GLP-1 Receptor Expression Research Articles

Glp1r-Lepr coexpressing neurons modulate the suppression of food intake and body weight by a GLP-1/leptin dual agonist.

Glucagon-like peptide-1 (GLP-1) and leptin signal recent feeding and long-term energy stores, respectively, and play complementary roles in the modulation of energy balance. Previous work using single-cell techniques in mice revealed the existence of a population of leptin receptor (Lepr)-containing dorsomedial hypothalamus (DMH) neurons marked by the expression of GLP-1 receptor (Glp1r; LepRGlp1r neurons) that play important roles in the control of feeding and body weight by leptin. Here, we demonstrate the existence of a population of LepRGlp1r neurons in the DMHs of nonhuman primates (NHPs), suggesting the potential translational relevance of these neurons. Consequently, we developed a GLP-1R/LepR dual agonist and demonstrated the physiological activity of both components in vivo using leptin-deficient and Lepr-deficient murine models. We further found roles for LepRGlp1r neurons in mediating the dual agonist's efficacy on food intake and body weight loss. Ablating Lepr in Glp1r-expressing neurons (LeprGlp1rKO mice) abrogated the suppression of food intake by the dual agonist. Furthermore, reactivation of Glp1r expression in Lepr neurons on an otherwise Glp1r-null background (Glp1rLeprRe mice) was sufficient to permit the suppression of food intake and body weight by the dual agonist. Hence, LepRGlp1r neurons represent targets for a GLP-1R/LepR dual agonist that potently reduces food intake and body weight.

GLP-1 receptor signaling restores aquaporin 4 subcellular polarization in reactive astrocytes and promotes amyloid β clearance in a mouse model of Alzheimer's disease.

The physiological actions of a gut hormone, glucagon-like peptide-1 (GLP-1), in Alzheimer's disease (AD) brain remain poorly understood, although GLP-1 receptor (GLP-1R) expression in this organ has been shown in several experimental studies. Therefore, we explored whether the GLP-1R signaling promotes the clearance of amyloid β (Aβ) (1-42) which is a core pathological hallmark of AD, focusing on the water channel protein aquaporin 4 (AQP4) localized to astrocyte endfeet perivascular membranes in intact brain. First, we confirmed that Glp1r mRNA is predominantly expressed at perivascular site of astrocytes in normal mouse cerebral cortex through in situ hybridization analysis. Next, we observed that 20-week subcutaneous administration of a GLP-1R agonist (GLP-1RA) liraglutide significantly reduced Aβ (1-42) accumulation in the cerebral cortex and improved spatial working memory in an AD mouse model, AppNL-G-F/NL-G-F mice. Furthermore, our current data revealed that the 4-week liraglutide treatment relocalized subcellular AQP4 in morphologically injured reactive astrocytes of AppNL-G-F/NL-G-F mice to the cell surface perivascular site through PKA-mediated AQP4 phosphorylation. Such translocation of phosphorylated AQP4 to astrocyte cell surface following incubation with liraglutide was observed also in the present in vitro study using the cell line in which AQP4 cDNA was introduced into immortalized human astrocyte. These results suggest that enhanced intracerebral GLP-1R signaling following peripheral administration of GLP-1RA restores AQP4 subcellular polarization in reactive astrocytes and would promote Aβ excretion possibly through increasing AQP4-mediated intracerebral water flux in the brain in AD.

Activation of the HPA axis does not explain non-responsiveness to GLP-1R agonist treatment in individuals with type 2 diabetes.

Glucagon-like peptide 1 receptor (GLP-1R) agonists fail to reduce weight and improve glucose control in a sizable minority of people with type 2 diabetes. We hypothesized that stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by GLP-1R agonists, thus inducing cortisol secretion, could explain this unresponsiveness to GLP-1R agonists. To assess the effects of GLP-1R agonist treatment on the HPA axis, we selected ten individuals with type 2 diabetes with (5 women/5 men) and nine without (4 women/5 men) an adequate response to GLP-1R agonists and used [68Ga]Ga-NODAGA-exendin-4 positron emission tomography (PET)/computed tomography (CT) to quantify GLP-1R expression in the pituitary. Oral glucose tolerance and 24 h urinary cortisol excretion was measured in all participants. Pituitary tracer uptake was observed in all participants with no significant difference between responders and non-responders. Pituitary tracer uptake correlated with the area under the curve for ACTH, urinary cortisol to creatinine ratio and age. Interestingly, men had higher pituitary tracer uptake than women. In conclusion, this study does not indicate a role for pituitary GLP-1R expression and HPA axis stimulation to explain the difference in treatment response to GLP-1R agonists among individuals with type 2 diabetes. The findings of substantial pituitary GLP-1R expression and the significant sex differences require further research.

