Glucagon-like Peptide-1 Receptor Gene Research Articles

Relationship between glucagon-like peptide-1 receptor gene polymorphism and bone mineral density in postmenopausal women in Shanghai.

Glucagon-like peptide-1 receptor (GLP-1R) agonists are able to inhibit bone resorption to a certain extent and improve bone formation. GLP-1R single nucleotide polymorphism (SNP) is related to its activity, but the relationship between GLP-1R SNP and osteoporosis in postmenopausal women was still unclear. This study was to investigate the association between GLP-1R SNP and bone mineral density (BMD) in postmenopausal women in Shanghai. Eight SNPs of GLP-1R were detected (rs3765467, rs1042044, rs2268657, rs6923761, rs2268641, rs2295006, rs4714210 and rs10305420) in 884 postmenopausal women in Shanghai. The correlation between GLP-1R SNP and BMD was further assessed. The A/A genotype of rs2295006 was negatively related to lumbar vertebrae 1-4 BMD (P<0.05). Allele A was negatively related to hip BMD (P<0.05). There was a negative correlation between haplotype CGAGCCA and lumbar BMD, and a positive correlation between haplotype CGGGCTA and lumbar BMD. The remaining seven GLP-1R SNPs had no relationship with BMD. The rs2295006 of GLP-1R is related to the BMD of postmenopausal women in Shanghai, China.

1659-P: Nutrients Consumption Dependent Association of the Glucagon-Like Peptide-1 Receptor Gene Polymorphism with Insulin Secretion

Objective: Since type 2 diabetes (DM) is a life-style related disease, life-style should be considered, when association between genetic factors and DM are examined. However, most studies did not examine genetic associations with such consideration, as the case of glucagon-like peptide-1 receptor (GLP-1R) gene. We examined the association in consideration with the interaction between the gene polymorphism and various nutrient factors. Research Design and Methods: Among participants of the population-based Iwaki study of Japanese held in 2014-2017, those with information of the genotype of GLP-1R polymorphism (db SNP ID: rs3765467: A/G)(p.Alg131Gln) as well as nutrients consumed (n=1817) were included. The following individuals were also excluded: 64 on medication for DM, and 52 with FBG levels below 63 mg/dl or over 140 mg/dl (to evaluate HOMA indices precisely). After these exclusions, 1,560 individuals (587 men, 973 women) aged 53.3± 16.1 years were included in the study. Results: Though not significant, insulin secretion indices assed by homeostasis model assessment (HOMA- ß) in subjects with the GG genotype tended to be lower than in those with the AA+AG genotypes in most groups stratified into tertiles based on their daily nutrients consumptions (high, middle, and low groups). The stratification also showed that the genotype GG was a significant risk for a decreased insulin secretion (HOMA-ß ≤ 30) even after adjustment for multiple factors (age, BMI, drinking alcohol) only in the highest tertiles of energy, protein and carbohydrate consumption in men (odds ratios (95% CI) in high energy, protein and carbohydrate consumption groups: 3.95 (1.03-15.1), 15.83 (1.58-158.9), and 4.23 (1.10-11.2), respectively). Conclusions: The GLP-1R gene was associated with a decreased insulin secretion dependently of nutrients consumption, which indicates interaction between GLP-1R and nutrient factors on pathophysiology leading to DM. Disclosure Y. Nishiya: None. M. Daimon: None. H. Murakami: None. M. Murabayashi: None. S. Mizushiri: None. T. Fujita: None. Y. Matsuhashi: None.

Association of GLP-1 receptor gene polymorphisms with sporadic Parkinson’s disease in Chinese Han population

The Glucagon Like Peptide 1 Receptor (GLP1R) plays a critical role in selective death of dopaminergic neurons and development of Parkinson’s disease (PD). However, little is known about genetic associations of GLP1R gene polymorphisms with PD susceptibility. Therefore, this study aimed to verify whether GLP1R polymorphisms contribute to PD risk in a Chinese Han population. We recruited 518 individuals comprising 259 sporadic PD patients and 259 healthy controls. All of the participants were genotyped for two possibly functional polymorphisms located in GLP1R (rs3765467 and rs6923761) using the Sequenom MassARRAY platform. The frequency of the rs3765467 GG genotype was significantly higher in the PD group compared with that in the control group (OR = 1.444, 95 % CI: 1.015–2.055, p = 0.041). Subgroup analysis revealed that male patients and late-onset patients with the rs3765467 GG genotype suffered an increased risk of PD compared with healthy controls (p = 0.021 and p = 0.012, respectively). However, the genotype and allele frequencies for rs6923761 were not significantly different between PD and healthy subjects. Our results indicate that the GLP1R rs3765467 GG genotype is a potential risk factor for PD, especially for male and late-onset PD patients in the Chinese Han population.

