Search Results (21)

Glucagon-like peptide-1 receptor (GLP1R) agonists, such as semaglutide, are used for treating type 2 diabetes mellitus and promoting weight loss. This study investigates genetic and molecular mechanisms underlying GLP1R activation using a novel in silico approach to identify effects on metabolism, glucose and insulin production, gastrointestinal motility, behavior, and satiety. This approach used three separate searchable web-based programs and databases (STRING, Pathway Commons, and BioGRID) to identify and analyze functional gene and protein interactions with mechanisms to query GLP1R and related metabolic and appetite regulatory networks with disease associations. We examined integrated gene–gene and protein–protein interactions, pathways, molecular functions, associated diseases, and biological processes for GLP1R, that reportedly involved in diabetes and obesity. GLP1R signaling cascades were described with the activation of the adenylate cyclase-modulating G protein-coupled receptor and increased intracellular cyclic AMP, collectively impacting glucagon production, insulin, glycogenolysis, vasoactive intestinal peptide, and other peptides and hormones required for satiety. Additional factors found were obesity-related peptides (i.e., POMC), hormone signaling, renin secretion, electrolytes and diuresis, circadian rhythm, and insulin secretion. These associations and interactions shift from hypoglycemia to broader endocrine dysfunction. A relationship was noted for GNAS having a role in growth, electrolytes, and skeletal disturbances with specific hormone sensitivity patterns. Understanding established and new interactions with genetics and gene-protein variants that impact type 2 diabetes and obesity would provide further insight into therapeutic GLP1R agonists response and consequences. Potential long-term systemic effects should be monitored, studied, and recorded with treatment protocols adjusted accordingly. Full article

Obesity is an epidemic that currently impacts many nations. The persistence of this disease is shaped by both genetic and epigenetic factors that extend beyond calorie balance. Research in the past year has revealed that epigenetic and cellular memory within adipose tissue can predispose individuals to weight regain after initial fat loss, as shown by studies indicating persistent transcriptional and chromatin changes even after fat mass reduction. Independent studies also demonstrate long-lasting metabolic shifts, such as those triggered by glucose-dependent insulinotropic polypeptide receptor (GIPR)-induced thermogenesis and sarcolipin (SLN) stabilization that also support a form of “metabolic memory” that is associated with sustained weight loss. At the neural level, rare variants in synaptic genes like BSN (Bassoon presynaptic cytomatrix protein), a presynaptic scaffold protein, and APBA1 (amyloid beta precursor protein binding family A member 1), a neuronal adaptor involved in vesicular trafficking, disrupt communication in feeding circuits, elevating obesity risk and illustrating how synaptic integrity influences food intake regulation. Similarly, the spatial compartmentalization of metabolic signaling within neuronal cilia is emerging as crucial, with cilia-localized receptors G protein-coupled receptor 75 (GPR75) and G protein-coupled receptor 45 (GPR45) exerting opposing effects on energy balance and satiety. Meanwhile, genome-wide association studies (GWAS) have advanced through larger, more diverse cohorts and better integration of environmental and biological data. These studies have identified novel obesity-related loci and demonstrated the value of polygenic risk scores (PRS) in predicting treatment responses. For example, genetic variants in GLP-1R (glucagon-like peptide-1 receptor) and GIPR (glucose-dependent insulinotropic polypeptide receptor) may modulate the effectiveness of incretin-based therapies, while PRS for satiation can help match individuals to the most appropriate anti-obesity medications. This review focuses on studies in the last two years that highlight how advances in obesity genetics are driving a shift toward more personalized and mechanism-based treatment strategies. Full article

