Figure - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Amino acid sequence alignment of GLP1R and its paralogous receptors. Amino acid sequences of human GLP1R, GLP2R, GCGR, and GIPR are compared. The signal peptides are indicated in gray. The residues colored in blue represent conserved sequences across the GLP-1-related peptide receptors. Residues in red are conserved sequences within orthologs of vertebrates such as mouse, anole, chicken, Xenopus tropicalis, medaka, fugu, tetraodon, stickleback, and zebrafish. The residues in black are variable sequences. The amino acid residues that interact with their peptides are shaded. The α-helix, β-sheets, and TMH domains of GLP1R are indicated.
Source publication
Glucagon-like peptide-1 (GLP-1) is a major player in the regulation of glucose homeostasis. It acts on pancreatic beta cells to stimulate insulin secretion and on the brain to inhibit appetite. Thus, it may be a promising therapeutic agent for the treatment of type 2 diabetes mellitus and obesity. Despite the physiological and clinical importance o...
Similar publications
Glucagon-like peptide 1 (GLP-1) receptor plays a major role in promoting glucose stimulated insulin secretion in pancreatic beta cells. Here in our present study we synthesized a novel functional analogue of GLP-1 conjugated to tetramethyl rhodamine to monitor the internalization of the receptor. Our data shows that receptor after being internalize...
Introduction: Obesity is an independent risk factor for cardiovascular disease (CVD) as it increases inflammation and oxidative stress in the body. Glucagon Like Peptide-1 (GLP-1 RA) agonist receptors, such as semaglutide, reduce weight, improve blood sugar levels, and promote cardioprotection. GLP-1 Ras extend the life of GLP-1, an incretin respon...
Glucagon-like peptide 1 receptor (GLP1R) agonists are widely used to treat diabetes. However, their function is dependent on adequate GLP1R expression, which is downregulated in diabetes. GLP1R is highly expressed on pancreatic beta cells and activation by endogenous incretin or GLP1R agonists increases cAMP generation, which stimulates glucose-ind...
Insulin secretion is enhanced upon the binding of Glucagon-like peptide-1 (GLP-1) to its receptor (GLP1R) in pancreatic beta cells. Although a reduced expression of GLP1R in pancreatic islets from type 2 diabetic patients and hyperglycaemic rats has been established, it is still unknown if this is caused by differential DNA methylation of GLP1R in...
Glucagon-like peptide 1 (GLP-1) agonists are promising therapeutic agents in the treatment of diabetes mellitus. This study examines the mechanism of the protective effects of exenatide in experimental diabetes employing four groups of 10 rats each, in which two groups were streptozotocin-induced diabetic and two were control groups. One control an...
Citations
... The pleiotropic effects of GLP-1 also include suppression of glucagon secretion, increased survival of pancreatic betacells, slowing of gastric emptying, increased peripheral insulin sensitivity, central appetite suppression, antiinflammatory, cardio-; reno-and neuroprotective impact (reviewed in Rowlands et al. (2018) and M€ uller et al. (2019)). GLP-1 effects are mediated through the G-protein-coupled GLP-1 receptor (GLP-1R), which is widely distributed in the arterial walls, pancreas, kidney, heart and brain tissues (Moon et al., 2012;Pyke et al., 2014). The rapid development of different GLP-1R agonists as antidiabetic and anti-obesity drugs in the past 20 years has significantly improved medical care for patients with T2DM, obesity and atherosclerotic vascular disease (Nauck et al., 2021). ...
... The binding is followed by the recognition of the ligand mediated by the specific residues present in extracellular domain at the N-terminal region of GLP-1R interacting with the α-helical region of the ligand (Runge et al., 2008;Underwood et al., 2010). Following this, the N-terminal residues of ligand binds with the extracellular loops and transmembrane helices of the receptor to induce the activation of GLP-1R (Al-Sabah & Donnelly, 2003;De Maturana et al., 2003;Moon et al., 2012). ...
... It has the α-helix at the N-terminal region of the extracellular domain and four β-strands arranged in two sheets antiparallelly. Three disulfide bonds connect these two sheets involving six cysteine (Cys) residues (Moon et al., 2012). The first disulfide bond between first and third Cys residues links the α-helix to the first β-sheet, whereas the second bond between second and fifth Cys residues connects two β-sheets. ...