Association between GLP-1 receptor gene polymorphisms with reward learning, anhedonia and depression diagnosis.

Glucagon-like peptide-1 receptors (GLP-1Rs) are widely expressed in the brain. Evidence suggests that they may play a role in reward responses and neuroprotection. However, the association of GLP-1R with anhedonia and depression diagnosis has not been studied. Here, we examined the association of GLP-1R polymorphisms with objective and subjective measures of anhedonia, as well as depression diagnosis. Objective [response bias assessed by the probabilistic reward task (PRT)] and subjective [Snaith-Hamilton Pleasure Scale (SHAPS)] measures of anhedonia, clinical variables and DNA samples were collected from 100 controls and 164 patients at McLean Hospital. An independent sample genotyped as part of the Psychiatric Genomics Consortium (PGC) was used to study the effect of putative GLP-1R polymorphisms linked to response bias in PRT on depression diagnosis. The C allele in rs1042044 was significantly associated with increased PRT response bias, when controlling for age, sex, case-control status and PRT discriminability. AA genotype of rs1042044 showed higher anhedonia phenotype based on SHAPS scores. However, analysis of PGC major depressive disorder data showed no association between rs1042044 and depression diagnosis. Findings suggest a possible association of rs1042044 with anhedonia but no association with depression diagnosis.

Влияние Roux-en-Y гастрошунтирования и продольной резекции желудка на метаболические и гормональные показатели и гипоталамический сигналинг у крыс с диабетом 2 типа

Bariatric surgery is widely used to correct the metabolic dysfunctions in type 2 diabetes mellitus (T2DM), but the mechanisms of its action are not fully understood. The aim of the work was to study the effect of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) on the metabolic and hormonal parameters and on the expression of the hypothalamic genes encoding appetite-regulating factors and the components of signaling systems controlling an energy metabolism in male rats with T2DM without obesity. The T2DM was induced by a 20-week high-fat diet and treatment of rats with 20 mg/kg of streptozotocin (STZ) at the 12th week of the experiment. The operations were performed 3 weeks after STZ treatment. The glucose sensitivity and the hormonal parameters were evaluated at the 19th week, and the hypothalamic tissues were taken at the 20th week to evaluate the gene expression. In rats with T2DM, both operations reduced the food intake, decreased the postprandial glucose levels, normalized the leptin levels, and lowered the plasma ghrelin levels in T2DM. The SG, which, in comparison with RYGB, had a lesser effect on the glucose homeostasis and the ghrelin level, reduced the food intake more effectively and, unlike RYGB, restored the glucagon-like peptide-1 (GLP-1) level decreased in T2DM. The RYGB led to a decrease in the expression of orexigenic genes, encoding agouti-like peptide and ghrelin receptor, increased in T2DM, and to an increase in the expression of anorexigenic genes, encoding the MC3- and MC4-melanocortin, the 5-HT2C-serotonin and leptin receptors and pro-opiomelanocortin. The largest contribution to the effects of SG is made by a significant increase in the hypothalamic expression of the GLP-1 receptor gene, associated with an increase in the plasma GLP-1 level. Thus, the RYGB and SG can be effective to correct the metabolic and functional dysfunctions in non-obese T2DM, and the restoration of the balance between the hypothalamic orexigenic and anorexigenic pathways makes a significant contribution to these effects.

