Search Results (284)

Diabetic foot ulcers (DFUs), which affect approximately 15% of individuals with diabetes mellitus (DM), result from complex molecular disturbances involving chronic hyperglycemia, immune dysfunction, and infection. At the molecular level, chronic hyperglycemia promotes the formation of advanced glycation end products (AGEs), activates the AGE-RAGE-NF-κB axis, increases oxidative stress, and impairs macrophage polarization from the pro-inflammatory M1 to the reparative M2 phenotype, collectively disrupting normal wound healing processes. The local wound environment is further worsened by antibiotic-resistant polymicrobial infections, which sustain inflammatory signaling and promote extracellular matrix degradation. The rising threat of antimicrobial resistance complicates infection management even further. Recent studies emphasize that optimal glycemic control using antihyperglycemic agents such as metformin, Glucagon-like Peptide 1 receptor agonists (GLP-1 receptor agonists), and Dipeptidyl Peptidase 4 enzyme inhibitors (DPP-4 inhibitors) improves overall metabolic balance. These agents also influence angiogenesis, inflammation, and tissue regeneration through pathways including AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), and vascular endothelial growth factor (VEGF) signaling. Evidence indicates that maintaining glycemic stability through continuous glucose monitoring (CGM) and adherence to antihyperglycemic treatment enhances antibiotic effectiveness by improving immune cell function and reducing bacterial virulence. This review consolidates current molecular evidence on the combined effects of glycemic and antibiotic therapies in DFUs. It advocates for an integrated approach that addresses both metabolic and microbial factors to restore wound homeostasis and minimize the risk of severe outcomes such as amputation. Full article

Obesity is considered a global pandemic. In Mexico, 7/10 adults, 4/10 adolescents, and 1/3 children are overweight or obese, and it is estimated that 90% of cases of type 2 diabetes (T2D) are attributable to these pathologies. Visceral adipose tissue (VAT) presents increased lipolysis, lower insulin sensitivity, and greater metabolic alterations. Glucagon-like peptide-1 (GLP-1) is a polypeptide incretin hormone that stimulates insulin secretion dependent on the amount of oral glucose consumed, reduces plasma glucagon concentrations, slows gastric emptying, suppresses appetite, improves insulin synthesis and secretion, and increases the sensitivity of β cells to glucose. Liraglutide is a synthetic GLP-1 analog that reduces VAT and improves the expression of Glucose transporter receptor type 4 (GLUT 4R), Mitogen-activated protein (MAP kinases), decreases Fibroblast growth factor type β (TGF-β), reactivates the peroxisome proliferator-activated receptor type ɣ (PPAR-ɣ) pathway, and decreases chronic inflammation. Currently, there are many studies that explain the decrease in VAT with these medications, but there are no studies that compare the decrease in patients with obesity and prediabetes vs. obesity and type 2 diabetes to know which population obtains a greater benefit from treatment with this pharmacological group; this is the reason for this study. The primary objective was to compare the difference in the determination of visceral adipose tissue in people with obesity and type 2 diabetes vs. obesity and prediabetes treated with liraglutide. Methods: A quasi-experimental, analytical, prolective, non-randomized, non-blinded study was conducted over a period of 6 months in a tertiary care center. A total of 36 participants were divided into two arms; group 1 (G1: Obesity and prediabetes) and group 2 (G2: Obesity and type 2 diabetes) for 6 months. Inclusion criteria: men and women ≥18 years with type 2 diabetes, prediabetes, and obesity. Exclusion criteria: Glomerular filtration rate (GFR) < 60 mL/min/1.73 m² elevated transaminases (>5 times the upper limit of normal), and use of non-weight-modifying antidiabetic agents. Conclusions: No statistically significant difference was found in the decrease in visceral adipose tissue when comparing G1 (OB and PD) with G2 (OB and T2D). When comparing intragroup in G2 (OB and T2D), greater weight loss was found [(−3.78 kg; p = 0.012) vs. (−3.78 kg; p = 0.012)], as well differences in waist circumference [(−3.9 cm; p = 0.049) vs. (−3.09 cm; p = 0.017)], and glucose levels [(−1.75 mmol/L; p = 0.002) vs. (−0.56 mmol/L; p = 0.002)], A1c% [(−1.15%; p = 0.001) vs. (−0.5%; p = 0.000)]. Full article