Genetic Evidence for GLP-1 and GIP Receptors as Targets for Treatment and Prevention of MASLD/MASH.

Glucagon-like peptide-1 receptor (GLP1R) agonists and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists may help treat metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). However, their definitive effects are still unclear. Our study aims to clarify this uncertainty. We utilised conventional Mendelian randomisation (MR) analysis to explore potential causal links between plasma GLP-1/GIP concentrations and MASLD and its related traits. Next, we conducted drug-target MR analysis using highly expressed tissue data to assess the effects of corresponding drug perturbation on these traits. Finally, mediation analysis was performed to ascertain whether the potential causal effect is direct or mediated by other MASLD-related traits. Circulating 2-h GLP-1 and GIP concentrations measured during an oral glucose tolerance test showed hepatoprotective effects on MASLD risk (ORGLP-1 = 0.168 [95% CI 0.033-0.839], p = 0.030; ORGIP = 0.331 [95% CI 0.222-0.494], p = 6.31 × 10-8). GLP1R expression in the blood had a minimal causal effect on MASLD risk, whereas GIPR expression significantly affected MASLD risk (OR = 0.671 [95% CI 0.531-0.849], p = 9.07 × 10-4). Expression levels of GLP1R or GIPR in the blood significantly influenced MASLD-related clinical traits. Mediation analysis revealed that GIPR expression protected against MASLD, even after adjusting for type 2 diabetes or body mass index. GLP-1/GIP receptor agonists offer promise in lowering MASLD/MASH risk. GIP receptor agonists can exert direct and indirect effects on MASLD mediated by weight reduction or glycemic control improvement.

Cystic fibrosis-related diabetes is associated with reduced islet protein expression of GLP-1 receptor and perturbation of cell-specific transcriptional programs

Insulin secretion is impaired in individuals with cystic fibrosis (CF), contributing to high rates of CF-related diabetes (CFRD) and substantially increasing disease burden. To develop improved therapies for CFRD, better knowledge of pancreatic pathology in CF is needed. Glucagon like peptide-1 (GLP-1) from islet α cells potentiates insulin secretion by binding GLP-1 receptors (GLP-1Rs) on β cells. We determined whether expression of GLP-1 and/or its signaling components are reduced in CFRD, thereby contributing to impaired insulin secretion. Immunohistochemistry of pancreas from humans with CFRD versus no-CF/no-diabetes revealed no difference in GLP-1 immunoreactivity per islet area, whereas GLP-1R immunoreactivity per islet area or per insulin-positive islet area was reduced in CFRD. Using spatial transcriptomics, we observed several differentially expressed α- and/or β-cell genes between CFRD and control pancreas. In CFRD, we found upregulation of α-cell PCSK1 which encodes the enzyme (PC1/3) that generates GLP-1, and downregulation of α-cell PCSK1N which inhibits PC1/3. Gene set enrichment analysis also revealed α and β cell-specific pathway dysregulation in CFRD. Together, our data suggest intra-islet GLP-1 is not limiting in CFRD, but its action may be restricted due to reduced GLP-1R protein levels. Thus, restoring β-cell GLP-1R protein expression may improve β-cell function in CFRD.

Effect of glucagon-like peptide-1 receptor agonists on prostate cancer: A review.

Glucagon-like peptide-1 receptor agonist (GLP-1RA) is widely used in the treatment of type 2 diabetes mellitus (T2DM) for its significant hypoglycemic effect, weight loss and small side effects. Some studies have shown that GLP-1RA has an inhibitory effect on prostate cancer, and its application will produce adverse effects associated with an increased or decreased risk of some tumors. GLP-1R is widely expressed by various types of cells and tissues in the human body, so GLP-1RA has attracted wide clinical attention to the occurrence, development and prognosis of tumors, which brings more new directions and hopes for the treatment of prostate cancer. This paper describes the expression of glucagon-like peptide-1 receptor (GLP-1R) in prostate cancer and the effects of glucagon-like peptide-1 receptor agonist (GLP-1RA) on prostate cancer.