Variation in the rates of evolution of the insulin and glucagon hormone and receptor genes in rodents

Insulin and glucagon are important hormones for regulating blood glucose levels. Rodents are useful models for understanding human physiology, however, differences exist between rodents and humans. Here I examined the evolution of the genes encoding insulin (Ins) and glucagon (Gcg, which also encodes GLP-1 and GLP-2) and the receptors for these hormones (Insr, Gcgr, Glp1r, and Glp2r). Our results show that the insulin 1 gene (Ins1) that originated by retroposition in some rodents such as mice, experienced selective constraints that are as strong as those acting upon the Ins2 gene found in the locus-of-origin. Previous studies had shown that the insulin hormones and genes in hystricomorph rodents, such as the guinea pig, have altered function and selective constraints, respectively. Here I show that the insulin receptor genes in hystricomorph rodents also experienced changes in evolutionary rates, but that these changes did not alter sites involved in hormone binding. While glucagon, but not GLP-1 and GLP-2, in hystricomorph rodents also show increased rates of sequence evolution, no changes in the evolution of the glucagon receptor gene (Gcgr) was seen. Intriguingly, the GLP2 receptor gene (Glp2r) in mice-like rodents evolved more rapidly than those in hystricomorph rodents. When the rates of evolution of the genes encoding the receptors for proglucagon-derived peptides, which are all G-protein coupled receptors, were compared, the GLP-1 receptor gene (Glp1r) was found to display increased levels of sequence constraint compared to the Gcgr and Glp2r genes.

Long-Lasting Effects of GSPE on Ileal GLP-1R Gene Expression Are Associated with a Hypomethylation of the GLP-1R Promoter in Female Wistar Rats.

Flavonoids have been shown to modulate GLP-1 in obesity. GLP-1 induces some of its effects through the intestinal GLP-1 receptor (GLP-1R), though no data exist on how flavonoids affect this receptor. Here, we examine how a dose of grape seed proanthocyanidin extract (GSPE) with anti-obesity activity affects intestinal GLP-1R and analyze whether epigenetics play a role in the long-lasting effects of GSPE. We found that 10-day GSPE administration prior to the cafeteria diet upregulated GLP-1R mRNA in the ileum 17 weeks after the GSPE treatment. This was associated with a hypomethylation of the GLP-1R promoter near the region where the SP1 transcription factor binds. In the colon, the cafeteria diet upregulated GLP-1R without showing any GSPE effect. In conclusion, we have identified long-lasting GSPE effects on GLP-1R gene expression in the ileum that are partly mediated by hypomethylation at the gene promoter and may affect the SP1 binding factor.

Screening GLP-1 Receptor Ligands from Natural Products in Herbs through High-Content Technique.

Screening of active components from a natural product, especially from a crude extract, is a great challenge. To avoid potential activity interference of the N-terminus modification in the most common constructs based on GCPRs labeled with GFP technology, a Cterminus tGFP-labeled hGLP-1 receptor containing recombinant cell line hGLP-1R-tGFP was constructed and tried to be used in the screening of natural products from Chinese herb. The GLP1 receptor gene was amplified and the inserts pCMV6-AC-tGFP and tGFP were fused at the C-terminus of GLP1 receptor to construct a recombinant plasmid. The recombinant was transfected into U2OS cell and selected with antibiotics and flow cytometry. The constructed cell line was named as hGLP-1R-tGFP cell line. The expression levels of GLP-1R-tGFP protein were confirmed by western-blot. The fluorescence imaging of re-distribution from diffusing to aggregate spots inside the cells was quantitated and analyzed by High Content Screening (HCS) assay. Meanwhile, the specificity, stability and C-terminus function of hGLP-1R-tGFP cell line were characterized. In order to allow the recombinant cell line of hGLP-1R-tGFP to be suitable in highcontent system of Arrayscan-infinity-700 in screening mode, several conditions have also been optimized. In the end, a total of 100 crude extract samples provided by the Yunnan Institute of Materia Medica have been screened with this method. Upon the activation of GLP-1 receptors by Exendin 4, fluorescent patches appeared on the cell membrane and subsequently internalized to form fluorescent aggregates inside the cells under fluorescent microscopy examination. The agonistic activity, sensitivity and specificity of the formation of fluorescent aggregate spot in hGLP-1R-tGFP cells have been confirmed by the activation of GLP-1R using the GLP-1analogues. The agonistic effects of GLP-1 analogues are blocked by a GLP-1R antagonist, Exendin9-39. The downstream of GLP-1 pathway, the activation of adenylate cyclase and the raising of cellular cAMP levels, remained intact in these tGFP modified C-terminus GLP-1 receptor cells. Meanwhile, a total of 100 crude extract samples from Chinese herbs have been screened by this method to find new active ingredients. Combined with High Content Screening image and data automatic acquisition processing, a new screening assay based on a recombinant U2OS cell line which GFP labeled at the C terminus of GLP1 receptor has been developed. GLP-1R agonist activity in extracts of Astragalus propinquus and Panax notoginseng from Chinese herbs has been determined by this method.