Incretin effect helps in regulating glucose homeostasis and maintaining glycaemic control within the human body. This effect is achieved by the two naturally occurring incretin hormones: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Such hormones released by specialized entero-endocrine cells of the gastrointestinal tract cause insulin augmentation after food consumption. However, incretin effects are impaired in type 2 diabetic, primarily attributed to the deterioration of GLP-1 function along with decreased GLP-1 receptor expression. Targeting this hormone has, therefore, become an important therapeutic approach to treat this diabetic condition. Native GLP-1’s brief half-life and rapid proteolytic degradation have generated significant enthusiasm in uncovering the long-acting GLP-1 receptor (GLP-1R) agonists to manage type 2 diabetes. These synthetic peptides mimic the natural GLP-1 to activate GLP-1R and effectively exert various physiological benefits in terms of weight management, blood pressure, lipid profile, obesity and major adverse cardiovascular event. This review paper provides insights into the structure, function and expression of GLP-1 and its receptor. It also summarizes existing literature regarding different types of GLP-1 receptor agonists, their effects on blood pressure and how they exert their actions. While animal models have contributed significantly to this area of study, the scarcity of human studies is noted, indicating a need for more investigation in this domain. Expanding research in humans will help in comprehending the impact of GLP-1 receptor agonists on blood pressure regulation and their underlying mechanisms.
... Serum from other animal species may provide a matrix that matches the complexity of the target matrix without interference from endogenous analytes. Chicken serum represents a promising surrogate matrix for pig serum since avian GLP-1 is unique from the GLP-1 conserved across mammals [17]. However, the calibration curve generated from chicken serum resulted in poor calibration dynamic ranges for insulin, osteocalcin, GLP-1 (7-36), and GLP-1 where an ideal R 2 could not be achieved ( Figure S9). ...
Hormones are important signaling molecules controlling physiological homeostasis. ELISA kits are commonly used to measure hormones; however, few ELISA kits are multiplex, not all species-specific ELISA kits are commercially available, and ELISA kits typically require a significant volume of biological fluids. Pigs resemble humans in digestive physiology, making them an excellent model in preclinical research of nutrition and metabolism. In this study, we developed and validated a simple liquid–liquid extraction procedure and LC-MS/MS method for the simultaneous quantification of insulin, cortisol, glucagon-like peptide-1 (GLP-1) (7-37) and (7-36), acyl and des-acyl ghrelin, and carboxylated osteocalcin in pig serum. The proposed method is specific, highly sensitive (LOQ in ng/mL and pg/mL), reasonably accurate (more than 76.2% of all quality control samples within 20% error from nominal values), and precise (intra-day CV ≤ 10% and inter-day CV ≤ 23.1%). The recoveries of all analytes and corresponding internal standards ranged from 83.7 to 116.0%. The method also requires a low serum volume of 50–100 μL, which is invaluable when sample volume is limited. These methods could be easily extended for use in other mammalian species.
... 23 Importing Ile 7 into MAR709 caused a sharp decline in GLP-1 activity. The mechanism remains unclear; Moon et al suggested a hypothesis that GLP-1 Thr 13 interacts with a binding pocket formed by Ile 196 , Leu 232 , and Met 233 of GLP-1R because Thr 7 -containing chimeric peptides are highly sensitive for the Ile 196 mutation; 24 but it contradicts the model constructed by Zhang et al that Lys 197 of GLP-1R is highly conserved and is hydrogen bonded to Thr 13 of GLP-1. 12 The substitution of GLP-1 Thr 13 or GIP Ile 7 with Ala obviously decreased their receptor-activating activities 25,26 and the substitution of GIP Ile 7 with Thr decreased its cAMP activity (pEC 50 : 9.76→9.58;Emax: ...
... GIP (1-30)-NH 2 , an active fragment of GIP with affinity and activity that align with those of integrated GIP, dramatically decreased somatostatinotropic activity in isolated perfused rat stomachs. Even when further broken down, GIP (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) and GIP (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) showed some activity. A study demonstrated that, among GIP (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), GIP (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), GIP (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), and GIP (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), GIP (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) was the only having activity although it is weak. ...
... Even when further broken down, GIP (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) and GIP (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) showed some activity. A study demonstrated that, among GIP (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), GIP (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), GIP (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), and GIP (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), GIP (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) was the only having activity although it is weak. 38 GIP Gln 19 may form hydrogen bonds with GIPR Gly 29 and Thr 31 . ...
