% at 12 months after GLP-1 RA initiation (p < 0.001) in women). By 12 months, a significantly greater proportion of women compared to men achieved ≥ 5% (51.1% vs. 28.4%, p = 0.019) and ≥10% weight loss (29.8% vs. 9.0%, p = 0.006), with both differences reaching statistical significance. A statistically significant difference in weight loss in mean weight change and percent weight change in men vs. women was observed from month 6 of therapy. Conclusions: These findings underscore the effectiveness of GLP-1 RAs in improving glycemic control and weight loss in a real-world setting and suggest that women may experience greater weight reduction. Understanding these differences could inform personalized treatment strategies for optimized outcomes in T2D management. Full article

Background/Objectives: Short bowel syndrome (SBS) is the leading cause of pediatric intestinal failure. Plasma citrulline is considered a marker indicating an enterocyte volume and may help evaluate the response to teduglutide; however, this interpretation may vary depending on the remnant bowel anatomy. Methods: We conducted a retrospective case series of four pediatric patients with SBS (aged < 15 years) who received teduglutide for 12 months at our hospital between 2018 and 2023. Changes in plasma citrulline levels and parenteral nutrition requirements were assessed in addition to bowel anatomy classification. Results: This study included two males and two females. All patients showed an increase in plasma citrulline levels and a reduction in the requirement for parenteral nutrition (PN) after 12 months of teduglutide treatment. In SBS type 2 (jejunocolic anastomosis), citrulline levels increased by 114% and 52%, with PN reduction rates of 100% and 30%, respectively. In SBS type 3 (jejunoileal anastomosis), citrulline levels increased by 13.6% and 34%, with PN reductions of 33% and 73%, respectively. Conclusions: Teduglutide treatment increased plasma citrulline levels and reduced PN levels in all cases. However, the magnitude of the citrulline change varied across bowel anatomy types, suggesting that the anatomical difference in the remnant bowel may influence the biomarker response. Further detailed pediatric cases are required to clarify the role of citrulline in evaluating GLP-2 analogue treatment outcomes. Full article

Disorders in glucose metabolism are well-established features of polycystic ovary syndrome (PCOS) and are linked to its clinical severity and phenotypic variability. This study aimed to assess serum concentrations of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and dipeptidyl peptidase-4 (DPP-4) and to examine their relationships with glucose and insulin levels, selected sex hormone concentrations, body weight, and exposure to tobacco smoke. Women with PCOS exhibited significantly elevated levels of fasting glucose, insulin, GIP, and GLP-1 compared to controls. Tobacco smoke exposure in women with PCOS was associated with reduced DPP-4 levels, which were approximately two-fold lower in smokers than in non-smokers. A significant negative correlation between DPP-4 and cotinine levels further supported this relationship. Comorbidities such as overweight/obesity or insulin resistance (IR) were also linked to elevated incretin hormone levels. However, no significant age-related trends in incretin levels were identified, despite the known association between age and glucose dysregulation. The notable alterations in incretin hormone profiles in PCOS, along with the consistent patterns of GIP or GLP-1 with metabolic and hormonal parameters, suggest that these hormones may play coordinated regulatory roles in the pathophysiology of PCOS. Full article

Enteroendocrine cells (EECs) are specialized secretory cells in the gut epithelium that differentiate from intestinal stem cells (ISCs). Mature EECs secrete incretin hormones that stimulate pancreatic insulin secretion and regulate appetite. Decreased EEC numbers and impaired secretion of the incretin glucagon-like peptide-1 (GLP1) have been implicated in obesity-associated metabolic complications. Gut microbial metabolites of dietary tryptophan (TRP) were recently shown to modulate ISC proliferation and differentiation. However, their specific effects on EEC differentiation are not known. We hypothesized that the gut microbial metabolites of dietary tryptophan counteract impaired GLP1 production and function in obesity by stimulating EEC differentiation from ISCs. We utilized complementary models of human and rat intestines to determine the effects of obesity or TRP metabolites on EEC differentiation. EEC differentiation was assessed by the EEC marker chromogranin A (CHGA) levels in the intestinal mucosa of normal versus obese rats. The effects of TRP metabolites on EEC differentiation were determined in human intestinal organoids treated with indole, a primary TRP metabolite, or the culture supernatant of Lactobacillus acidophilus grown in TRP media (LA-CS-TRP). Our results showed that the mRNA and protein levels of CHGA, the EEC marker, were significantly decreased (~60%) in the intestinal mucosa of high-fat-diet-induced obese rat intestines. The expression of the transcription factors that direct the ISC differentiation towards the EEC lineage was also decreased in obesity. In human organoids, treatment with indole or LA-CS-TRP significantly increased (more than 2-fold) CHGA levels, which were blocked by the aryl hydrocarbon receptor (AhR) antagonist CH-223191. Thus, the stimulation of EEC differentiation by colonic microbial metabolites highlights a novel therapeutic role of TRP metabolites in obesity and associated metabolic disorders. Full article

