Glucagon-like Peptide-1 Receptor Gene Research Articles

384 ASSOCIATION OF A GLUCAGON-LIKE PEPTIDE-1 RECEPTOR GENE VARIANT WITH METABOLIC DYSFUNCTION ASSOCIATED LIVER DISEASE (MASLD)

384 ASSOCIATION OF A GLUCAGON-LIKE PEPTIDE-1 RECEPTOR GENE VARIANT WITH METABOLIC DYSFUNCTION ASSOCIATED LIVER DISEASE (MASLD)

Development of Syringaldehyde as an Agonist of the GLP-1 Receptor to Alleviate Diabetic Disorders in Animal Models.

The phenolic aldehyde syringaldehyde (SA) has been shown to have an antihyperglycemic effect in diabetic rats due to increased glucose utilization and insulin sensitivity. To understand the direct effect of SA on the GLP-1 receptor, STZ-induced diabetic rats were used. The levels of pro-inflammatory cytokines, liver enzymes, and renal function were measured using specific ELISA kits. The mechanisms of SA effects were investigated using CHO-K1 cells, pancreatic Min-6 cells, and cardiomyocyte H9c2 cells. The results indicated that the antihyperglycemic effect of SA in diabetic rats was abolished by blocking the GLP-1 receptor with an antagonist. SA has a direct effect on the GLP-1 receptor when using CHO-K1 cells transfected with the exogenous GLP-1 receptor gene. In addition, SA stimulated insulin production in Min-6 cells by activating GLP-1 receptors. SA caused a dose-dependent rise in GLP-1 receptor mRNA levels in cardiac H9c2 cells. These in vitro results support the notion that SA has a direct effect on the GLP-1 receptor. Otherwise, SA inhibited the increase of pro-inflammatory cytokines, including interleukins and tumor TNF-α, in type 1 diabetic rats in a dose-dependent manner. Moreover, as with liraglutide, SA reduced plasma lipid profiles, including total cholesterol and triglyceride, in mixed diet-induced type 2 diabetic rats. Intriguingly, chronic treatment with SA (as with liraglutide) reversed the functions of both the liver and the kidney in these diabetic rats. SA displayed less efficiency in reducing body weight and food consumption compared to liraglutide. In conclusion, SA effectively activates GLP-1 receptors, resulting in a reduction in diabetic-related complications in rats. Therefore, it is beneficial to develop SA as a chemical agonist for clinical applications in the future.

Significance of single-nucleotide variants of anorexigenic hormone genes in childhood obesity

Obesity-induced dysregulation of hypothalamic neurons is not completely eliminated by restoring body weight, therefore the most urgent task of modern precision medicine is to predict the trajectory of development of metabolic disorders associated with obesity in children. The aim of the study was to determine the level of association of single-nucleotide variants of genes that determine eating behavior – Neuronal growth regulator 1, Fat mass and obesity associated gene, Glucagon-like peptide-1 receptor, ghrelin, leptin receptor, cholecystokinin, in the development of metabolically unhealthy obesity. 252 obese children aged 6-18 years were examined. The main group (n=152) consisted of children with metabolically unhealthy obesity (MUO) according to Identification and prevention of Dietary- and Lifestyle-induced Health Effects in Children and Infants 2014 criteria. The control group (n=100) consisted of children with metabolically healthy obesity (MHO). All children underwent a general clinical, immunobiochemical examination at the Synevo laboratory (Ukraine). Whole-genome sequencing (CeGat, Germany) was performed in 31 children of the primary and 21 children of the control group. Static analysis: variance analysis ANOVA, method of estimating data dispersion, ROC-analysis, method of testing statistical hypotheses. The level of single nucleotide variants association of anorexigenic hormone genes with MUO that exceeded the threshold accepted by 75% of the available data was, respectively, in ascending order: leptin receptor (LEPR) rs1137101 (40.38%), Glucagon-like peptide-1 receptor (GLP1R) rs1126476 (40.38%), GLP1R rs2235868 (42.31%), GLP1R rs1042044 (42.31%), LEPR rs3790435 (48.08%), cholecystokinin (CCK) rs754635 (50%), LEPR rs2186248 (55.76%), GLP1R rs6918287 (55.76%). Genotypes of the GLP1R gene, such as CC rs10305421 determine insulin resistance (F=5.6); GA/AA rs3765468 – meta-inflammation (F=5.8); AA rs6918287 – basal hyperglycemia (F=6.3) and triglyceridemia (F=51.3), p<0.05. Single-nucleotide variants of the gene GLP1R rs6918287, LEPR rs2186248, CCK rs754635 of the anorexic hormones that control eating behavior are highly associated with the presence of metabolically unhealthy obesity in children.