Glucagon-like peptide 1 (GLP-1), a hormone derived from the proglucagon gene, regulates various physiological processes; however, its impact on pregnancy outcomes remains poorly understood. Assessing the effects of GLP-1 on neonates is vital as GLP-1 is increasingly administered during pregnancy. This study evaluates the effect of GLP-1 exposure on maternal complications and neonatal defects in mice. Pregnant female A/J mice received subcutaneous injections of recombinant GLP-1 (rGLP-1; 1000 nmol/kg) on embryonic day 1 (EP, early pregnancy) or day 15 (E15, late pregnancy). Maternal and neonatal body weights, morphology, and mortality were recorded, and mRNA sequencing was conducted to analyze gene expression in neonatal tissues. Maternal body weight decreased following rGLP-1 exposure, and pups born to both the early and late exposure groups experienced significant weight loss. Pups in the late exposure group exhibited uniform skin detachment and a dramatically higher mortality rate than those born to the early exposure group. Further, RT-PCR analysis confirms the significantly increased expression of selected genes in the skin and associated pathogenesis. RNA sequencing of pups’ skin, brain, lung, and liver tissues from the late exposure group showed altered gene expression. Since maternal weight loss, increased neonatal mortality, and altered gene expression have been observed, GLP-1 receptor agonists (GLP-1RAs) should be avoided during pregnancy. Full article

HMG-CoA reductase inhibitors, statins, are extensively used to treat hyperlipidemia, coronary artery disease, and other atherosclerotic disorders. However, one of the common side effects of statin therapy is a mild elevation in liver aminotransferases, observed in less than 3% of patients. Atorvastatin and simvastatin, in particular, are most frequently associated with statin-induced liver injury, leading to treatment discontinuation. Recent research has highlighted the antioxidant and anti-inflammatory properties of glucagon-like peptide-1 receptor (GLP-1R) activation in protecting against liver injury. Nonetheless, the potential protective effects of liraglutide (LIRA), a GLP-1R agonist, against atorvastatin (ATO)-induced liver dysfunction have not been fully elucidated. In this context, the present study aimed to investigate the protective role of LIRA in mitigating ATO-induced liver injury in rats, offering new insights into managing statin-associated hepatotoxicity. Indeed, LIRA treatment improved liver function enzymes and attenuated histopathological alterations. LIRA treatment enhanced antioxidant defenses by increasing Nrf2 content and superoxide dismutase (SOD) activity, while reducing NADPH oxidase. Additionally, LIRA suppressed inflammation by downregulating the HMGB1/TLR-4/RAGE axis and inhibiting the protein expression of pY323-MAPK p38 and pS635-NFκB p65 content resulting in decreased proinflammatory cytokines (TNF-α and IL-1β). Furthermore, LIRA upregulated GLP-1R gene expression and promoted autophagic influx via the activation of the pS473-Akt/pS486-AMPK/pS758-ULK1/Beclin-1 signaling cascade, along with inhibiting apoptosis by reducing caspase-3 content. In conclusion, LIRA attenuated ATO-induced oxidative stress and inflammation via activation of the Nrf-2/SOD cascade and inhibition of the HMGB1/TLR-4/RAGE /MAPK p38/NFκB p65 axis. In parallel, LIRA stimulated autophagy via the AMPK/ULK1/Beclin-1 axis and suppressed apoptosis, thus restoring the balance between autophagy and apoptosis. Full article

Cancer metabolism is a hallmark of cancer. However, the impact of systemic metabolism and diet on tumour evolution is less understood. This study delves into the role of glucagon, as a component of the pancreatic microenvironment, in regulating features of pancreatic neuroendocrine tumour (pNET) cells and the metabolic remodelling occurring in the presence and absence of glucose. pNET cell lines (BON-1 and QGP-1) and the non-malignant pancreatic α-TC1 cell line were used as models. Results showed that pNET cells responded differently to glucose deprivation than α-TC1 cells. Specifically, pNET cells upregulated the GCGR in the absence of glucose, while α-TC1 cells did so in high-glucose conditions, allowing the glucagon-related pERK1/2 activation under these conditions in pNET cells. Glucagon enhanced cancerous features in pNET BON-1 cells under glucose-deprived and hyperglucagonemia-compatible concentrations. In the α-TC1 cell line, glucagon modulated cell features under high-glucose and physiological glucagon levels. NMR exometabolome analysis revealed differences in metabolic processes based on glucose availability and glucagon stimulation across cell lines, highlighting amino acid metabolism, glycolysis, and gluconeogenesis. The expression of metabolic genes was consistent with these findings. Interestingly, QGP-1 and α-TC1 cells produced glucose in no-glucose conditions, and glucagon upregulated glucose production in α-TC1 cells. This suggests that gluconeogenesis may be beneficial for some pNET subsets, pointing out novel metabolism-based strategies to manage pNETs, as well as a step forward in endocrinology and systemic metabolism. The association between GCGR expression and malignancy and a negative correlation between glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) expression was observed, indicating a biological role of glucagon in pNETs that deserves to be explored. 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