The role of Leu260Phe polymorphism of the receptor gene to GLP-1 incretin in the pathogenesis of diabetes type 2 diabetes with obesity

BACKGROUND: Glucagon-like peptide-1 (GLP-1) stimulates the proliferation of β-cells, enhances their resistance to apoptosis and increases glucose-dependent insulin secretion. AIMS: Study of the relationship of Leu260Phe polymorphism (rs1042044) of the GLP-1R gene with postprandial hormone production (C-peptide, insulin, ghrelin, GLP-1) in obese patients with type 2 diabetes. MATERIALS AND METHODS: A total of 174 patients, 82 patients with obesity with type 2 diabetes (BMI=40.4±14.3 kg/m 2 )and 92 conditionally healthy donors (BMI=22.6±2.7 kg/m 2 ) were studied. The material for the study was venous blood taken on an empty stomach and 60 minutes after the test breakfast. Genotyping was performed by PCR using the sets for determining polymorphism (rs1042044) of the GLP-1R gene (Sintol) and the amplificator (CFX96 BioRad, USA). Plasma hormone levels were evaluated by flow fluorimetry (Bio-PlexProteinAssaySystem, Bio-Rad, USA) using commercial test systems (Bio-PlexProHumanDiabetes 10-Plex Assay, Bio-Rad, USA). Statistical analysis and graphs were obtained at R Statistical Software. RESULTS: A violation of postprandial production of GLP-1 and ghrelin after a test breakfast in obese patients with type 2 diabetes was found. A postprandial increase in C-peptide levels of 3.25[1.83;4.16] ng/ml and insulin 3048 [1978;4972] ng/ml in carriers of the CC genotype compared with carriers of the CA genotype in the group of patients with obesity with type 2 diabetes type In carriers of the CA genotype, there was a decrease in the C-peptide level of 2.21 [1.8;2.49] ng/ml and insulin 1462 [1146; 2304] ng/ml with a constant concentration of GLP-1. The postprandial level of ghrelin in carriers of the CA genotype of the Leu260Phe polymorphism increased to 118[96.1;157] ng/ml compared to carriers of the AA 98 genotype [86; 109] ng/ml. CONCLUSION: The presence of the CC genotype of the Leu260Phe polymorphism of the GLP-1 receptor gene is associated with an increase in postprandial plasma levels of C-peptide and insulin in obese patients with type 2 diabetes, and the CA genotype with a decrease in these indicators and an increase in ghrelin content.

The role of Leu260Phe polymorphism of the receptor gene to GLP-1 incretin in the pathogenesis of diabetes type 2 diabetes with obesity