GLP1R rs3765467 Polymorphism Is Associated with the Risk of Early Onset Type 2 Diabetes.

To investigate the relationship between glucagon-like peptide-1 receptor gene polymorphisms and susceptibility to early onset type 2 diabetes. Samples from 316 type 2 diabetes patients with early onset type 2 diabetes (n = 137) and late-onset type 2 diabetes (n = 179) and 145 nondiabetic individuals were analyzed. Multiplex PCR combined with resequencing Hi-Reseq technology was used to detect single nucleotide polymorphisms of the glucagon-like peptide-1 receptor gene, and the allele frequency, genotype distribution, and clinical parameters were analyzed between each diabetes subgroup and the control group. Sixteen single nucleotide polymorphisms were identified in the exonic region of the glucagon-like peptide-1 receptor gene according to the minor allele frequency (MAF > 0.05) in the participants. Among these, the glucagon-like peptide-1 receptor rs3765467 (G⟶A) mutation was statistically associated with early onset type 2 diabetes. Compared with that of the GG carriers, carriers of genotype AA at rs3765467 had a decreased risk of early onset type 2 diabetes after adjusting for sex and body mass index. In the dominant model, the frequencies of the rs3765467 AA + GA genotype were significantly decreased in the early onset type 2 diabetes group, and carriers of genotype AA + GA at rs3765467 had a decreased risk of early onset type 2 diabetes after adjusting for sex and body mass index. Moreover, fasting C peptide levels were significantly higher in GA + AA genotype carriers than those in GG genotype carriers. The glucagon-like peptide 1 receptor rs3765467 polymorphism was significantly associated with age at type 2 diabetes diagnosis and thus may be used as a marker to screen and detect individuals at risk of developing early onset type 2 diabetes.

Polymorphisms in the glucagon-like peptide-1 receptor gene and their interactions on the risk of osteoporosis in postmenopausal Chinese women.

Postmenopausal osteoporosis (PMOP) is a prevalent form of primary osteoporosis, affecting over 40% of postmenopausal women. Previous studies have suggested a potential association between single nucleotide polymorphisms (SNPs) in glucagon-like peptide-1 receptor (GLP-1R) and PMOP in postmenopausal Chinese women. However, available evidence remains inconclusive. Therefore, this study aimed to investigate the possible association between GLP-1R SNPs and PMOP in Han Chinese women. Thus, we conducted a case-control study with 152 postmenopausal Han Chinese women aged 45-80 years, including 76 women with osteoporosis and 76 without osteoporosis. Seven SNPs of the GLP-1R were obtained from the National Center of Biotechnology Information and Genome Variation Server. We employed three genetic models to assess the association between GLP-1R genetic variants and osteoporosis in postmenopausal women, while also investigating SNP-SNP and SNP-environment interactions with the risk of PMOP. In this study, we selected seven GLP-1R SNPs (rs1042044, rs2268641, rs10305492, rs6923761, rs1126476, rs2268657, and rs2295006). Of these, the minor allele A of rs1042044 was significantly associated with an increased risk of PMOP. Genetic model analysis revealed that individuals carrying the A allele of rs1042044 had a higher risk of developing osteoporosis in the dominant model (P = 0.029, OR = 2.76, 95%CI: 1.09-6.99). Furthermore, a multiplicative interaction was found between rs1042044 and rs2268641 that was associated with osteoporosis in postmenopausal women (Pinteraction = 0.034). Importantly, this association remained independent of age, menopausal duration, family history of osteoporosis, and body mass index. However, no significant relationship was observed between GLP-1R haplotypes and PMOP. In conclusion, this study suggests a close association between the A allele on the GLP-1R rs1042044 and an increased risk of PMOP. Furthermore, this risk was significantly augmented by an SNP-SNP interaction with rs2268641. These results provide new scientific insights into the development of personalized prevention strategies and treatment approaches for PMOP.