Background: Glucagon-like peptide-2 (GLP-2) is a gut hormone secreted in response to nutrient intake and regulates lipid metabolism in the gut. The present study aims to elucidate the underlying mechanism of GLP-2 in stimulating gut lipid secretion in the fasted state by testing whether GLP-2 signals through the brain’s GLP-2 receptor and melanocortin 4 receptor (MC4R). Methods: Sprague-Dawley rats were implanted with a mesenteric lymph duct cannula for measuring gut lipid secretion and an intracerebroventricular cannula for infusion of a GLP-2R antagonist (GLP-2(11-33)), an MC4R antagonist (SHU9119), or saline as a control. The rat received a lipid infusion into the small intestine and a peritoneal injection of GLP-2 five hours later. Results: Brain administration of a GLP-2R antagonist or an MC4R antagonist attenuated the stimulatory effects of peripheral GLP-2 on lymph triglyceride output. These effects were associated with differential changes in the expression of key genes in jejunal endothelial cells, smooth muscle cells, and neuronal cells. Conclusions: These results support the involvement of central GLP-2R and MC4R in a neural pathway for GLP-2 to mobilize lipids stored in the gut during the post-absorptive state. Full article

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have emerged as a promising therapeutic option beyond their established role in managing type 2 diabetes mellitus (T2DM) and obesity. Recent research has highlighted their beneficial effects on liver, kidney, and cardiovascular health, mediated by both direct and indirect mechanisms. In the liver, GLP-1 RAs contribute to the improvement of metabolic dysfunction-associated steatotic liver disease (MASLD) by reducing hepatic fat accumulation, inflammation, and oxidative stress. Additionally, they enhance insulin sensitivity and lipid metabolism. Similarly, in diabetic kidney disease (DKD), GLP-1 RAs exhibit renoprotective properties by mitigating inflammation, oxidative stress, and glomerular hypertension. Furthermore, they promote natriuresis and stabilize renal function. Moreover, GLP-1 RAs present significant cardiovascular benefits, including improved myocardial function, reduced atherosclerosis progression, enhanced endothelial health, and decreased major adverse cardiovascular events (MACEs). Additionally, emerging evidence suggests GLP-1 RAs may exert substantial neuropsychiatric benefits, including reductions in depressive symptoms, anxiety, substance use behaviors, and lowering the risk of Alzheimer’s disease, Parkinson’s disease, and other dementias likely mediated by the modulation of neurotransmitter systems and neuroinflammation. Genetic polymorphisms in the GLP1R gene also impact the therapeutic response, highlighting the importance of personalized medicine in optimizing GLP-1 RA efficacy. This review synthesizes preclinical and clinical evidence supporting the multifaceted effects of GLP-1 RAs across multiple organ systems, highlighting their therapeutic potential beyond glycemic control. As research advances, further exploration of their mechanisms of action and long-term clinical outcomes, safety and effectiveness across diverse patient populations will be essential in optimizing their use in treating metabolic and neuropsychiatric conditions. Full article