BACKGROUND: Glucagon-like peptide-1 (GLP-1) stimulates the proliferation of -cells, enhances their resistance to apoptosis and increases glucose-dependent insulin secretion.&#x0D; AIMS: Study of the relationship of Leu260Phe polymorphism (rs1042044) of the GLP-1R gene with postprandial hormone production (C-peptide, insulin, ghrelin, GLP-1) in obese patients with type 2 diabetes.&#x0D; MATERIALS AND METHODS: A total of 174 patients, 82 patients with obesity with type 2 diabetes (BMI=40.414.3 kg/m2)and 92 conditionally healthy donors (BMI=22.62.7 kg/m2) were studied. The material for the study was venous blood taken on an empty stomach and 60 minutes after the test breakfast. Genotyping was performed by PCR using the sets for determining polymorphism (rs1042044) of the GLP-1R gene (Sintol) and the amplificator (CFX96 BioRad, USA). Plasma hormone levels were evaluated by flow fluorimetry (Bio-PlexProteinAssaySystem, Bio-Rad, USA) using commercial test systems (Bio-PlexProHumanDiabetes 10-Plex Assay, Bio-Rad, USA). Statistical analysis and graphs were obtained at R Statistical Software.&#x0D; RESULTS: A violation of postprandial production of GLP-1 and ghrelin after a test breakfast in obese patients with type 2 diabetes was found. A postprandial increase in C-peptide levels of 3.25[1.83;4.16] ng/ml and insulin 3048 [1978;4972] ng/ml in carriers of the CC genotype compared with carriers of the CA genotype in the group of patients with obesity with type 2 diabetes type In carriers of the CA genotype, there was a decrease in the C-peptide level of 2.21 [1.8;2.49] ng/ml and insulin 1462 [1146; 2304] ng/ml with a constant concentration of GLP-1. The postprandial level of ghrelin in carriers of the CA genotype of the Leu260Phe polymorphism increased to 118[96.1;157] ng/ml compared to carriers of the AA 98 genotype [86; 109] ng/ml.&#x0D; CONCLUSION: The presence of the CC genotype of the Leu260Phe polymorphism of the GLP-1 receptor gene is associated with an increase in postprandial plasma levels of C-peptide and insulin in obese patients with type 2 diabetes, and the CA genotype with a decrease in these indicators and an increase in ghrelin content.

The Effect of Different Types of Bariatric Surgery on Metabolic and Hormonal Parameters in Rats with a Decompensated Form of Type II Diabetes Mellitus

Bariatric surgery (BS), including sleeve gastrectomy (SG), gastric bypass (GB), and ileal transposition (IT), is one of the approaches currently used for the correction of metabolic disturbances in type 2 diabetes mellitus (DM2) with obesity. However, the efficiency of these approaches and their impact on hypothalamic signaling and hormonal status in severe forms of DM2 without obesity remain poorly characterized. The aim of this work is to study the effect of IT, SG, and GB on insulin, leptin, ghrelin, and glucagon-like peptide-1 (GLP-1) levels in the blood and on the expression of the genes encoding the main components of the hypothalamic signaling systems in rats with a decompensated form of DM2 induced by a high-fat diet (three months) and a single low dose of streptozotocin (25 mg/kg, two months after the start of the diet). Pronounced hyperglycemia, impaired glucose tolerance, a decrease in the glucose-stimulated GLP-1 level, a slight decrease in the insulin and leptin levels, and a slight increase in the ghrelin level are detected in diabetic rats. Expression of genes encoding the GLP-1 receptor, the orexigenic agouti-related peptide (AgRP), and phosphotyrosine phosphatase 1B and SOCS3, the negative regulators of the leptin and insulin pathways, is increased in the hypothalamus. IT in diabetic rats leads to a reduction of glucose levels 120 min after glucose loading, an increase of basal and glucose-stimulated GLP-1 levels, and normalization of the expression levels of the phosphotyrosine phosphatase 1B, SOCS3, AgRP, and GLP-1 receptor genes, which is indicative of restoration of the hypothalamic signaling responsible for the control of energy metabolism and insulin sensitivity. Glucose tolerance is improved in the case of SG and GB, and an increase in the basal and glucose-stimulated GLP-1 levels is demonstrated in the case of SG, but no significant effects on the expression of the hypothalamic genes are observed in SG and GB. Thus, IT is the most efficient bariatric surgical intervention among those studied for the treatment of severe DM2 forms without obesity.