Altered chronic glycemic control in a clinically relevant model of rat thoracic spinal contusion.

The lifetime risk for Type 2 diabetes mellitus remains higher in people with spinal cord injuries (SCIs) than in the able-bodied population. However, the mechanisms driving this disparity remain poorly understood. The goal of the present study was to evaluate the impact of a palatable high-fat diet (HFD) on glycemic regulation using a rodent model of moderate thoracic contusion. Animals were placed on either Chow or HFD and tolerance to glucose, insulin, and ENSURE mixed meal were investigated. Important targets in the gut-brain axis were investigated. HFD consumption equally induced weight gain in SCI and naïve rats over chow (CH) rats. Elevated blood glucose was observed during intraperitoneal glucose tolerance test in HFD-fed rats over CH-fed rats. Insulin tolerance test (ITT) was unremarkable among the three groups. Gavage of ENSURE resulted in high glucagon-like peptide 1 (GLP-1) release from SCI rats over naïve controls. An elevation in terminal total GLP-1 was measured, with a marked reduction in circulating dipeptidyl peptidase 4, the GLP-1 cleaving enzyme, in SCI rats, compared with naïve. Increased glucagon mRNA in the pancreas and reduced immunoreactive glucagon-positive staining in the pancreas in SCI rats compared with controls suggested increased glucagon turnover. Finally, GLP-1 receptor gene expression in the ileum, the primary source of GLP-1 production and release, in SCI rats suggests the responsivity of the gut to altered circulating GLP-1 in the body. In conclusion, the actions of GLP-1 and its preprohormone, glucagon, are markedly uncoupled from their actions on glucose control in the SCI rat. More work is required to understand GLP-1 in the human.

Genetic variants of the GLP-1R gene affect the susceptibility and glucose metabolism of gestational diabetes mellitus: a two-center nested case‒control study

BackgroundGestational diabetes mellitus (GDM) is the most common complication during pregnancy, occurring under the combined action of environmental and genetic factors. Genetic variants of glucagon-like peptide-1 receptor (GLP-1R) have been reported to affect insulin secretion and susceptibility to type 2 diabetes. This study aimed to explore the role of GLP-1R polymorphisms in GDM and glucose metabolism.MethodsA two-center nested case‒control study was designed, including 200 pregnant women with GDM and 200 pregnant women without GDM genotyped for five tag SNPs of GLP-1R using Sanger sequencing. Logistic regression was used to evaluate the relationship between GLP-1R polymorphisms and GDM risk. Glucose and insulin concentrations were measured based upon the 75 g oral glucose tolerance test (OGTT). Beta cell function of different genotypes was estimated with the 60 min insulinogenic index (IGI60) and OGTT-derived disposition index (DI).ResultsMutant genotype AG + GG of tag SNP rs6458093 nominally increased GDM risk (p = 0.049), especially among subjects younger than 35 years (p = 0.024) and with BMI no less than 24 (p = 0.041), after adjusting for confounders. Meanwhile, compared with subjects with wild genotype AA, subjects with genotype AG + GG of rs6458093 also showed nominally significantly lower IGI60 (p = 0.032) and DI (p = 0.029), as well as significantly higher 75 g OGTT-based 1 h glucose load plasma glucose levels (p = 0.045). Moreover, the mutant heterozygous genotype GA of tag SNP rs3765467 nominally decreased GDM risk among subjects older than 35 years (p = 0.037) but showed no association with insulin secretion and glucose homeostasis.ConclusionsTag SNP rs6458093 of GLP-1R was nominally associated with increased GDM risk and affected beta cell function and postprandial glucose metabolism, while tag SNP rs3765467 of GLP-1R was nominally associated with decreased GDM risk, providing evidence for molecular markers and etiological study of GDM.