Emerging evidence suggests that glucagon-like peptide-1 receptor (GLP1R) agonists may have potential benefits for mental illnesses. However, their exact effects remain unclear. This study investigated the causal relationship between glucagon-like peptide-1 receptor agonist (GLP1RA) and the risk of 10 common mental illnesses, including attention deficit and hyperactivity disorder, anorexia nervosa, anxiety disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, post-traumatic stress disorder, schizophrenia, cannabis use disorder, and alcohol use disorder. We selected GLP1RA as the exposure and conducted a Mendelian randomization (MR) analysis. The cis-eQTLs of the drug target gene GLP1R, provided by eQTLGen, were used to simulate the pharmacological effects of GLP1RA. Type 2 diabetes and BMI were included as positive controls. Using data from both the Psychiatric Genomic Consortium and FinnGen, we conducted separate MR analyses for the same disease across these two independent databases. Meta-analysis was used to pool the results. We found genetic evidence suggesting a causal relationship between GLP1RA and a reduced risk of schizophrenia [OR (95% CI) = 0.84 (0.71–0.98), I² = 0.0%, common effects model]. Further mediation analysis indicated that this effect might be unrelated to improvements in glycemic control but rather mediated by BMI. However, the findings of this study provide insufficient evidence to support a causal relationship between GLP1RA and other mental illnesses. Sensitivity analyses did not reveal any potential bias due to horizontal pleiotropy or heterogeneity in the above results (p > 0.05). This study suggests that genetically proxied activation of glucagon-like peptide-1 receptor is associated with a lower risk of schizophrenia. GLP1R is implicated in schizophrenia pathogenesis, and its agonists may exert potential benefits through weight management. Our study provides useful information for understanding the neuropsychiatric effects of GLP1RA, which may contribute to refining future research designs and guiding clinical management. Moreover, our findings could have significant implications for overweight individuals at high risk of schizophrenia when selecting weight-loss medications. Future research should further investigate the potential mechanisms underlying the relationship between GLP1RA and schizophrenia. Full article

Sexual maturation in goats is a dynamic process regulated precisely by the hypothalamic–pituitary–gonadal axis and is essential for reproduction. The hypothalamus plays a crucial role in this process and is the control center of the reproductive activity. It is significant to study the molecular mechanisms in the hypothalamus regulating sexual maturation in goats. We analyzed the serum hormone profiles and hypothalamic mRNA expression profiles of female goats during sexual development (1 day old (neonatal, D1, n = 5), 2 months old (prepuberty, M2, n = 5), 4 months old (sexual maturity, M4, n = 5), and 6 months old (breeding period, M6, n = 5)). The results indicated that from D1 to M6, serum hormone levels, including FSH, LH, progesterone, estradiol, IGF1, and leptin, exhibited an initial increase followed by a decline, peaking at M4. Furthermore, we identified a total of 508 differentially expressed genes in the hypothalamus, with a total of four distinct expression patterns. Nuclear receptor subfamily 1, group D, member 1 (NR1D1), glucagon-like peptide 1 receptor (GLP1R), and gonadotropin-releasing hormone 1 (GnRH-1) may contribute to hormone secretion, energy metabolism, and signal transduction during goat sexual maturation via circadian rhythm regulation, ECM receptor interactions, neuroactive ligand–receptor interactions, and Wnt signaling pathways. This investigation offers novel insights into the molecular mechanisms governing the hypothalamic regulation of goat sexual maturation. Full article