Combined Amylin/GLP-1 pharmacotherapy to promote and sustain long-lasting weight loss

A growing appreciation of the overlapping neuroendocrine mechanisms controlling energy balance has highlighted combination therapies as a promising strategy to enhance sustained weight loss. Here, we investigated whether amylin- and glucagon-like-peptide-1 (GLP-1)-based combination therapies produce greater food intake- and body weight-suppressive effects compared to monotherapies in both lean and diet-induced obese (DIO) rats. In chow-maintained rats, systemic amylin and GLP-1 combine to reduce meal size. Furthermore, the amylin and GLP-1 analogs salmon calcitonin (sCT) and liraglutide produce synergistic-like reductions in 24 hours energy intake and body weight. The administration of sCT with liraglutide also led to a significant enhancement in cFos-activation in the dorsal-vagal-complex (DVC) compared to mono-therapy, suggesting an activation of distinct, yet overlapping neural substrates in this critical energy balance hub. In DIO animals, long-term daily administration of this combination therapy, specifically in a stepwise manner, results in reduced energy intake and greater body weight loss over time when compared to chronic mono- and combined-treated groups, without affecting GLP-1 receptor, preproglucagon or amylin-receptor gene expression in the DVC.

Glucagon-like peptide-1 receptor gene polymorphism is associated with fat mass in Chinese nuclear families with male offspring.

Glucagon-like peptide-1 receptor gene polymorphism is associated with fat mass in Chinese nuclear families with male offspring.

8PREVALENCE OF CLINICALLY WELL-ESTABLISHED CNV SYNDROMES WITHIN A TORONTO SCHIZOPHRENIA PATIENT POPULATION

There is an increasing interest in the putative role of glucagon-like peptide 1 receptor (GLP-1R) agonists as novel therapeutic agents for mental disorders. Herein, we investigated the expressions of GLP-1R and GLP-2R genes, and its relationship with body mass index (BMI), in the post-mortem brain tissue of patients with mood (MD) and psychotic disorders. Brain samples were localized to the dorsolateral prefrontal cortex (dlPFC) (n = 459) and hippocampus (n = 378). After adjustment for age, sex, ethnicity, post-mortem interval (PMI) and BMI, we observed significant differences, between healthy controls and MD subjects, in GLP-1R and GLP-2R gene expression in the dlPFC (β = 1.504, p = 0.004; and β = 1.305, p = 0.011, respectively); whereas in the hippocampus, only GLP-1R expression was significantly associated with MD (β = −1.28, p = 0.029). No significant differences were found in relation to schizophrenia. In addition, we observed a moderating effect of MD diagnosis on the associations between BMI, GLP-1R and GLP-2R expression values in the dlPFC (β = −0.05, p = 0.003; and β = −0.04, p = 0.004, respectively). There was a similar moderating effect for GLP-1R in the hippocampus (β = 0.043, 95% CI 0.003; 0.08 p = 0.03), but in an opposite direction than observed in the dlPFC. This is the first evidence of abnormal gene expression of GLP-1R and GLP-2R in postmortem brain of individuals with MD, providing a rationale for further inquiry and proof of principle interventional studies.

S.21.01 Molecular and synaptic mechanisms underlying cognitive malfunction and cognitive enhancement

There is an increasing interest in the putative role of glucagon-like peptide 1 receptor (GLP-1R) agonists as novel therapeutic agents for mental disorders. Herein, we investigated the expressions of GLP-1R and GLP-2R genes, and its relationship with body mass index (BMI), in the post-mortem brain tissue of patients with mood (MD) and psychotic disorders. Brain samples were localized to the dorsolateral prefrontal cortex (dlPFC) (n = 459) and hippocampus (n = 378). After adjustment for age, sex, ethnicity, post-mortem interval (PMI) and BMI, we observed significant differences, between healthy controls and MD subjects, in GLP-1R and GLP-2R gene expression in the dlPFC (β = 1.504, p = 0.004; and β = 1.305, p = 0.011, respectively); whereas in the hippocampus, only GLP-1R expression was significantly associated with MD (β = −1.28, p = 0.029). No significant differences were found in relation to schizophrenia. In addition, we observed a moderating effect of MD diagnosis on the associations between BMI, GLP-1R and GLP-2R expression values in the dlPFC (β = −0.05, p = 0.003; and β = −0.04, p = 0.004, respectively). There was a similar moderating effect for GLP-1R in the hippocampus (β = 0.043, 95% CI 0.003; 0.08 p = 0.03), but in an opposite direction than observed in the dlPFC. This is the first evidence of abnormal gene expression of GLP-1R and GLP-2R in postmortem brain of individuals with MD, providing a rationale for further inquiry and proof of principle interventional studies.