Expression of Glucagon-Like Peptide-1 Receptors in the Submandibular Gland of Mice and Its Implications in Type 2 Diabetes.

Introduction Type 2 diabetes mellitus (T2DM) not only affects the pancreas directly involved in glucose metabolism but also impairs salivary gland function. Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone that lowers postprandial blood glucose levels by stimulating insulin secretion from the pancreas. Previous studies have revealed the presence of GLP-1 receptors (GLP-1R) in salivary glands. However, the effect of diabetes on salivary gland GLP-1R remains unclear. This study aimed to observe the impact of T2DM on GLP-1R in the submandibular gland (SMG). Materials and methods Twenty-five-week-old mice were randomly divided into four groups (n=5 each): 11w and 13w control groups (CON), and 11w and 13wdiabetes mellitusgroups (DM). After a five-day adaptation period, the DM group mice were subjected to a high-fat diet, while the CON group received a standard diet. The DM group mice were then induced into a state of T2DM by a single low-dose streptozotocin injection at nine weeks of age. Oral glucose tolerance tests (OGTT) were conducted to evaluate mouse glucose tolerance. At 11 and 13 weeks of age, SMG was excised under general anesthesia, and the morphology of SMG was evaluated by hematoxylin-eosin staining, while the distribution and expression of GLP-1R were assessed by immunohistochemical staining. The data obtained were subjected to the Shapiro-Wilk test to confirm normal distribution, the t-test for the OGTTresults, and statistical analysis for other results by one-way analysis of variance. Results Consistent with previous reports, the mice in the DM group showed higher body weight and lower glucose tolerance.Histological analysis revealed an increase in the acinar area and a decrease in the ductal area of the SMG in the DM group. Although there was no significant decrease in the cell count regarding the ductal area, a tendency towardluminal dilation was observed. Interestingly, the expression pattern of GLP-1R was limited to the ductal portion of the SMG, with a decrease in anti-GLP-1R-positive areas observed in the DM group compared to the CON group.While there was no significant difference in anti-GLP-1R-positive areas between the CON11w and CON13w groups, the DM13w group exhibited a significant decrease compared to the DM11w group. These data suggest that diabetes induces both structural changes in the SMG and a reduction in GLP-1R expression, particularly in the ductal regions. Conclusions We found that the expression level of GLP-1R in SMG was decreased in the DM group mice. This data demonstrates the potential relationship between T2DM and GLP-1R expression. Moreover, there was an indication of a temporal decrease in anti-GLP-1R positive areas over time.Thisresult may suggest the involvement of salivary gland GLP-1R in the mechanism of impaired SMG function caused by T2DM, potentially mediated through the decrease in blood GLP-1 levels.

Targeting microglial GLP1R in epilepsy: A novel approach to modulate neuroinflammation and neuronal apoptosis

BackgroundEpilepsy is a prevalent disorder of the central nervous system. Approximately, one-third of patients show resistance to pharmacological interventions. The pathogenesis of epilepsy is complex, and neuronal apoptosis plays a critical role. Aberrantly reactive astrocytes, induced by cytokine release from activated microglia, may lead to neuronal apoptosis. This study investigated the role of glucagon-like peptide 1 receptor (GLP1R) in microglial activation in epilepsy and its impact on astrocyte-mediated neurotoxicity. MethodsWe used human hippocampal tissue from patients with temporal lobe epilepsy and a pilocarpine-induced epileptic mouse model to assess neurobiological changes in epilepsy. BV2 microglial cells and primary astrocytes were used to evaluate cytokine release and astrocyte activation in vitro. The involvement of GLP1R was explored using the GLP1R agonist, Exendin-4 (Ex-4). ResultsOur findings indicated that reduced GLP1R expression in hippocampal microglia in both epileptic mouse models and human patients, correlated with increased cytokine release and astrocyte activation. Ex-4 treatment restored microglial homeostasis, decreased cytokine secretion, and reduced astrocyte activation, particularly of the A1 phenotype. These changes were associated with a reduction in neuronal apoptosis. In addition, Ex-4 treatment significantly decreased the frequency and duration of seizures in epileptic mice. ConclusionsThis study highlights the crucial role of microglial GLP1R in epilepsy pathophysiology. GLP1R downregulation contributes to microglial- and astrocyte-mediated neurotoxicity, exacerbating neuronal death and seizures. Activation of GLP1R with Ex-4 has emerged as a promising therapeutic strategy to reduce neuroinflammation, protect neuronal cells, and control seizures in epilepsy. This study provides a foundation for developing novel antiepileptic therapies targeting microglial GLP1R, with the potential to improve outcomes in patients with epilepsy.