In Silico Analysis of Gene Expression Location and Single Nucleotide Polymorphisms (SNPs) of The Glucagon Like Peptide 1 Receptor (GLP-1R)

Association studies of SNPs have become very important in determining how genetic variants are linked to complex diseases, quantitative traits, and physiological responses. Genetic polymorphisms in the GLP-1R gene have potentially decreased protein stability and are associated with many diseases, especially diabetes and obesity. This study aimed to screen the expression and investigate the genetic polymorphism of the GLP-1R by using several beneficial bioinformatics tools. We observed database Ensembl, GTEx portal, and KEGG to identify the structure, expression, and molecular pathway of GLP-1R. In silico computational methods (SIFT, PolyPhen v2, PROVEAN, and PhD-SNP) were used to identify nsSNPs of the GLP-1R that potentially influence protein structure and function. I-Mutant was used to investigate possibly damaging nsSNPs, while GeneMANIA was used to investigate GLP-1R gene-gene interactions. GLP-1R is localized on chromosome 6p21, contains 13 exons, and has the regulation variant (CTCF, promotor, enhancer, and promotor flank region). GLP-1R is highly expressed in the pancreas to stimulate glucose-dependent insulin secretion and suppress glucagon secretion. Seven nsSNPs of the GLP-1R gene were found to be potentially deleterious: rs10305421, rs201672448, rs10305492, rs2295006, rs6923761, rs1042044, rs140642887, and rs10305510. I-Mutant server showed that nsSNPs rs140642887 was unstable, decreased GLP-1R protein stability, and impaired other genes' interaction and function (SP1, SP3, GNAS, and GCG). This study is the first in silico analysis of the polymorphic GLP-1R gene, and will serve as a great resource for developing precision medications to treat diseases associated with these polymorphisms.

Activation of glucagon-like peptide-1 receptors reduces the acquisition of aggression-like behaviors in male mice

Aggression is a complex social behavior, which is provoked in the defense of limited resources including food and mates. Recent advances show that the gut-brain hormone ghrelin modulates aggressive behaviors. As the gut-brain hormone glucagon-like peptide-1 (GLP-1) reduces food intake and sexual behaviors its potential role in aggressive behaviors is likely. Therefore, we investigated a tentative link between GLP-1 and aggressive behaviors by combining preclinical and human genetic-association studies. The influence of acute or repeated injections of a GLP-1 receptor (GLP-1R) agonist, exendin-4 (Ex4), on aggressive behaviors was assessed in male mice exposed to the resident-intruder paradigm. Besides, possible mechanisms participating in the ability of Ex4 to reduce aggressive behaviors were evaluated. Associations of polymorphisms in GLP-1R genes and overt aggression in males of the CATSS cohort were assessed. In male mice, repeated, but not acute, Ex4 treatment dose-dependently reduced aggressive behaviors. Neurochemical and western blot studies further revealed that putative serotonergic and noradrenergic signaling in nucleus accumbens, specifically the shell compartment, may participate in the interaction between Ex4 and aggression. As high-fat diet (HFD) impairs the responsiveness to GLP-1 on various behaviors the possibility that HFD blunts the ability of Ex4 to reduce aggressive behaviors was explored. Indeed, the levels of aggression was similar in vehicle and Ex4 treated mice consuming HFD. In humans, there were no associations between polymorphisms of the GLP-1R genes and overt aggression. Overall, GLP-1 signaling suppresses acquisition of aggressive behaviors via central neurotransmission and additional studies exploring this link are warranted.

Bolus Injection of Liraglutide Raises Plasma Glucose in Normal Rats by Activating Glucagon-like Peptide 1 Receptor in the Brain.

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.

The glucagon-like peptide-1 system is modulated by acute and chronic alcohol exposure: Findings from human laboratory experiments and a post-mortem brain study.