Lijing Wang College of Life Sciences and Technology, China Pharmaceutical University, Nanjing, Jiangsu, People’s Republic of ChinaCorrespondence: Lijing Wang, College of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Jiangning District, Nanjing, Jiangsu, People’s Republic of China, Tel +86 182 860 69474, Email w359398300@gmail.com; 3220030021@stu.cpu.edu.cnAbstract: Improving type 2 diabetes using incretin analogues is becoming increasingly plausible. Currently, tirzepatide is the most promising listed incretin analogue. Here, I briefly explain the evolution of drugs of this kind, analyze the residue discrepancies between tirzepatide and endogenous incretins, summarize some existing strategies for prolonging half-life, and present suggestions for future research, mainly involving biased functions. This review aims to present some useful information for designing a dual glucagon like peptide-1 receptor/glucose-dependent insulinotropic polypeptide receptor agonist.Keywords: tirzepatide, GLP-1, GIP, Aib, structure–activity relationship, structure–function relationship
... The secondary structures have been used as an essential index to characterize proteins and peptides [63]. Previous studies suggested an α-helical rich structure for LPP [37,40,64]. Therefore in the current study, Raman, ATR-FTIR, and CD spectroscopy analyses were used to carefully investigate the secondary structures of the produced LPP and the hybrid protein. ...
Nowadays, a small number of incretin mimics are used to treat type 2 diabetes mellitus (T2DM) due to their longer half-life. The present study aimed to introduce a novel method for producing the liraglutide precursor peptide (LPP) and developing a potentially new incretin mimic. Here, human αB-crystallin (αB-Cry) was ligated to the LPP at the gene level, and the gene construct was expressed in Escherichia coli with a relatively good efficiency. The hybrid protein (αB-lir) was then purified by a precipitation method followed by anion exchange chromatography. After that, the peptide was released from the carrier protein by a chemical cleavage method yielding about 70%. The LPP was then purified by gel filtration chromatography, and HPLC estimated its purity to be about 98%. Also, the molecular mass of the purified peptide was finally confirmed by mass spectroscopy analysis. Assessment of the secondary structures suggested a dominant α-helical structure for the LPP and a β-sheet rich structure for the hybrid protein. The subcutaneous injection of the LPP and the αB-lir hybrid protein significantly reduced the blood sugar levels in healthy and diabetic mice and stimulated insulin secretion. Also, the hybrid protein exerts its bioactivities more effectively than the LPP over a relatively longer period of time. The results of this study suggested a novel method for the easy and cost-effective production of the LPP and introduced a new long-acting incretin mimic that can be potentially used for the treatment of T2DM patients.
... There is also a rising interest in dual GLP-1R/GIPR agonists as neuroprotective drugs that act on respective homoreceptors located in the central nervous system (CNS), with proof that these peptides could also pass through the BBB (62-64). The GLP-1 receptor belongs to the G protein-coupled receptor (GPCR) B family, consisting of seven transmembrane helices (TMH) interconnected by intracellular loops, with a Cterminal intracellular domain and a large (∼120 amino acid) Nterminal extracellular domain (ECD) (65). GLP-1 receptors are substantively expressed and are most abundant in the pancreas, gut and the CNS, but also in the peripheral nervous system (PNS), heart, vasculature, kidneys, and lungs (66). ...
The public and social health burdens of ischemic stroke have been increasing worldwide. Hyperglycemia leads to a greater risk of stroke. This increased risk is commonly seen among patients with diabetes and is in connection with worsened clinical conditions and higher mortality in patients with acute ischemic stroke (AIS). Therapy for stroke focuses mainly on restoring cerebral blood flow (CBF) and ameliorating neurological impairment caused by stroke. Although choices of stroke treatment remain limited, much advance have been achieved in assisting patients in recovering from ischemic stroke, along with progress of recanalization therapy through pharmacological and mechanical thrombolysis. However, it is still necessary to develop neuroprotective therapies for AIS to protect the brain against injury before and during reperfusion, prolong the time window for intervention, and consequently improve neurological prognosis. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are broadly regarded as effective drugs in the treatment of type 2 diabetes mellitus (T2DM). Preclinical data on GLP-1 and GLP-1 RAs have displayed an impressive neuroprotective efficacy in stroke, Parkinson's disease (PD), Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), and other neurodegenerative diseases. Based on the preclinical studies in the past decade, we review recent progress in the biological roles of GLP-1 and GLP-1 RAs in ischemic stroke. Emphasis will be placed on their neuroprotective effects in experimental models of cerebral ischemia stroke at cellular and molecular levels.