Curcumin alone not combined with piperine exerts cardioprotective effects in pressure-overload rats by increasing glucagon-like peptide-1 receptor signaling and additional properties

Background and aimCurcumin has shown significant cardiovascular protective effects. However, the low bioavailability limits its practical application. As a natural bioenhancer, piperine is expected to increase the bioavailability of curcumin, and then, enhance its beneficial effects. Meanwhile, glucagon-like peptide-1 receptor (GLP-1R) signaling has been confirmed to be involved in the regulation of cardiovascular events. Herein, this study aimed to investigate whether piperine could enhance the beneficial effects of curcumin in pressure-overload rats and whether GLP-1/GLP-1R signaling is involved in their action mechanism. Methods and resultsMale Sprague-Dawley (SD) adult rats were subjected to abdominal aortic constriction (AAC) surgery to 16 weeks, which elevated blood pressure and induced cardiac hypertrophy. Curcumin (100 mg/kg/day) or/and piperine (20 mg/kg/day) were orally given for 4 weeks from the 17th week after AAC surgery. Curcumin alone treatment significantly lowered blood pressure, ameliorated cardiovascular remodeling, improved left ventricular performance and endothelium-dependent vascular relaxation. Accompanied by these results, GLP-1R expression in the myocardium was up-regulated. Piperine alone also exhibited a certain positive inotropic cardiac activity, but the effect was less significant. The combination of curcumin and piperine didn't show enhanced cardiovascular protective effects relative to curcumin, along with decreased fasting serum GLP-1 level and GLP-1R expression in the myocardium. ConclusionCurcumin exerts cardiovascular protective effects in pressure-overload rats by upregulating GLP-1R, and inhibiting of GLP-1/GLP-1R signaling pathway may be related to the limited beneficial effects of combination of curcumin and piperine. This study provides a new thinking that oral administration of some spices may affect cardiovascular function by modulating the GLP-1/GLP-1R system in a mode of gut-heart axis regulation.

Building the Glucagon-Like Peptide-1 Receptor Brick by Brick: Revisiting a 1993 Diabetes Classic by Thorens etal.

The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor involved in the regulation of blood glucose levels and food intake. Stabilized agonists targeting GLP-1R are used in the treatment of type 2 diabetes and have recently become a breakthrough obesity therapy. Here, we revisit a classic article in Diabetes by Thorens etal. that described the cloning, sequencing, and functional expression of the human GLP-1R. The article also demonstrated that exendin4(1-39) was a full agonist of the human GLP-1R whereas exendin4(9-39) was a full antagonist. We discuss how the knowledge imparted by these studies has gone on to inform multiple strands of GLP-1R biology over the past three decades, including pharmacology, signaling, human genetics, structural biology, and chemical biology.