S.05.04 RNA processing impairments in neurodegeneration syndromes

There is an increasing interest in the putative role of glucagon-like peptide 1 receptor (GLP-1R) agonists as novel therapeutic agents for mental disorders. Herein, we investigated the expressions of GLP-1R and GLP-2R genes, and its relationship with body mass index (BMI), in the post-mortem brain tissue of patients with mood (MD) and psychotic disorders. Brain samples were localized to the dorsolateral prefrontal cortex (dlPFC) (n = 459) and hippocampus (n = 378). After adjustment for age, sex, ethnicity, post-mortem interval (PMI) and BMI, we observed significant differences, between healthy controls and MD subjects, in GLP-1R and GLP-2R gene expression in the dlPFC (β = 1.504, p = 0.004; and β = 1.305, p = 0.011, respectively); whereas in the hippocampus, only GLP-1R expression was significantly associated with MD (β = −1.28, p = 0.029). No significant differences were found in relation to schizophrenia. In addition, we observed a moderating effect of MD diagnosis on the associations between BMI, GLP-1R and GLP-2R expression values in the dlPFC (β = −0.05, p = 0.003; and β = −0.04, p = 0.004, respectively). There was a similar moderating effect for GLP-1R in the hippocampus (β = 0.043, 95% CI 0.003; 0.08 p = 0.03), but in an opposite direction than observed in the dlPFC. This is the first evidence of abnormal gene expression of GLP-1R and GLP-2R in postmortem brain of individuals with MD, providing a rationale for further inquiry and proof of principle interventional studies.

The effect of body mass index on glucagon-like peptide receptor gene expression in the post mortem brain from individuals with mood and psychotic disorders

There is an increasing interest in the putative role of glucagon-like peptide 1 receptor (GLP-1R) agonists as novel therapeutic agents for mental disorders. Herein, we investigated the expressions of GLP-1R and GLP-2R genes, and its relationship with body mass index (BMI), in the post-mortem brain tissue of patients with mood (MD) and psychotic disorders. Brain samples were localized to the dorsolateral prefrontal cortex (dlPFC) (n = 459) and hippocampus (n = 378). After adjustment for age, sex, ethnicity, post-mortem interval (PMI) and BMI, we observed significant differences, between healthy controls and MD subjects, in GLP-1R and GLP-2R gene expression in the dlPFC (β = 1.504, p = 0.004; and β = 1.305, p = 0.011, respectively); whereas in the hippocampus, only GLP-1R expression was significantly associated with MD (β = −1.28, p = 0.029). No significant differences were found in relation to schizophrenia. In addition, we observed a moderating effect of MD diagnosis on the associations between BMI, GLP-1R and GLP-2R expression values in the dlPFC (β = −0.05, p = 0.003; and β = −0.04, p = 0.004, respectively). There was a similar moderating effect for GLP-1R in the hippocampus (β = 0.043, 95% CI 0.003; 0.08 p = 0.03), but in an opposite direction than observed in the dlPFC. This is the first evidence of abnormal gene expression of GLP-1R and GLP-2R in postmortem brain of individuals with MD, providing a rationale for further inquiry and proof of principle interventional studies.

A Pilot Study Investigating the Influence of Glucagon-Like Peptide-1 Receptor Single Nucleotide Polymorphisms on Gastric Emptying Rate in Caucasian Men.

Gastric emptying rate in humans is subject to large individual variability, but previous research on the influence of genetics is scarce. Variation in the glucagon-like peptide-1 receptor (GLP1R) gene is a plausible candidate gene to partially explain the high variance. This study aimed to investigate the influence of genetic variation in the GLP1R gene on gastric emptying rate of a glucose solution in humans. Forty eight healthy Caucasian males took part in this investigation. Gastric emptying rate of a 6% glucose solution was assessed using the 13C breath test method and a venous blood sample was obtained from each participant. Participants were genotyped for 27 Tag single nucleotide polymorphisms (SNPs) in the GLP1R locus using Sequenom MassARRAY iPLEX GOLD analysis and MALDI-TOF mass spectrometry. The time at which maximal emptying rate occurred (Tlag) was faster in participants with the CC genotype than in TT and TC genotypes for SNP rs742764: [median (quartiles) CC, 35 (30–36) min vs. TT, 43 (39–46) min, and TC, 41 (39–45) min; P < 0.01]. Tlag was also slower in participants with the AA genotype compared to the TT and TA genotypes for SNP rs2254336: [AA, 43 (39–49) min vs. TT, 36 (34–41) min, and TA, 39 (35–42) min; P < 0.05]. Analysis by phenotype also showed differences in half-emptying time (T12) and Tlag for SNPs rs9283907, rs2268657, and rs2254336. Several neighboring Tag SNPs within the GLP1R gene were found to be associated with gastric emptying rate, and should be further investigated.