Growing evidence suggests that the glucagon-like peptide-1 (GLP-1) system modulates alcohol seeking and consumption, and GLP-1 analogues may represent novel pharmacotherapies for alcohol use disorder (AUD). Accordingly, it is important to understand the potential effects of alcohol on the endogenous GLP-1 system. In a series of secondary analyses of previous human laboratory experiments, we first examined the effects of alcohol administration, with different doses and routes of administration, on peripheral active GLP-1 concentrations in heavy-drinking individuals with AUD enrolled in placebo-controlled pharmacological studies (only placebo conditions were analysed here). Alcohol administration resulted in a significant reduction of GLP-1 levels across the four experiments (oral alcohol, variable dose: F3,28 = 6.52, p = 0.002; oral alcohol, fixed dose: F7,75.94 = 5.08, p < 0.001; intravenous alcohol, variable dose: F4,37.03 = 20.72, p < 0.001; intravenous alcohol, fixed dose: F4,13.92 = 10.44, p < 0.001). Next, central expression of the GLP-1 receptor (GLP-1R) in post-mortem brain tissues (amygdala, ventral tegmental area, nucleus accumbens, hippocampus and prefrontal cortex) was compared between individuals with AUD and controls. Fold change of GLP-1R mRNA in the hippocampus was significantly higher in individuals with AUD, compared to controls (F1,21 = 6.80, p = 0.01). A trend-level effect with the same direction was also found in the prefrontal cortex (F1,20 = 3.07, p = 0.09). Exploratory analyses showed that GLP-1R gene expression levels were correlated with behavioural measures of alcohol drinking (hippocampus) and cigarette smoking (hippocampus and prefrontal cortex). Collectively, these data provide novel information on the crosstalk between alcohol and GLP-1 in a clinically relevant sample. Further studies are needed to understand the underlying mechanisms of this link.

Abstract 3: Developing a translational tool for GLP-1-based therapeutic agonists in humanized GLP1R mice

Abstract Glucagon-like peptide-1 (GLP1) is a pleiotropic hormone released from gut enteroendocrine cells following nutrient ingestion. In addition to promoting insulin secretion and inhibiting glucagon secretion, GLP1 acts via the glucagon-like peptide-1 receptor (GLP1R) to reduce gastric emptying and food intake. Therefore, development of GLP1R agonists appears to be a promising therapeutic option for type 2 diabetes. To evaluate the efficacy of GLP1 analogs in preclinical studies, Biocytogen has successfully generated a novel humanized GLP1R (B-hGLP1R) knock-in mouse line to support related drug development studies. In this mouse model, the full coding sequence of the human GLP1R gene was inserted into the mouse Glp1r gene locus. Human GLP1R mRNA expression was detected by RT-PCR in B-hGLP1R mice but not in wild-type mice. Protein expression of human GLP1R in B-hGLP1R mice was confirmed by western blot analysis and immunohistochemistry using pancreatic tissues. Furthermore, flow cytometry analysis of leukocyte subpopulations showed that B-hGLP1R mice do not exhibit a change in the overall development, differentiation, or distribution of immune cell types in the spleen, blood, and lymph nodes. Additionally, our in vivo efficacy study confirmed Dulaglutide, a GLP1 receptor agonist, reduced the non-fasting blood glucose, fasting blood glucose, glucagon, and food intake levels in B-hGLP1R obese mice and increased plasma insulin and GLP1 secretion. In B-hGLP1R mice, glucose tolerance (GTT) was also improved by Dulaglutide treatment, similar GTT results were observed after treatment with PF-06882961, a phase II agent specifically recognizing human GLP1R. Altogether, B-hGLP1R mice provide an efficacious preclinical animal model to evaluate novel GLP1 based therapeutic drugs. Keywords: Humanized mice, GLP1R, agonist Citation Format: Yuelei Shen, Jiawei Yao, Mostafa Kokabee, Yanan Guo, Yang BaI, Chengzhang Shang. Developing a translational tool for GLP-1-based therapeutic agonists in humanized GLP1R mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3.

Association between glucagon-like peptide-1 receptor gene polymorphism and treatment response to GLP1R agonists in Chinese patients with type 2 diabetes: a prospective cohort study.