Glucagon-like peptide-1 increases heart rate by a direct action on the sinus node.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used to treat type 2 diabetes and obesity. Albeit cardiovascular outcomes generally improve, treatment with GLP-1 RAs is associated with increased heart rate, the mechanism of which is unclear. We employed a large animal model, the female landrace pig, and used multiple in vivo and ex vivo approaches including pharmacological challenges, electrophysiology, and high-resolution mass spectrometry to explore how GLP-1 elicits an increase in heart rate. In anaesthetized pigs, neither cervical vagotomy, adrenergic blockers (alpha, beta, or combined alpha-beta blockade), ganglionic blockade (hexamethonium), nor inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (ivabradine) abolished the marked chronotropic effect of GLP-1. GLP-1 administration to isolated perfused pig hearts also increased heart rate, which was abolished by GLP-1 receptor blockade. Electrophysiological characterization of GLP-1 effects in vivo and in isolated perfused hearts localized electrical modulation to the atria and conduction system. In isolated sinus nodes, GLP-1 administration shortened the action potential cycle length of pacemaker cells and shifted the site of earliest activation. The effect was independent of HCN blockade. Collectively, these data support a direct effect of GLP-1 on GLP-1 receptors within the heart. Consistently, single nucleus RNA sequencing showed GLP-1 receptor expression in porcine pacemaker cells. Quantitative phosphoproteomics analyses of sinus node samples revealed that GLP-1 administration leads to phosphorylation changes of calcium cycling proteins of the sarcoplasmic reticulum, known to regulate heart rate. GLP-1 has direct chronotropic effects on the heart mediated by GLP-1 receptors in pacemaker cells of the sinus node, inducing changes in action potential morphology and the leading pacemaker site through a calcium signalling response characterized by PKA-dependent phosphorylation of Ca2+ cycling proteins involved in pacemaking. Targeting the pacemaker calcium clock may be a strategy to lower heart rate in people treated with GLP-1 RAs.

#411 Magnesium deficiency abrogates the activation of Insulin-like growth factor-1 signaling pathway in the kidney induced by DPP4 inhibitor

Abstract Background and Aims Dipeptidyl peptidase-4 (DPP-4) inhibitor could attenuate cisplatin nephrotoxicity dependent on the glucagon-like peptide-1 (GLP-1) signaling pathway [1]. We had previously reported that the use of a DPP-4 inhibitor might also attenuate cisplatin nephrotoxicity in diabetic cancer patients [2], and its renoprotective effect was lost under magnesium (Mg) deficiency [3]. However, it remains to be investigated how the GLP-1 signaling pathway changes after the treatment of a DPP-4 inhibitor under Mg deficiency. The purpose of this study was to examine the changes in the downstream pathway of the GLP-1 signaling pathway after the treatment of DPP-4 inhibitor under Mg deficiency. Method Sprague Dawley rats received a Mg-deficient diet for 7 days to induce Mg deficiency (low Mg group). Control diet was given to the normal Mg group. Oral administration of a DPP-4 inhibitor was injected 1 day before sacrifice. The changes in serum active GLP-1, insulin, insulin-like growth factor (IGF-1), and the expression of their receptor in the kidney were examined. In addition, the phosphorylation of insulin/IGF-1 receptors in the kidney were investigated. Results Serum active GLP-1 increased equally in both groups with DPP-4 inhibitor administration. Renal GLP-1 receptor expression was not observed in the renal tubules. Serum IGF-1 did not change with DPP-4 inhibitor administration in the normal Mg group but increased in the low Mg group. In normal Mg group, renal IGF-1 receptor expression tended to increase with DPP-4 inhibitor administration, and its phosphorylation increased significantly. In contrast, the expression and phosphorylation of the IGF-1 receptor did not change with DPP-4 inhibitor administration in the low Mg group. The increase in serum insulin with the DPP-4 inhibitor was enhanced in the low Mg group, compared to the normal Mg group. The expression and phosphorylation of the insulin receptor did not change with DPP-4 inhibitor administration in both groups. Conclusion DPP-4 inhibitor activated the renal IGF-1 signaling pathway, but this effect disappeared under Mg deficiency. Further investigation is needed to determine whether the renal protective effect of DPP-4 inhibitor is dependent on the IGF-1 signaling pathway.

GLP-1 modulated the firing activity of nigral dopaminergic neurons in both normal and parkinsonian mice