Pre-metabolic syndrome (pre-MetS) may represent the best transition phase to start treatments aimed at reducing cardiometabolic risk factors of MetS. In this study, we investigated the effects of the marine microalga Tisochrysis lutea F&M-M36 (T. lutea) on cardiometabolic components of pre-MetS and its underlying mechanisms. Rats were fed a standard (5% fat) or a high-fat diet (20% fat) supplemented or not with 5% of T. lutea or fenofibrate (100 mg/Kg) for 3 months. Like fenofibrate, T. lutea decreased blood triglycerides (p < 0.01) and glucose levels (p < 0.01), increased fecal lipid excretion (p < 0.05) and adiponectin (p < 0.001) without affecting weight gain. Unlike fenofibrate, T. lutea did not increase liver weight and steatosis, reduced renal fat (p < 0.05), diastolic (p < 0.05) and mean arterial pressure (p < 0.05). In visceral adipose tissue (VAT), T. lutea, but not fenofibrate, increased the β3-adrenergic receptor (β3ADR) (p < 0.05) and Uncoupling protein 1 (UCP-1) (p < 0.001) while both induced glucagon-like peptide-1 receptor (GLP1R) protein expression (p < 0.001) and decreased interleukin (IL)-6 and IL-1β gene expression (p < 0.05). Pathway analysis on VAT whole-gene expression profiles showed that T. lutea up-regulated energy-metabolism-related genes and down-regulated inflammatory and autophagy pathways. The multitarget activity of T. lutea suggests that this microalga could be useful in mitigating risk factors of MetS. Full article

Substantial evidence suggests crosstalk between reproductive and gut-axis but mechanisms linking metabolism and reproduction are still unclear. The present study evaluated the possible role of glucose-dependent-insulinotropic-polypeptide (GIP) and glucagon-like-peptide-1 (GLP-1) in reproductive function by examining receptor distribution and the effects of global GIPR and GLP-1R deletion on estrous cycling and reproductive outcomes in mice. GIPR and GLP-1R gene expression were readily detected by PCR in female reproductive tissues including pituitary, ovaries and uterine horn. Protein expression was confirmed with histological visualisation of incretin receptors using GIPR-Cre and GLP1R-Cre mice in which the incretin receptor expressing cells were fluorescently tagged. Functional studies revealed that female GIPR^−/− and GLP-1R^−/− null mice exhibited significantly (p < 0.05 and p < 0.01) deranged estrous cycling compared to wild-type controls, indicative of reduced fertility. Furthermore, only 50% and 16% of female GIPR^−/− and GLP-1R^−/− mice, respectively produced litters with wild-type males across three breeding cycles. Consistent with a physiological role of incretin receptors in pregnancy outcome, litter size was significantly (p < 0.001–p < 0.05) decreased in GIPR^−/− and GLP-1R^−/− mice. Treatment with oral metformin (300 mg/kg body-weight), an agent used clinically for treatment of PCOS, for a further two breeding periods showed no amelioration of pregnancy outcome except that litter size in the GIPR^−/− group was approximately 2 times greater in the second breeding cycle. These data highlight the significance of incretin receptors in modulation of female reproductive function which may provide future targets for pharmacological intervention in reproductive disorders. Full article

Aim: Calorie restriction (CR) diets and glucagon-Like Peptide-1 (GLP-1) analogs are known to alter energy homeostasis with the potential to affect the expression of obesity-related genes (ORGs). We hypothesized that CR and GLP-1 administration can alter ORGs expression in spermatozoa and testes, as well as the sperm parameters implicated in male fertility. Materials and Methods: Six-week-old adult male Wistar rats (n = 16) were divided into three groups, submitted either to CR (n = 6, fed with 30% less chow diet than the control rats), GLP-1 administration (n = 5, 3.5 pmol/min/kg intraperitoneal) for 28 days, or used as controls (n = 5, fed ad libitum). Selected ORGs expression, namely the fat mass and obesity-associated (FTO), melanocortin-4 receptor (MC4R), glucosamine-6-phosphate deaminase 2 (GNPDA2), and transmembrane protein 18 (TMEM18) were evaluated in testes and spermatozoa by a quantitative polymerase chain reaction (qPCR). Results: CR resulted in lower body weight gain and insulin resistance, but a higher percentage of sperm head defects. GLP-1 administration, despite showing no influence on body weight or glucose homeostasis, resulted in a lower percentage of sperm head defects. CR and GLP-1 administration were associated with a higher expression of all ORGs in the testes. Under CR conditions, the genes FTO and TMEM18 expression in the testes and the MC4R and TMEM18 transcripts abundance in sperm were positively correlated with the spermatozoa oxidative status. The abundance of FTO and TMEM18 in the spermatozoa of rats under CR were positively correlated with sperm concentration, while the testes’ TMEM18 expression was also positively correlated with sperm vitality and negatively correlated with insulin resistance. Testes GNPDA2 expression was negatively correlated with sperm head defects. Conclusions: CR and GLP-1 administration results in higher ORGs expression in testes, and these were correlated with several alterations in sperm fertility parameters. Full article

