The GLP-1 receptor was originally isolated from a rat pancreatic islet cDNA library by expression cloning Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8641-5. The rat receptor is 463 amino acids and is a member of the GPCR family. The GLP-1 receptor has also been cloned from human tissues including brain, lung, and heart. Hybridization studies have localized the human GLP-1R to 6p21. To date, no families have been identified with loss of function mutations in the GLP-1R that are linked to an increased risk of diabetes however emerging human genetic data links the GLP1R to metabolic phenotypes.

The GLP-1R is fairly widely expressed in pancreatic islets, brain, heart, kidney, and the GI tract (see Divergent tissue-specific and developmental expression of receptors for glucagon and glucagon-like peptide-1 in the mouse. Endocrinology. 1994 May;134(5):2156-64. and Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor. Endocrinology. 1996 Jul;137(7):2968-78

Classic ligands for the GLP-1R include GLP-1(7-37) and GLP-1(7-36)amide, as well as structurally related GLP-1R agonists such as exendin-4. Activation of the GLP-1R may also be achieved through allosteric modulation of the interaction between GLP-1(9-36) and the GLP-1R using small molecule allosteric modulators (albeit at high concentrations) both in vitro and in vivo. Allosteric GLP-1R modulation was biased towards activation of cAMP signaling, with little signaling through intracellular calcium or ERK1/2 activation. The allosteric modulators BETP and CPD2 markedly potentiated the ability of GLP-1(9-36) to activate the GLP-1R, as assessed by cyclic AMP formation, and also potentiated the insulinotropic activity of GLP-1(9-36) both in islets in vitro, and during a glucose tolerance test in rats in vivo. Allosteric Modulation of Endogenous Metabolites as an Avenue for Drug Discovery Mol Pharmacol. 2012 May 10

The GLP-1R may form heterodimers with the GIPR, as demonstrated in studies using BRET to identify interactions amongst class B family GPCRs in HEK cells that overexpress the transfected receptors. GLP-1, GLP-2, and GLP-1(9-36) increased the extent of the interaction, however GIPappeared to reduced the BRET interaction signal activated by GLP-1. Furthermore, the GLP-1R agonists oxyntomodulin and exendin-4 did not induce receptor heterodimerization, that was actually reduced by exendin-4. Co-expression of the GLP-1R and GIPR also diminished the calcium response to GLP-1 in HEK cells.  Lateral Allosterism in the Glucagon Receptor Family: GLP-1 Induces GPCR Heteromer Formation Mol Pharmacol. 2011 Nov 22. [Epub ahead of print]

The GLP-1R also forms homodimers, which affects signaling bias by peptide ligands. Disruption of the TM4 interface using a variety of techniques abolished GLP-1R homodimerization, and decreased cAMP formation and ERK phosphorylation, with a complete loss of intracellular calcium accumulation in response to GLP-1(7-36)amide without affecting cell surface GLP-1R expression. In contrast, allosteric modulation and potentiation of GLP-1R signaling did not require homodimerization. Glucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):18607-12

Partial crystal structures, for the GLP-1 receptor, alone or in association with ligands, have been reported or deduced, enabling rationale design of small molecule and peptide agonists and antagonists. Crystal structure of the ligand-bound glucagon-like peptide-1 receptor extracellular domain J Biol Chem. 2008 Apr 25;283(17):11340-7. Predicted structure of agonist-bound glucagon-like peptide 1 receptor, a class B G protein-coupled receptor Proc Natl Acad Sci U S A. 2012 Dec 4;109(49):19988-93  Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators Nature. 2017 May 17. doi: 10.1038/nature22378. Crystal structure of the GLP-1 receptor bound to a peptide agonist Nature. 2017 May 31. doi: 10.1038/nature22800