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly encompassed under nonalcoholic fatty liver disease (NAFLD), is a growing global health burden associated with progression to cirrhosis and hepatocellular carcinoma. Resmetirom, a thyroid hormone receptor-β (THR-β) agonist, and semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), have emerged as promising agents targeting distinct metabolic and inflammatory pathways. This systematic review compares the safety and efficacy of resmetirom and semaglutide in MASLD. Methods: We conducted a comprehensive search of PubMed, Embase, and Google Scholar for randomized controlled trials and clinical studies published between January 2014 and April 2025, following PRISMA guidelines. Studies assessing the efficacy and safety of resmetirom and/or semaglutide in MASLD or NASH were included. Data extraction was performed by two independent reviewers, and a narrative synthesis was undertaken due to the heterogeneity in study design and outcome measures. Results: Fourteen studies encompassing over 4500 patients were analyzed. Resmetirom demonstrated consistent reductions in hepatic fat (≥30% in >50% of patients) and improvements in fibrosis (≥1 stage in up to 26.4% of patients), as evidenced in the MAESTRO-NASH trial. Semaglutide achieved higher rates of NASH resolution (up to 62.9%) without worsening fibrosis, especially among patients with type 2 diabetes or obesity, although fibrosis improvement was less consistently observed. Resmetirom was well tolerated with low discontinuation rates, while semaglutide was associated with more frequent, yet manageable, gastrointestinal adverse events. Conclusions: Both resmetirom and semaglutide show therapeutic potential for MASLD. Resmetirom offers more consistent antifibrotic effects, while semaglutide excels in NASH resolution and metabolic improvement. The absence of direct comparative trials underscores the need for future head-to-head studies to guide tailored treatment strategies in MASLD management. Full article

The development of orally bioavailable non-peptidomimetic glucagon-like peptide-1 receptor agonists (GLP-1RAs) offers a promising therapeutic avenue for the treatment of type 2 diabetes mellitus (T2DM) and obesity. An extensive in silico approach combining structure-based drug design and ligand-based strategies together with pharmacokinetic properties and drug-likeness predictions is implemented to identify novel non-peptidic GLP-1RAs from the COCONUT and Marine Natural Products (CMNPD) libraries. More than 700,000 compounds were screened by shape-based similarity filtering in combination with precision docking against the orthosteric site of the GLP-1 receptor (PDB ID: 6X1A). The docked candidates were further assessed with the molecular mechanics MM-GBSA tool to check the binding affinities; the final list of candidates was validated by running a 500 ns long MD simulation. Twenty final hits were identified, ten from each database. The hits contained compounds with reported antidiabetic effects but with no evidence of GLP-1 agonist activity, including hits 1, 6, 7, and 10. These findings proposed a novel mechanism for these hits through GLP-1 activity and positioned the other hits as potential promising scaffolds. Among the studied compounds—especially hits 1, 5, and 9—possessed strong and stable interactions with critical amino acid residues such as TRP-203, PHE-381, and GLN-221 at the active site of the 6X1A-substrate along with favorable pharmacokinetic profiles. Moreover, the RMSF and RMSD plots further suggested the possibility of stable interactions. Specifically, hit 9 possessed the best docking score with a ΔG_bind value of −102.78 kcal/mol, surpassing even the control compound in binding affinity. The ADMET profiling also showed desirable drug-likeness and pharmacokinetic characteristics for hit 9. The pipeline of computational integration underscores the potential of non-peptidic alternatives in natural product libraries to pursue GLP-1-mediated metabolic therapy into advanced preclinical validation. Full article

This study aims to investigate the effects of dietary proanthocyanidins (PACs) on growth performance, intestinal inflammation and barrier function, and bile acid metabolism-related genes in weaned piglets challenged with lipopolysaccharide (LPS). A total of 18 21-day-old castrated piglets (7.16 ± 1.66 kg) were randomly assigned to three groups: (1) CON (a basal diet), (2) LPS (a basal diet + LPS), (3) LPS + PAC (a basal diet + LPS + 250 mg/kg PAC), with each group consisting of six replicates of 1 piglet per treatment. The study lasted for 21 days. On the 14th and 21st days of the experiment, piglets in the LPS and LPS + PAC groups received an intraperitoneal injection of 100 µg/kg body weight of LPS, while the piglets in the CON group received an injection of 0.9% normal saline solution. The LPS + PAC group exhibited a significantly higher average daily gain (ADG) than the LPS group (p < 0.05). LPS stimulation resulted in a decreased (p < 0.05) villus height of the jejunum and ileum and an increased number of goblet cells. These effects were alleviated (p < 0.05) in the LPS + PAC group. The LPS + PAC group decreased the level of TNF-α and D-lactate in serum and the gene expression of IL-6 and IL-1β in the ileal tissue, compared with the LPS group, while increasing the gene expression of Occludin and ZO-1 in the ileal tissue (p < 0.05). LPS stimulation down-regulated the expression of genes regulating bile acid synthesis and transport, including hepatic CYP7A1 and ileum ASBT, whereas dietary PAC had no significant effect on the expression of these genes (p > 0.05). Nevertheless, supplementation with PAC significantly increased the expression levels of GLP-2R, GCG, and TGR5 in the ileum of piglets (p < 0.05). Additionally, piglets in the LPS + PAC group exhibited a significant increase in the level of glucagon-like peptide 2 (GLP-2) compared with the LPS group (p < 0.05). PAC generally improves the ADG, intestinal morphology, and intestinal barrier function of piglets by activating TGR5 to stimulate the intestinal secretion of GLP-2. Full article