The spontaneous firing activity of nigral dopaminergic neurons is associated with some important roles including modulation of dopamine release, expression of tyrosine hydroxylase (TH), as well as neuronal survival. The decreased neuroactivity of nigral dopaminergic neurons has been revealed in Parkinson's disease. Central glucagon-like peptide-1 (GLP-1) functions as a neurotransmitter or neuromodulator to exert multiple brain functions. Although morphological studies revealed the expression of GLP-1 receptors (GLP-1Rs) in the substantia nigra pars compacta, the possible modulation of GLP-1 on spontaneous firing activity of nigral dopaminergic neurons is unknown. The present extracellular in vivo single unit recordings revealed that GLP-1R agonist exendin-4 significantly increased the spontaneous firing rate and decreased the firing regularity of partial nigral dopaminergic neurons of adult male C57BL/6 mice. Blockade of GLP-1Rs by exendin (9–39) decreased the firing rate of nigral dopaminergic neurons suggesting the involvement of endogenous GLP-1 in the modulation of firing activity. Furthermore, the PKA and the transient receptor potential canonical (TRPC) 4/5 channels are involved in activation of GLP-1Rs-induced excitatory effects of nigral dopaminergic neurons. Under parkinsonian state, both the exogenous and endogenous GLP-1 could still induce excitatory effects on the surviving nigral dopaminergic neurons. As the mild excitatory stimuli exert neuroprotective effects on nigral dopaminergic neurons, the present GLP-1-induced excitatory effects may partially contribute to its antiparkinsonian effects.

Intestinal perfusion of unacylated ghrelin alleviated metabolically associated fatty liver disease in rats via a central glucagon-like peptide-1 pathway.

Unacylated ghrelin (UAG), the unacylated form of ghrelin, accounts for 80%-90% of its circulation. Accumulated studies have pointed out that UAG may be used to treat metabolic disorders. This study aimed to investigate the effect of intestinal perfusion of UAG on metabolically associated fatty liver disease (MAFLD) induced by a high-fat diet and its possible mechanisms. Neuronal retrograde tracking combined with immunofluorescence, central administration of a glucagon-like peptide-1 receptor (GLP-1R) antagonist, and hepatic vagotomy was performed to reveal its possible mechanism involving a central glucagon-like peptide-1 (GLP-1) pathway. The results showed that intestinal perfusion of UAG significantly reduced serum lipids, aminotransferases, and food intake in MAFLD rats. Steatosis and lipid accumulation in the liver were significantly alleviated, and lipid metabolism-related enzymes in the liver were regulated. UAG upregulated the expression of GLP-1 receptor (GLP-1R) in the paraventricular nucleus (PVN) and GLP-1 in the nucleus tractus solitarii (NTS), as well as activated GLP-1 neurons in the NTS. Furthermore, GLP-1 fibers projected from NTS to PVN were activated by the intestinal perfusion of UAG. However, hepatic vagotomy and GLP-1R antagonists delivered into PVN before intestinal perfusion of UAG partially attenuated its alleviation of MAFLD. In conclusion, intestinal perfusion of UAG showed a therapeutic effect on MAFLD, which might be related to its activation of the GLP-1 neuronal pathway from NTS to PVN. The present results provide a new strategy for the treatment of MAFLD.NEW & NOTEWORTHY Intestinal perfusion of UAG, the unacylated form of ghrelin, has shown promising potential for treating MAFLD. This study unveils a potential mechanism involving the central GLP-1 pathway, with UAG upregulating GLP-1R expression and activating GLP-1 neurons in specific brain regions. These findings propose a novel therapeutic strategy for MAFLD treatment through UAG and its modulation of the GLP-1 neuronal pathway.

GLP1R and GIPR expression and signaling in pancreatic alpha cells, beta cells and delta cells

Glucagon-like peptide-1 receptor (GLP1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) are transmembrane receptors involved in insulin, glucagon and somatostatin secretion from the pancreatic islet. Therapeutic targeting of GLP1R and GIPR restores blood glucose levels in part by influencing beta cell, alpha cell and delta cell function. Despite the importance of the incretin-mimetics for diabetes therapy, our understanding of GLP1R and GIPR expression patterns and signaling within the islet remain incomplete. Here, we present the evidence for GLP1R and GIPR expression in the major islet cell types, before addressing signaling pathway(s) engaged, as well as their influence on cell survival and function. While GLP1R is largely a beta cell-specific marker within the islet, GIPR is expressed in alpha cells, beta cells, and (possibly) delta cells. GLP1R and GIPR engage Gs-coupled pathways in most settings, although the exact outcome on hormone release depends on paracrine communication and promiscuous signaling. Biased agonism away from beta-arrestin is an emerging concept for improving therapeutic efficacy, and is also relevant for GLP1R/GIPR dual agonism. Lastly, dual agonists exert multiple effects on islet function through GIPR > GLP1R imbalance, increased GLP1R surface expression and cAMP signaling, as well as beneficial alpha cell-beta cell-delta cell crosstalk.