Clinical response to glucagon-like peptide-1 receptor agonists (GLP1RAs) varies considerably among patients with type 2 diabetes mellitus (T2DM). The aim of the current study was to examine the potential association between the genetic variants in GLP1R gene polymorphism with the therapeutic efficacy as well as gastrointestinal adverse drug reactions (ADRs) of GLP1RAs in Chinese T2DM patients. Adult T2DM patients were eligible to participate in this prospective cohort study. Subjects received 12-week treatment with either exenatide (20μg/day) or liraglutide (1.2mg/day). GLP1R rs10305420 and rs3765467 genotyping was performed using the Sanger sequencing method. Clinical response to GLP1RAs was assessed in the patients who completed the 12-week treatment and defined by the change of fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), and body mass index (BMI) from the baseline. A total of 176 subjects (mean age 50.9 ± 12.7years, 111 men) were enrolled. The planned 12-week treatment was completed by 156 patients. HbA1c reduction was significantly larger in subjects carrying the rs3765467 GG genotype vs. GA + AA genotypes (1.7% ± 2.4% vs. 0.8% ± 1.8%; P = 0.002). Similarly, the 7.0% target HbA1c attainment rate was significantly higher in subjects carrying the rs3765467 GG genotype vs. GA + AA genotypes (50.9% vs. 23.8%; P = 0.002). Gastrointestinal ADRs did not differ significantly among different genotypes. GLP1R rs3765467 polymorphism is associated with therapeutic response to GLP1RAs in Chinese T2DM patients. HbA1c reduction is more pronounced in subjects with the GG genotype.

Association study of variation of glucagon-like peptide-1 receptor gene rs3765467 and type 2 diabetes mellitus

Association study of variation of glucagon-like peptide-1 receptor gene rs3765467 and type 2 diabetes mellitus

Associations of TCF7L2 rs11196218 (A/G) and GLP-1R rs761386 (C/T) Gene Polymorphisms with Obesity in Chinese Population.

IntroductionThis study aimed to investigate the genetic polymorphism associations with obesity of the transcription factor 7-like 2 (TCF7L2) gene rs11196218 (A/G) and glucagon-like peptide 1 receptor (GLP1-R) gene rs761386 (C/T) in the Chinese population.Patients and MethodsThis was a case–control pilot study involving 60 patients with obesity and 69 non-obesity Chinese adults, and the two groups were sex and age matched. Anthropometric indices of obesity, fasting blood glucose, blood pressure, and blood lipids were assessed. Both polymorphisms were genotyped using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF).ResultsThere were significant differences in the allelic frequencies of the TCF7L2 rs11196218 and GLP1-R rs761386 between obesity and non-obesity groups (P = 0.003, OR = 2.32, 95% CI [1.31~4.09]; P = 0.034, OR = 1.94, 95% CI [1.05~3.60], respectively). In allele model, the genotypic frequencies of TCF7L2 rs11196218 and GLP1-R rs761386 also differed between obesity and non-obesity groups (P = 0.014 and 0.033, respectively). In dominant model, the TCF7L2 rs11196218 A-carrier (AA/AG) had a higher risk of obesity than GG genotype (P = 0.014, OR = 2.54, 95% CI [1.21~5.35]). Comparison of clinical and biochemical parameters between genotypes showed no significant difference.ConclusionThese findings suggest that the rs11196218 (A/G) polymorphism of the TCF7L2 gene and the rs761386 (C/T) polymorphism of the GLP1-R gene were associated with obesity in the Chinese population.

Generation of iPSC lines (KAUSTi011-A, KAUSTi011-B) from a Saudi patient with epileptic encephalopathy carrying homozygous mutation in the GLP1R gene.

Glucagon-like peptide-1 receptor (GLP1R) is a seven-transmembrane-spanning helices membrane protein expressed in multiple human tissues including pancreatic islets, lung, brain, heart and central nervous system (CNS). GLP1R agonists are commonly used as antidiabetic drugs, but a neuroprotective function in neurodegenerative disorders is emerging. Here, we established two iPSC lines from a patient harboring a rare homozygous splice site variant in GLP1R (NM_002062.3; c.402+3delG). This patient displays severe developmental delay and epileptic encephalopathy. Therefore, the derivation of these iPSC lines constitutes a primary model to study the molecular pathology of GLP1R dysfunction and develop novel therapeutic targets.