Background: GLP-1 receptor agonists (GLP-1 RAs) lower glucose and reduce cardiovascular events in type 2 diabetes, with noted renal benefits. Few studies directly compare GLP-1 RAs. This study aims to compare the effects of semaglutide and dulaglutide on renal function decline and proteinuria reduction in diabetic patients. Methods: The present study was conducted at Wanfang Hospital, Taipei Medical University. Diabetic patients using either semaglutide or dulaglutide for more than 1 year in the outpatient department from 1 January 2022 to 30 September 2024 were enrolled retrospectively. The outcome events in the present study included a decline in the estimated glomerular filtration rate (eGFR), an increase in the urine albumin–creatinine ratio (UACR), and patient death. Results: A total of 268 patients on dulaglutide and 747 on semaglutide were included. Baseline eGFR levels were similar in both groups. After 12 months, eGFR levels did not significantly decline in both groups. However, the dulaglutide group showed significantly higher UACR increases than the semaglutide group (p < 0.01). More death events also occurred in the dulaglutide group (p < 0.01). Multivariate logistic regression revealed a higher risk of UACR increase with dulaglutide (p < 0.01). Subgroup analysis found dulaglutide associated with higher UACR in patients younger than 60, males, those with hypertension, without heart failure, those using angiotensin receptor blockers, biguanides, and statins, and those not using sodium-glucose cotransporter-2 inhibitors. Conclusions: Dulaglutide and semaglutide had comparable effects on slowing eGFR decline. However, dulaglutide was less effective in reducing UACR, particularly in the subgroups mentioned above. Full article

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide. Epidemiological data demonstrate that the overlap between CVD, Type 2 Diabetes (T2DM), chronic kidney disease (CKD) and heart failure (HF) is becoming increasingly apparent, with aging populations making these patient cohorts more difficult to treat. In the last decade, three standout drug classes have emerged with the potential to broaden the treatment options for patients with multi-morbid CVD and heart failure. These are sodium–glucose cotransporter 2 (SGLT2) inhibitors, non-steroidal mineralocorticoid receptor antagonists (MRAs), e.g., Finerenone, and glucagon-like peptide 1 receptor agonists (GLP-1RAs). These medications are now entering UK and European guidelines for the treatment of CVDs including HF whilst crucially providing associated prognostic benefits for patients with T2DM and CKD. The future of these agents for CVD risk stratification may involve primary care at the forefront, alongside tailored, patient-specific medication regimens. This review article aims to discuss these three main drug classes (SGLT2 inhibitors, GLP-1RAs and non-steroidal MRAs) in detail by exploring their current evidence base across heart failure (HF) and CVD management and future clinical implications of their usage as mainstream medical therapies. Full article

Emerging clinical data support the paradoxical notion that glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) agonism and antagonism can provide additive weight loss when combined with a glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonist. In this review, we examine data that motivated the initiation of these seemingly contradictory drug discovery programs. We focus on the physiologic role of GIP in humans, human genetics evidence, rodent genetic models, and preclinical rodent and non-human primate pharmacology studies. Furthermore, we highlight where early preclinical findings translated into relevant clinical efficacy in the development of tirzepatide and maridebart cafraglutide (MariTide). Full article