GLP1R boosts survival, migration and invasion of endometrial cancer cells and protects against ferroptotic cell death

Background Despite the strong evidence concerning carcinogenic roles of glucagon-like peptide 1 receptor (GLP1R), the role of this gene in endometrial cancer (EC) remains elusive. This study investigated the properties of GLP1R on EC in vitro. Methods The expression of GLP1R in EC was detected by RT-qPCR, immunohistochemistry, and western blotting. Cell viability, cell cycle, apoptosis, migration, invasion and ferroptosis were assessed through CCK-8, flow cytometry, wound healing, transwell, DCFH-DA and western blotting, respectively. Results We found that GLP1R was up-regulated in EC than normal specimens. It had the highest expression in AN3CA cells. Cell viability, migration and invasion were significantly reduced, while cell cycle arrest and apoptosis were induced following GLP1R knockdown. The malignant biological behaviours of AN3CA cells were investigated when treated with exendin-4 (GLP1R agonist). Moreover, GLP1R lowered intracellular ROS level and expression of SLC7A11, and FTH1, but mitigated GPX4 expression in AN3CA cells. Conclusion In a word, GLP1R was up-regulated in EC and its up-regulation facilitated the proliferative and metastatic potentials, and protected cells from ferroptosis, thereby accelerating EC progression. These data emphasised the potency of GLP1R as a therapeutic agent against EC.

Investigation of the Effects of Curcumin on GLP1-R in Liver Tissue of Diabetic Rats

The study aimed to examine the effect of curcumin, known for its antidiabetic properties, on the immunohistochemical localization and gene expression of glucagon-like peptide-1 receptor (GLP-1R) in the liver tissues of rats with experimental diabetic using reverse transcription polymerase chain reaction (RT-PCR). For this, 24 Sprague–Dawley rats were divided into four groups—control, sham, diabetic, and diabetic + curcumin groups. No administrations were performed for the control group, and 50 mg/kg streptozotocin was administered to the rats in the diabetic and diabetic + curcumin groups. After diabetes was established, 100 mg/kg curcumin was administered intraperitoneally to the diabetic + curcumin group rats for 21 days. In the sham group, intraperitoneal ethanol and isotonic sodium chloride solution were administered. Tissues sampled at the end of the experiment were examined histologically and immunohistochemically for GLP-1R localization, and RT-PCR was used to determine GLP-1R gene expression levels. In the histological examinations, a normal histological structure was observed in the tissue samples of the control and sham groups, whereas various degenerations such as sinusoidal wall enlargement and vacuolization in the hepatocytes were observed in the diabetic group. Furthermore, these degenerative findings were alleviated in the diabetic + curcumin group. In the immunohistochemical examinations, mostly the hepatocytes around the vena centralis, some endothelial, and some Kupffer cells were found to be positive for GLP-1R. The intensity of immunoreactivity was lower in the diabetic group and higher in the diabetic + curcumin group compared to the diabetes group. With regard to molecular analysis, there was no significant difference between the groups in terms of GLP-1R gene expression, but the mean expression level was higher in the diabetic + curcumin group. In conclusion, curcumin was seen to increase GLP-1R expression in the liver of the rats with diabetes. Since GLP-1R is one of the targets of diabetes treatment, curcumin can be used as a therapeutic agent for treating diabetes and alleviating its complications.

Consumption of carotenoid-rich Momordica cochinchinensis (Gac) aril improves glycemic control in type 2 diabetic mice partially through taste receptor type 1 mediated glucagon-like peptide 1 secretion.