... These data suggest that GIP cooperates with other unknown feeding-dependent factors to develop thyroid follicles. We next injected an incretin receptor antagonist peptide (exendin-3 (9-39) amide) that inhibits the receptors of incretin across species 47,48 into fed tadpoles to confirm whether incretin function is required for feeding-dependent thyroid follicle formation ( Figure 6I). The injection of the antagonist and concurrent feeding were performed for 9 days from st. 46. ...
Developing animals absorb nutrients either through the placenta or from ingested food; however, the mechanisms by which embryos use external nutrients for individual organ morphogenesis remain to be elucidated. In this study, we assessed nutrient-dependent thyroid follicle morphogenesis in Xenopus laevis and investigated the role of secreted gastrointestinal (GI) hormones post-feeding. We found that feeding triggers thyroid follicle formation, and the thyroid cells showed transient inactivation of cell proliferation after feeding. In addition, the thyroid cells with multi-lumina were frequently observed in the fed tadpoles. The expression of the particular GI hormone incretin, glucose-dependent insulinotropic polypeptide (GIP), responded to feeding in the intestines of Xenopus tadpoles. Inhibition of dipeptidyl peptidase 4 (Dpp4), a degradative enzyme of incretin, increased the size of the thyroid follicles by facilitating follicular lumina connection, whereas inhibition of the sodium-glucose cotransporter (SGLT) reversed the effects of Dpp4 inhibition. Furthermore, injection of GIP peptide in unfed tadpoles initiated thyroid follicle formation-without requiring feeding-and injection of an incretin receptor antagonist suppressed follicle enlargement in the fed tadpoles. Lastly, GIP receptor knockout in neonatal mice showed smaller follicles in the thyroid, suggesting that the GI hormone-dependent thyroid morphogenesis is conserved in mammals. In conclusion, our study links external nutrients to thyroid morphogenesis and provides new insights into the function of GI hormone as a regulator of organ morphology in developing animals.
... Thus, the naturally occurring GCGR mutations, D63N/A, P86S, and R116H listed in Fig. 9 might have some defects in receptor pharmacology. ECLs play a crucial role in ligand binding and selectivity in GPCRs (Dods & Donnelly, 2015;Koole et al., 2012;Mann, Al-Sabah, de Maturana, Sinfield, & Donnelly, 2010;Moon et al., 2012). Three labgenerated mutants, R201D, D208Q, and W215L in ECL1 of GCGR have no binding despite normal cell surface expression (Siu et al., 2013). ...
... In TMD1, Y148 1.43 may play an important role as Y148 1.43 A/ N/F mutations have normal cell surface expression but no detectable binding or reduced affinity and decreased potency (Zhang, Zhang, Zou, & Miller, 2016). In TMD2, site-directed mutagenesis has been performed on 17 residues (Coopman et al., 2011;Lopez de Maturana & Donnelly, 2002;Mathi et al., 1997;Moon et al., 2012;Underwood et al., 2011;Wootten et al., 2016;Xiao, Jeng, & Wheeler, 2000;Yang et al., 2016). The mutations, including R176 2.46 A (Mathi et al., 1997), H180 2.50 R with normal cell surface expression (Heller et al., 1996), and H180 2.50 A with decreased cell surface expression (Wootten, Savage, et al., 2013), display reduced ligand binding affinity and signaling potency. ...
... ECL2 is a key region for ligand binding and selectivity (Dods & Donnelly, 2015;Koole et al., 2012;Mann et al., 2010;Moon et al., 2012). C296 in ECL2 of rat or human GLP-1R is involved in forming the disulfide bond with C226 in TMD3, and it is crucial for ligand binding (Koole et al., 2012;Mann et al., 2010;Siu et al., 2013;Underwood et al., 2011). ...