Background: Semaglutide and Liraglutide are medications in the Glucagon-like peptide-1 agonists (GLP-1 RAs) class used to manage type 2 diabetes mellitus and obesity in Saudi Arabia. Although the 1.0 mg once weekly dosage of Semaglutide does not have a labeled indication for the management of obesity, many believe that this dosage is more effective than the 3.0 mg once daily Liraglutide dosage for the management of both diabetes and obesity. Objective: To compare the effectiveness of the dosage of 1.0 mg of Semaglutide administered once weekly versus 3.0 mg of Liraglutide administered once daily in controlling HbA1c levels, promoting weight loss, and evaluating their financial implications among obese patients in Saudi Arabia using real-world data. Methods: A retrospective review of Electronic Medical Records (EMRs) from January 2021 to June 2024 was conducted on patients prescribed Semaglutide or Liraglutide for at least 12 months. Exclusion criteria included pre-existing severe conditions (e.g., cardiovascular disease, stroke, or cancer) and missing baseline data. The primary outcomes assessed were changes in HbA1c, weight, and direct medical costs. Results: Two hundred patients (100 patients on the 1.0 mg once weekly dose of Semaglutide and 100 patients on the 3.0 mg once daily dose of Liraglutide) of those randomly selected from the EMRs met the inclusion criteria and were included in the analysis. Of the 200 eligible patients (65.5% female, mean age 48.54 years), weight loss was greater with Semaglutide (−8.09 kg) than Liraglutide (−5.884 kg). HbA1c reduction was also greater with Semaglutide (−1.073%) than Liraglutide (−0.298%). The use of Semaglutide resulted in lower costs of USD −1264.76 (95% CI: −1826.82 to 33.76) and greater reductions in weight of −2.22 KG (95% CI: −7.68 to −2.784), as well as lower costs of USD −1264.76 (95% CI: (−2368.16 to −239.686) and greater reductions in HbA1c of −0.77% (95% CI: −0.923 to −0.0971) in more than 95% of the cost effectiveness bootstrap distributions. Conclusions: Semaglutide 1.0 mg weekly seems to be more effective and cost-saving in managing prediabetes, diabetes, and obesity compared to Liraglutide 3.0 mg daily. Future studies should examine these findings using a more representative sample and a robust study design. Full article

Diabetes mellitus and atrial fibrillation (AF) frequently coexist, creating a complex bidirectional relationship that exacerbates cardiovascular risk and challenges clinical management. Diabetes fosters a profibrotic, pro-inflammatory, and proarrhythmic atrial substrate through a constellation of pathophysiologic mechanisms, including metabolic remodeling, oxidative stress, mitochondrial dysfunction, ion channel dysregulation, and autonomic imbalance, thereby promoting AF initiation and progression. Conventional rhythm control strategies remain less effective in diabetic individuals, underscoring the need for innovative, substrate-targeted interventions. In this context, sodium–glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as promising agents with pleiotropic antiarrhythmic properties, modulating fibrosis, inflammation, and mitochondrial integrity. Moreover, advances in anti-inflammatory, antifibrotic, and ion channel-modulating therapeutics, coupled with novel mitochondrial-targeted strategies, are reshaping the therapeutic landscape. Multi-omics approaches are further refining our understanding of diabetes-associated AF, facilitating precision medicine and biomarker-guided interventions. This review delineates the molecular nexus linking diabetes and AF, critically appraises emerging rhythm control strategies, and outlines translational avenues poised to advance individualized management in this high-risk population. Full article

Ganoderma lucidum polysaccharides (GLPs) are natural compounds with a broad spectrum of biological activities. β-1,3-glucosyltransferase (GL20535) plays an important role in polysaccharide synthesis by catalyzing the transfer of UDP-glucose to extend sugar chains, but its underlying mechanism remains unclear. In this study, the regulatory mechanism of GL20535 in polysaccharide synthesis was elucidated by overexpressing and silencing gl20535 in G. lucidum. Overexpression of gl20535 resulted in maximum increases of 18.08%, 79.04%, and 18.01% in intracellular polysaccharide (IPS), extracellular polysaccharide (EPS), and β-1,3-glucan contents, respectively. In contrast, silencing gl20535 resulted in maximum reductions of 16.97%, 30.20%, and 23.56% in IPS, EPS, and β-1,3-glucan contents, respectively. These phenomena in the overexpression strains were attributed to gl20535-mediated promotion of UDP-glucose synthesis in the sugar donor pathway and upregulation of the expression of glycoside hydrolase genes. The opposite trend was observed in the silenced strains. In mycelial growth studies, neither overexpression nor silencing of gl20535 affected biomass and cell wall thickness. Furthermore, the GL20535 isozyme gene gl24465 remained unaffected in gl20535-overexpressed strains but was upregulated in gl20535-silenced strains, suggesting a compensatory regulatory relationship. These findings reveal the regulatory role of GL20535 on gene expression in the GLPs synthesis pathway and deepen our understanding of GL20535 function in the polysaccharide network of edible and medicinal fungi. Full article