Glucagon-like peptide-1 (GLP-1) is a hormone secreted from enteroendocrine cells that can promote weight loss and blood glucose improvement. We screened probiotic strains that effectively stimulate GLP-1 secretion from human enteroendocrine cells and then investigated the efficacy of this strain in a high-fat diet (HFD)-induced mouse model of obesity. Lactiplantibacillus plantarum GB104 greatly induced GLP-1 secretion by increasing expression of the proglucagon gene (GCG), but not the proprotein convertase subtilisin/kexin type 1 gene (PCSK1) in the human enteroendocrine cell line NCI-H716. In an HFD-induced mouse model of obesity, GB104 inhibited weight gain and improved blood glucose levels by increasing blood GLP-1 levels. It also tended to attenuate the HFD-induced changes in blood levels of other hormones and suppressed fat accumulation in the liver and adipose tissues. In white adipose tissue, GB104 suppressed inflammation by reducing pro-inflammatory M1 macrophages and increasing anti-inflammatory M2 macrophages and regulatory T cells. Probiotic strains that promote GLP-1 secretion, such as GB104, may serve as a promising candidate for dietary intervention against obesity and metabolic diseases. Full article

Obesity, insulin resistance, type 2 diabetes mellitus (T2DM) and metabolic syndrome have been largely correlated to a reduction in bacterial load and diversity, resulting in a condition known as intestinal dysbiosis. The recent emergence of novel antidiabetic medications has been demonstrated to exert a favourable influence on the composition of the intestinal microbiota. Incretin-based therapy exerts a multifaceted influence on the composition of the gut microbiota, leading to alterations in bacterial flora. Of particular significance is the capacity of numerous metabolites produced by the gut microbiota to modulate the activity and hormonal secretion of enteroendocrine cells. This review examines the effects of dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists and GLP-1/gastric inhibitory polypeptide (GIP) receptor dual agonists on the composition of the gut microbiota in both mice and human subjects. The nature of this interaction is complex and bidirectional. The present study demonstrates the involvement of the incretinic axis in modulating the microbial composition, with the objective of providing novel preventative strategies and potential personalised therapeutic targets for obesity and T2DM. Full article

Inflammatory bowel diseases (IBDs) are complex immune-mediated disorders characterised by an unpredictable direction and commonly associated metabolic comorbidities along with obesity and type 2 diabetes mellitus (T2DM). Recent evidence has highlighted the therapeutic capacity of glucagon-like peptide 1 receptor agonists (GLP-1 RAs), already employed in treating T2DM and obesity, in modulating systemic and intestinal inflammatory responses. This narrative review examines the general organic traits of GLP-1, with a specific awareness of its primary gastrointestinal actions and the efficacy of GLP-1 RAs in promoting weight loss and dealing with glycaemic control, mainly in sufferers with IBD. Furthermore, the effects of those agonists on the progression of IBD, their protection profile, their impact on bowel preparation for endoscopic procedures, and their therapeutic capacity, supported through preclinical and early clinical studies, are discussed. GLP-1 RAs appear to lessen the intestinal inflammatory burden by enhancing intestinal epithelial barrier features and modulating the gut microbiota. However, further clinical research will be necessary to verify whether GLP-1 RAs could play a position in IBD treatment. Full article

Background: Camel milk is considered to be an important source of bioactive peptides with potential anti-diabetic effects. However, the mechanism by which these active peptides exert their anti-diabetic effects is not clear. The aim of this study was to systematically evaluate the in vivo anti-diabetic effects of Leucine-Leucine-Proline-Lysine (LLPK), a novel dipeptidyl peptidase-4 (DPP-4) inhibitory peptide identified from the in vitro gastrointestinal digestion product of camel milk. Methods: A db/db diabetic mouse model was used, and LLPK was administered to mice at doses of 50 mg/kg BW and 100 mg/kg BW as a daily oral gavage for 30 days. The effects of LLPK on fasting blood glucose (FBG), oral glucose tolerance test (OGTT), insulin tolerance test (ITT), and serum lipid levels were monitored, and possible mechanisms of action were elucidated using proteomics. Results: The results demonstrated that LLPK significantly improved diabetic symptoms, including FBG, OGTT, ITT, and serum lipid levels in db/db diabetic mice. Furthermore, significantly increased levels of serum glucagon-like peptide 1 (GLP-1) and reduced serum DPP-4 activity were observed in the LLPK-treated group compared to the control group. Hepatic proteomics indicated that LLPK improved glucose and lipid metabolism via the PPAR signaling pathway, where the key targets were Scd1, Acox1, Acaa1b, Slc27a1, Acsl1, and Ehhadh. Conclusions: In summary, this study provided new insights into the anti-diabetic mechanisms of camel milk and supported the development of camel milk-based anti-diabetic functional foods or nutraceuticals. Full article