Nutrient consumption-dependent association of a glucagon-like peptide-1 receptor gene polymorphism with insulin secretion

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 in consideration with lifestyle. Glucagon-like peptide-1 (GLP-1) receptor (GLP1R) mediates the insulinotropic action of GLP-1 in β-cells. We here examined the association while taking into consideration of interactions between the gene polymorphism and various nutrient factors. Participants from the population-based Iwaki study of Japanese subjects held in 2014–2017 with information on nutritional intake evaluated by self-administered dietary history questionnaire, and GLP1R genotype (rs3765467: A/G), were included (n = 1,560). Although not significant, insulin secretion indices assessed by homeostasis model assessment of β-cell function (HOMA-β) 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 daily nutrient consumptions (high, middle, and low). Stratification also showed that the GG genotype was a significant risk for decreased insulin secretion (HOMA-β ≤ 30) even after adjustment for multiple factors (age, body mass index, alcohol consumption), but only in the highest tertiles of energy, protein and carbohydrate consumption in men [odds ratios (95% confidence interval) 3.95 (1.03–15.1), 15.83 (1.58–158.9), and 4.23 (1.10–11.2), respectively]. A polymorphism of the GLP1R gene was associated with decreased insulin secretion in a nutrient consumption-dependent manner in Japanese men, indicating an interaction between GLP1R and nutritional factors in the pathophysiology of DM.

Discordance between GLP-1R gene and protein expression in mouse pancreatic islet cells

The insulinotropic actions of glucagon-like peptide 1 receptor (GLP-1R) in β-cells have made it a useful target to manage type 2 diabetes. Metabolic stress reduces β-cell sensitivity to GLP-1, yet the underlying mechanisms are unknown. We hypothesized that Glp1r expression is heterogeneous among β-cells and that metabolic stress decreases the number of GLP-1R-positive β-cells. Here, analyses of publicly available single-cell RNA-Seq sequencing (scRNASeq) data from mouse and human β-cells indicated that significant populations of β-cells do not express the Glp1r gene, supporting heterogeneous GLP-1R expression. To check these results, we used complementary approaches employing FACS coupled with quantitative RT-PCR, a validated GLP-1R antibody, and flow cytometry to quantify GLP-1R promoter activity, gene expression, and protein expression in mouse α-, β-, and δ-cells. Experiments with Glp1r reporter mice and a validated GLP-1R antibody indicated that >90% of the β-cells are GLP-1R positive, contradicting the findings with the scRNASeq data. α-cells did not express Glp1r mRNA and δ-cells expressed Glp1r mRNA but not protein. We also examined the expression patterns of GLP-1R in mouse models of metabolic stress. Multiparous female mice had significantly decreased β-cell Glp1r expression, but no reduction in GLP-1R protein levels or GLP-1R-mediated insulin secretion. These findings suggest caution in interpreting the results of scRNASeq for low-abundance transcripts such as the incretin receptors and indicate that GLP-1R is widely expressed in β-cells, absent in α-cells, and expressed at the mRNA, but not protein, level in δ-cells.

GLP1R Single-Nucleotide Polymorphisms rs3765467 and rs10305492 Affect β Cell Insulin Secretory Capacity and Apoptosis Through GLP-1.

The increased secretion of glucagon-like peptide-1 (GLP-1) after Roux-en-Y gastric bypass (RYGB) is regarded as the main reason for the improvement of blood glucose. However, the single-nucleotide polymorphisms (SNPs) of GLP-1 Receptor (GLP1R) impair receptor function, subsequently affecting β cell insulin secretion function, ultimately affecting the efficacy of RYGB. In this study, we revealed that two SNPs in GLP1R gene, rs3765467 and rs10305492, could significantly reduce the insulin secreted by β cells and the cyclic AMP concentration, whereas promote β cell apoptosis. Under high glucose exposure, rs3765467 and rs10305492 impaired β cell secretion of insulin and β cell viability in the same way; in other words, GLP1R rs3765467 and rs10305492 exert an effect on pancreatic β cell glucose-stimulated insulin secretion. Moreover, GLP-1 antagonist Exendin (9-39) further enhanced, whereas GLP-1 agonist Exendin-4 partially attenuated the effects of SNPs on the functions and apoptosis of β cells. In conclusion, the rs3765467 and rs10305492 SNPs in GLP1R show to exert a critical effect on regulating insulin secretory capacity of β cells and β cell mass. Through leading to the dysfunction and apoptosis of β cells, GLP1R rs3765467 and rs10305492 might also impair GLP-1 interaction with GLP1R, therefore attenuating the therapeutic effect of RYGB.

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.