G protein-coupled receptors (GPCRs) are the largest family of membrane receptors involved in the regulation of almost all known physiological processes. Dysfunctions of GPCR-mediated signaling have been shown to cause various diseases. The prevalence of obesity and type 2 diabetes mellitus (T2DM), two strongly associated disorders, is increasing worldwide, with tremendous economical and health burden. New safer and more efficacious drugs are required for successful weight reduction and T2DM treatment. Multiple GPCRs are involved in the regulation of energy and glucose homeostasis. Mutations in these GPCRs contribute to the development and progression of obesity and T2DM. Therefore, these receptors can be therapeutic targets for obesity and T2DM. Indeed some of these receptors, such as melanocortin-4 receptor and glucagon-like peptide 1 receptor, have provided important new drugs for treating obesity and T2DM. This review will focus on the naturally occurring mutations of several GPCRs associated with obesity and T2DM, especially incorporating recent large genomic data and insights from structure-function studies, providing leads for future investigations.
... Moreover, GLP-1 expressed in the liver has been reported, while no other publications showed its expression in hepatocytes (44). In terms of structure, GLP-1R is constituted by seven transmembrane helices (TMH) interconnected by intracellular loops, accompanied by a C-terminal intracellular domain and a large (w120 amino acid) N-terminal extracellular domain (ECD) (45). GLP-1 binds to GLP-1R in a complicated procedure, with GLP-1 peptide stably anchored in its position through an extensive network of interactions (40). ...
GLP-1 is derived from intestinal L cells, which takes effect through binding to GLP-1R and is inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4). Since its discovery, GLP-1 has emerged as an incretin hormone for its facilitation in insulin release and reduction of insulin resistance (IR). However, GLP-1 possesses broader pharmacological effects including anti-inflammation, neuro-protection, regulating blood pressure (BP), and reducing lipotoxicity. These effects are interconnected to the physiological and pathological processes of Alzheimer’s disease (AD), hypertension, and non-alcoholic steatohepatitis (NASH). Currently, the underlying mechanism of these effects is still not fully illustrated and a better understanding of them may help identify promising therapeutic targets of AD, hypertension, and NASH. Therefore, we focus on the biological characteristics of GLP-1, render an overview of the mechanism of GLP-1 effects in diseases, and investigate the potential of GLP-1 analogues for the treatment of related diseases in this review.
... Signaling by GLP-1 receptor for the amplification of GSIS. Produced in intestinal L-enterocytes, GLP-1 from the bloodstream activates its receptor (GLP1R) on the plasma membrane of pancreatic b-cells (170). GLP1R activation preferentially stimulates G-proteins Gas, but also Gaq or Ga 11 (Fig. 10), and recruits b-arrestin, depending on a biased agonism differently to different agonists, such as exendin-4 and oxyntomodulin (238,275). ...
Significance:
Mitochondria determine glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells by elevating ATP synthesis. As the metabolic and redox hub, mitochondria provide numerous links to the plasma membrane channels, insulin granule vesicles (IGVs), cell redox, NADH, NADPH, and Ca2+-homeostasis, all affecting insulin secretion. Recent Advances: Mitochondrial redox signaling was implicated in several modes of insulin secretion (branched-chain ketoacid-, fatty acid-stimulated). Mitochondrial Ca2+-influx was found to enhance GSIS, reflecting cytosolic Ca2+-oscillations induced by action potential spikes (intermittent opening of voltage-dependent Ca2+ and K+ channels) or the superimposed Ca2+-release from the endoplasmic reticulum (ER). The ATPase inhibitory factor IF1 was reported to tune the glucose-sensitivity range for GSIS. Mitochondrial protein kinase-A was implicated in preventing the IF1-mediated inhibition of the ATP-synthase.
Critical issues:
It is unknown how the redox signal spreads up to the plasma membrane and what its targets are, what the differences in metabolic, redox, NADH/NADPH, and Ca2+-signaling and homeostasis are between the 1st and 2nd GSIS phase; and whether mitochondria can replace ER in the amplification of IGV exocytosis.
Future directions:
Metabolomics studies performed to distinguish between the mitochondrial matrix and cytosolic metabolites will elucidate further details. Identifying the targets of cell signaling into mitochondria and of mitochondrial retrograde metabolic and redox signals to the cell will uncover further molecular mechanisms for insulin secretion stimulated by glucose, branched-chain keto acids, and fatty acids, and the amplification of secretion by GLP-1 and metabotropic receptors. They will identify the distinction between the hub β-cells and their followers in intact/diabetic states.