Introduction: GLP-1 receptor agonists are valuable therapeutic agents for managing obesity and type 2 diabetes. The link between prostate cancer and obesity was described. The modulation of incretin hormone-dependent pathways may decrease the prostate cancer aggressiveness and progression. Objectives: The purpose of this study was to review and summarize the literature on the role of GLP-1 agonists in prostate cancer. Material & Methods: We performed a scoping literature review of PubMed from January 2002 to February 2025. Search terms included “glucagon-peptide like 1”, “incretin hormone”, “GLP-1 receptor agonist”, and “prostate cancer”. Secondary search involved reference lists of eligible articles. The key criterion was to identify studies that included GLP-1 receptor, incretin hormones, GLP-1 receptor agonists, and their role in prostate cancer development. Results: 77 publications were selected for inclusion in this review. The studies contained in publications allowed us to summarize the data on the role of GLP-1 receptor and it’s agonists in prostate cancer biology and development. The following review aims to discuss and provide information about the role of incretin hormones in prostate cancer pathogenesis and its clinical implication in patients with prostate cancer. Conclusion: Incretin hormone-dependent pathways play an important role in prostate cancer pathogenesis. Moreover, GLP-1 receptor agonists seems to be a promising therapeutical agents when it comes to finding new therapies in patients with more aggressive and/or advanced stages of prostate cancer. Full article

Background: Though evidence is limited, animal products like pork sausages and cheese may affect satiety differently due to their distinct protein, fat, and calcium content. This study therefore compared their acute effects on breakfast using appetite-related markers. Methods: A total of 11 women and 13 men, with a mean age of 23.0 ± 2.6 years and mean BMI of 24.5 ± 2.6 kg/m², participated in this crossover design study. Concentrations of active ghrelin, glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), insulin, glucose, leptin, and blood lipids were measured. Subjective feelings of appetite using visual analogue scales were analyzed (0–4 h) as a response to two test breakfasts meals with a similar energy and macronutrient content. Appetite feelings and energy intake from an ad libitum buffet lunch were subsequently measured. Data were analyzed using two different ANOVA methods. Results: The pork sausage breakfast was characterized by an earlier triglyceride (TG) peak than the cheese. A slower TG clearance was seen with the cheese breakfast. Ghrelin suppression was longer in the pork sausage breakfast. Active GLP-1 concentration was higher following the cheese breakfast and active GIP declined slower. The two ANOVA methods disagreed regarding the insulin effect. Subjective feelings of hunger before buffet and ad libitum energy intake were higher in males (791 ± 64 kcal) compared with females (344 ± 32 kcal), but did not differ between breakfast types. Conclusions: Acute consumption of pork and cheese of the same energy, fat, and protein content provided detectable differences in appetite-related hormones and lipid responses. Appetite and lipid metabolism were affected by the major differentiators of the test meals, namely calcium, fatty acids and amino acids compositions. Full article

Background/Objectives: Dietary glucose is transported across the intestinal absorptive cell into the systemic circulation by the apically located Na⁺-dependent glucose transporter 1 (SGLT1, SLC5A1) and basally residing Na⁺-independent glucose transporter 2 (GLUT2, SLC2A2). Whilst recent experimental evidence has shown that sensing of sweet compounds by the gut-expressed sweet taste receptor T1R2–T1R3 and glucagon-like peptide-2 receptor signalling are components of the pathway controlling SGLT1 expression, little is known about the mechanisms involved in the regulation of GLUT2. In this study, we tested the hypothesis that T1R2–T1R3 and its downstream signalling pathway participate in the regulation of intestinal GLUT2. Methods: We used in vivo and in vitro approaches employing a weaning pig model, a heterologous expression assay, and knockout mice for elucidating the regulation of GLUT2 by luminal sugars. Results: A plant-based sweetener formulation included in piglets’ diet led to a marked increase in GLUT2 expression in piglets’ intestine, compared to controls. The sweeteners that do not activate pig T1R2–T1R3 failed to upregulate GLUT2. There was a significant increase in GLUT2 expression when the sweetener sucralose, which activates T1R2–T1R3, was included in the drinking water of wild-type mice. However, in knockout mice, in which the genes for the sweet receptor subunit T1R3 and the associated G-protein gustducin were deleted, there was no upregulation of GLUT2 expression in response to sucralose supplementation. There was a notable increase in GLUT2 expression in wild-type mice fed a high-carbohydrate diet compared to when maintained on a low-carbohydrate diet. However, in GLP-2 receptor knockout mice kept on the high-carbohydrate diet, there was no enhancement in GLUT2 expression. Conclusions: The experimental evidence suggests that luminal sweet sensing via T1R2–T1R3 and the enteroendocrine-derived GLP-2 are constituents of the regulatory pathway controlling GLUT2 expression. Full article