The glucagon-like peptide-1 receptor (GLP-1R) plays a key role in metabolism and is an important therapeutic target in diabetes and obesity. Recent studies in experimental animals have shown that certain subsets of T cells express functional GLP-1R, indicating an immune regulatory role of GLP-1. In contrast, less is known about the expression and function of the GLP-1R in human T cells. Here, we provide evidence that activated human T cells express GLP-1R. The expressed GLP-1R was functional, as stimulation with a GLP-1R agonist triggered an increase in intracellular cAMP, which was abrogated by a GLP-1R antagonist. Analysis of CD4⁺ T cells activated under T helper (Th) 1, Th2, Th17 and regulatory T (Treg) cell differentiation conditions indicated that GLP-1R expression was most pronounced in induced Treg (iTreg) cells. Through multimodal single-cell CITE- and TCR-sequencing, we detected GLP-1R expression in 29–34% of the FoxP3⁺CD25⁺CD127^- iTreg cells. GLP-1R⁺ cells showed no difference in their TCR-gene usage nor CDR3 lengths. Finally, we demonstrated the presence of GLP-1R⁺CD4⁺ T cells in skin from patients with allergic contact dermatitis. Taken together, the present data demonstrate that T cell activation triggers the expression of functional GLP-1R in human CD4⁺ T cells. Given the high induction of GLP-1R in human iTreg cells, we hypothesize that GLP-1R⁺ iTreg cells play a key role in the anti-inflammatory effects ascribed to GLP-1R agonists in humans. Full article

Diabetes is commonly treated with glucagon-like peptide-1 receptor (GLP-1R) agonists including liraglutide and others. However, liraglutide was found to raise plasma glucose levels in normal rats. The current study aims to determine how liraglutide causes this contentious condition in rats, both normal and diabetic. An adrenalectomy was performed to investigate the relationship between steroid hormone and liraglutide. To investigate the effect of central liraglutide infusion on blood glucose in rats, rats were intracerebroventricularly administrated with liraglutide with or without HPA axis inhibitors such as berberine and dexamethasone. The results showed that a single injection of liraglutide caused a temporary increase in blood glucose in healthy rats. Another GLP-1R agonist, Exendin-4 (Ex-4), increased blood sugar in a manner similar to that of liraglutide. The effects of liraglutide were also blocked by guanethidine pretreatment and vanished in normal rats with adrenalectomy. Additionally, central infusion of liraglutide via intracerebroventricular (icv) injection into normal rats also causes a temporary increase in blood glucose that was blocked by GLP-1R antagonists or the inhibitors such as berberine and dexamethasone. Similarly, central liraglutide treatment causes temporary increases in plasma glucose, adrenocorticotropic hormone (ACTH), and cortisol levels, which were reversed by inhibitors for the hypothalamic-pituitary-adrenal (HPA) axis. In normal rats, the temporary glucose-increasing effect of liraglutide was gradually eliminated during consecutive daily treatments, indicating tolerance formation. Additionally, liraglutide and Ex-4 cross-tolerance was also discovered in normal rats. Liraglutide was more effective in diabetic rats than in normal rats in activating GLP-1R gene expression in the isolated adrenal gland. Interestingly, the effect of liraglutide on glycemic control varied depending on whether the rats were diabetic or not. In normal rats, bolus injection of liraglutide, such as Ex-4, may stimulate the HPA axis, resulting in hyperglycemia. The cross-tolerance of liraglutide and Ex-4 provided a novel perspective on GLP-1R activation. Full article