Polymorphisms in the Glucagon-Like Peptide 1 Receptor (GLP-1R) Gene Are Associated with the Risk of Coronary Artery Disease in Chinese Han Patients with Type 2 Diabetes Mellitus: A Case-Control Study.

Background Glucagon-like peptide 1 (GLP-1) bestows protective effects upon the cardiovascular system through direct cardiovascular interactions or by improvements to metabolic function. Both these effects are thought to be at least partly mediated by the GLP-1 receptor (GLP-1R). This case-controlled study investigated whether polymorphisms in the GLP-1R gene affect the risk of cardiovascular disease in type 2 diabetic patients in the Chinese Han population. Methods Eleven haplotype-tagging single nucleotide polymorphisms (SNPs), distributed across 22 kb of the 39 kb GLP-1R gene, were selected and genotyped in diabetic patients from a Chinese Han population. Patients were classified based on the severity of coronary artery stenosis. Coronary artery stenosis was ≥50% in 394 patients (coronary artery disease- (CAD-) positive group), and coronary artery stenosis was <50% in 217 patients (control group). Allele and genotype frequencies were compared between the two groups at all 11 SNPs. Results When considered in recessive inheritance mode, patients with the GG genotype at rs4714210 had a lower CAD risk than patients with other genotypes (OR = 0.442, 95% CI = 0.258–0.757, p = 0.002), even when other known CAD risk factors were taken into account (ORa = 0.440, 95% CIa = 0.225–0.863, p a = 0.017). In additive inheritance mode, GG genotype carriers at rs4714210 exhibited a lower risk of CAD than AA carriers (ORa = 0.475, CIa = 0.232–0.970, p a = 0.041). Conclusion In type 2 diabetic patients from a Han Chinese population, some variations in the GLP-1R gene were associated with a lower risk of developing CAD.

Exenatide upregulates gene expression of glucagon-like peptide-1 receptor and nerve growth factor in streptozotocin/nicotinamide-induced diabetic mice.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that has modulating effects on insulin release. GLP-1 and receptors for GLP-1 are widely expressed throughout the body including the brain. The expression of GLP-1 receptors is very specific to large neurons in hippocampus, neocortex, and cerebellum. GLP-1 receptor stimulation enhances glucose-dependent insulin secretion and lowers blood glucose in type 2 diabetes mellitus. Studies on adipobiology of neurotrophins have focused on nerve growth factor (NGF) as an example of adipose-derived neurotrophins. Compromised trophic factor signaling may underlie neurodegenerative diseases ranging from Alzheimer's disease to diabetic neuropathies. Exenatide, a potent and selective agonist for the GLP-1 receptor, is currently approved for the treatment of type 2 diabetes mellitus. The aim of this study was to assess the effect of chronic exenatide treatment on the hippocampal gene expression levels of GLP-1 receptor and NGF in diabetic mice. The effects of chronic exenatide treatment (0.1 μg/kg, s.c., twice daily for 2 weeks) on GLP-1 receptor and NGF gene expression levels in the hippocampus of streptozotocin/nicotinamide (STZ-NA)-induced diabetic mice were assessed by quantitative real-time polymerase chain reaction (RT-PCR). The results of this study revealed that hippocampal gene expression of GLP-1 receptor and NGF were downregulated in diabetic mice. Importantly, a significant increase in the gene expression level of GLP-1 receptor and NGF was determined after 2 weeks of exenatide administration. Increased gene expression level of GLP-1 receptor and NGF may underlie the beneficial action of exenatide in STZ/NA-induced diabetes.