Incretin-based therapies are widely used to improve glycemic control and β cell dysfunction in the treatment of type 2 diabetes. Momordica cochinchinensis (Gac fruit), a nutritious melon cultivated in many regions, has underexplored health benefits, particular its edible aril. This study comprehensively investigates the stimulatory effect of Gac aril on glucagon-like peptide 1 (GLP-1) secretion, identifies the responsible active constituents, and explores the underlying mechanisms related to its anti-diabetic effects. GLP-1-secreting STC-1 intestinal L cells were used to assess bioactivity and molecular mechanisms. Additionally, the in vivo anti-diabetic effects of Gac aril consumption were evaluated using type 2 diabetic mice induced by a high fat diet and streptozotocin injection, with or without GLP-1 receptor expression. The results demonstrated that Gac pulp and aril stimulated GLP-1 secretion, while Gac seeds did not. β-Carotene, a major constituent of Gac aril, was identified as the key mediator of GLP-1 secretion via sweet taste receptor-mediated signaling in STC-1 cells. Dietary intake of Gac aril significantly improved fasting blood glucose, glucose tolerance, insulin sensitivity, β-cell function, and hemoglobin A1c in type 2 diabetic mice. GLP-1 levels increased 2-fold, and decreased levels of ghrelin and adiponectin were restored. The anti-diabetic effects were partially diminished in GLP-1 receptor knockout mice, suggesting Gac aril's effects are mediated, in part, through GLP-1. In conclusion, Gac aril consumption may provide health benefits for managing type 2 diabetes, partially by enhancing endogenous GLP-1 levels.

Effects of glucagon-like peptide-1 receptor agonists on spermatogenesis-related gene expression in mouse testis and testis-derived cell lines.

Glucagon-like peptide-1 (GLP-1) is an incretin released into the gastrointestinal tract after food ingestion, and stimulates insulin secretion from the beta cells of the pancreatic islets. Incretins have recently been reported to have extrapancreatic actions, and they are anticipated to have potential efficacy for conditions such as male infertility as well as diabetes. However, the effects of incretins on male reproductive function remain unclear. In this study, GLP-1 receptor expression and the effects of GLP-1 on spermatogenesis-associated genes were investigated using mouse testes and testis-derived cultured cell lines. Glp1r mRNA and GLP-1 protein were expressed in mouse testes at levels comparable to or greater than those in positive control adipose tissue, and the liver and intestine, and also in a Sertoli cell line (TM4) and a Leydig cell line (MA-10) as well as the GC-1 spg and GC-2 spd (ts) germ cell lines. TM4 cells treated with the GLP-1 receptor agonist exenatide showed transiently and significantly upregulated Kitl, Pdgfa, and Glp1r mRNA expression. Furthermore, at 1 hr post-exenatide administration to male mice, Kitl and Glp1r mRNA expression levels were significantly increased, and Pdgfa mRNA expression level also showed a tendency toward increase. TM4 cells were treated with various cell-activating agents, and bucladesine elicited significantly increased Glp1r mRNA expression. We suggest that GLP-1 provides acute stimulation of Sertoli cells in the mouse testis and has a stimulatory effect on the expression of spermatogenesis-related genes.

The GLP-1 receptor is expressed in vivo by human metastatic prostate cancer.

The glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, reduces human prostate cancer incidence, and similar GLP-1 receptor agonists reduce in vitro proliferation and in vivo growth of prostate cancer cell lines. Primary human prostate cancer expresses the GLP-1 receptor (GLP-1R) in vitro. Cancer evolves with stage, and whether advanced-stage human prostate cancer expresses GLP-1R is unknown. We hypothesised and aimed to prove that human metastatic castrate-resistant prostate cancer (mCRPC) expresses the GLP-1R in vivo. We hypothesised that mCRPC would thus be detectable by positron emission tomography/computed tomography (PET/CT) using a radiotracer bound to a GLP-1R ligand, as in exendin PET/CT. Men with mCRPC, with more than one prostate-specific membrane antigen (PSMA)-avid lesion on PET/CT scanning (pathognomic in that setting for prostate cancer lesions), were approached to undergo PET/CT with gallium68-Dota-exendin-4. We documented PET/CT PSMA-avid lesions, which were also PET/CT exendin avid, as evidence of in vivo GLP-1R expression. Out of the 24 men referred, three did not meet the inclusion criteria. Seventeen declined, largely because the study offered them no therapeutic benefit. Among the four men imaged, three had no exendin-avid lesions, while one had six osseous PSMA-avid lesions, three of which were also exendin avid. We demonstrated in vivo GLP-1R expression by human mCPRC, detecting PET/CT lesions avid for both PSMA and exendin, in one of four participants. GLP-1R expression may thus occur even in advanced-stage prostate cancer. Our data contribute to growing evidence supporting the testing of GLP-1 receptor agonists for therapeutic benefit in prostate cancer.