GLP1R genetics

Despite the important physiological role(s) of GLP-1R signaling in the control of glucose homeostasis, genetic evidence linking variation within the human GLP1R to control of glucose, beta cell function, or diabetes risk, has been elusive. Wessel et al identified a low-frequency nonsynonomous SNV within the GLP1R coding sequence, A316T, rs10305492, that associates with lower fasting glucose and reduced T2D risk, yet lower insulin response to a glucose challenge, lower insulinogenic index and higher 2 h PC glucose. Receptor conformation modelling studies suggested that this amino acid substitution might affect receptor signaling, which was not directly tested. Previous studies that have examined the biology of thr GLP1R A316 variant either reported no effect on cAMP responses Pharmacological characterization of human incretin receptor missense variants J Pharmacol Exp Ther. 2010 Jan;332(1):274-80 , and/or a 75% reduction of receptor cell surface expression and reduced intracelular calcium mobilization Polymorphism and ligand dependent changes in human glucagon-like peptide-1 receptor (GLP-1R) function: allosteric rescue of loss of function mutation Mol Pharmacol. 2011 Sep;80(3):486-97. 12 other GLP1R SNVs that associated with variation in fasting glucose were also identified. Paradoxically, variation within GIPR revealed that the fsting glucose lowering allele is associated with a high risk for T2D. Hence, understanding the physiological importance of these alleles in normal and diabetic human populations will take considerable additional investigation. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nat Commun. 2015 Jan 29;6:5897.

Mahajan and colleagues also identified the low-frequency non-synonymous GLP-1Rvariant rs10305492 p.Ala316Thr (MAF = 1.5%, P = 4.6×10−7; associating with reduced fasting glucose in human population studies and commented that the alanine residue at p.Ala316Thr "is conserved across vertebrate GLP-1Rs    Identificationand functional characterization of G6PC2 coding variants influencing glycemic traits define aneffector transcript at the G6PC2-ABCB11 locus PLOS Genetics 2015 Jan 27;11(1):e1004876.

A follow up study evaluating metabolic traits associating with genetic variation at rs10305492 Ala316Thr confirmed the link between variation within the GLP1R at this site, and a lower risk of T2D. A single individual was also identified in the UK10k study with a loss of function GLP1R allele W297, but this person did not exhibit an extreme dysglycemic phenotype., with normal levels of fasting glucose and insulin, with 6 more putative LOF GLP1Rvariants reported in the database assembled by the Exome Aggregation Consortium.

Remarkably, analysis of 61,488 individuals with coronary artery disease and 163,728 controls revealed a significant association between the rs10305492 GLP1R variant and protection against coronary artery disease, beyond that expected from the reduction in fasting glucose levels. Non-significant trends in reductions of LDL cholesterol, triglycerides, systolic blood pressure and higher HDL were also observed in subjects with this GLP1R variant. See A genomic approach to therapeutic target validation identifies a glucose-loweringGLP1R variant protective for coronary heart disease Sci Translational Medicine 01 JUN 2016 : 341RA76 

Does genetic variation in the GLP-1R predict responsivity to GLP-1 administration?  Athananthan and colleagues studied 88 healthy subjects with a hyperglycemic clamp and 2 hrs of concomitant GLP-1 administration. Two SNPs (rs6923761 and rs3765467) wereassociated with modestly altered b-cell responsivity in response to GLP-1 infusion. One of these nsSNPs, rs6923761 (with a minor allele frequency of ~29% in Caucasians) results in the substitution of serine for glycine at position 168, and confers a modest decrease in responsiveness to infused GLP-1. The other SNP , rs3765467, results in substitution of glutamine for arginine at position 131, and alters the responsivity to glucose alone suggesting that endogenous GLP-1 may play a role in the data obtained in carriers of this genotype. Whether these genetic variations influences the responsivity to incretin-based therapy requires further study. See Common Genetic Variation in GLP1R and Insulin Secretion in Response to Exogenous GLP-1 in Nondiabetic Subjects: A pilot study Diabetes Care September 2010 33:2074-2076

Genetic variation in the rodent Glp1r may contribute to the biology of the sleep wake cycle in rodents. Following a genetic screen that identifiied QTLs in candidate genes that may regulate a number of parameters related to the sleep wake cycle in rodents, the authors pursued a pharmacological validation approach. QTLs within the Glp1r were linked to Latency to non-REM sleep, Non-REM sleep, Total Sleep and the wake state. Peripheral administration of the GLP-1R agonists exenatide or liraglutide induced light sleep in rats and reduced the time spent in the 'wake' state. Pharmacological validation of candidate causal sleep genes identified in an N2 cross J Neurogenet. 2011 Dec;25(4):167-81

Caveats in GLP-1R localization

Monoclocal GLP-1R antisera for use with human and murine cells & tissues now available

The GLP-1R has beeen localized to multiple tissues and cell types in the endocrine pancreas, central and peripheral nervous system, gastrointestinal tract, cardiovascular system, kidney, and lung. A large number of commercially available antisera have been used to detect GLP-1R expression by Western blot analysis and immunocytochemistry. Panjwani and colleagues assessed Glp1r expression by PCR using primer pairs that spanned the entire Glp1r open reading frame, and evaluated the sensitivity and specificity of 3 different commercially available GLP-1R antisera. Contrary to previous reports, full length Glp1r mRNA trancripts could not be detected in murine macrophages or hepatocytes. Furthermore, although GLP-1R antisera detected immunoreactive proteins of the ~ Mw of the authentic GLP-1R, the identical bands were detected using extracts from lung tisue of Glp1r-/- mice. Furthermore, the 3 antisera failed to detect GLP-1R expression using extracts from fibroblast cells transfected with the murine GLP-1R cDNA, either using conventional Western blotanalysis or a combination of immunoprecipitation/immunoblotting to enhance detection sensitivity. These findings raise issues for studies reporting GLP-1R expression in cells and tissues without rigorous controls to carefully evaluate the presence or absence of full length Glp1r RNA and protein. GLP-1 Receptor Activation Indirectly Reduces Hepatic Lipid Accumulation But Does Not Attenuate Development of Atherosclerosis in Diabetic Male ApoE−/− Mice Endocrinology en.2012-1937; doi:10.1210/en.2012-1937

Pyke and colleagues reported GLP-1R localization in monkey and human tissues with a monoclonal antibody directed against the GLP-1R. Pancreatic localization was primarily in beta cells, however a weak signal in acinar cells could not be excluded. GLP-1R immunopoisitivity was also detected in vascular smooth muscle cells, myocytes of the sinoatrial node, Brunners glands in the duodenum, the gut myenteric plexus, renal arterioles (smooth muscle) and some renin+ juxtaglomerular cells. Complementary localization studies were carried out in some tissues using ligand binding GLP-1 receptor localization in monkey and human tissue; Novel distribution revealed with extensively validated monoclonal antibody January 27, 2014http://dx.doi.org/10.1210/en.2013-1934

Dal Molin et al used quantitative in situ hybridization to assess GLP1R expression in various human pancreas cell types, including endocrine cells, acinar cells, and ductal cells, within the human pancreas, including samples from pancreatic neplasia, and pre-neoplastic lesions. GLP1R mRNA transcripts were not very abundant, yet detected in all cell tyes examined, with greatest abundance in pancreatic endocrine cells (islets) and lowest abundance in ductal cells. Specimens studied included cases with PDAC and Pan-IN lesions of all grades, 1-3. The progression from normal pancreatic cells (acinar or ductal cells) to PanINs and eventually PDAC was not associated with a significant increase in expression of the GLP1R, which remained very low in all of these cell types. No "outliers" with high level GLP1R expression in PDACs were detected. Glucagon-Like Peptide-1 Receptor Expression in Normal and Neoplastic Human Pancreatic Tissues Pancreas 2015 in press

Similar findings of low level expression of GLP-1R binding sites (receptor autoradiography) in the normal human pancreas have been reported using the technique of in situ radiography. Pheochromocytomas exhibited the highest density of GLP-1 binding sites; lower but detectable binding was observed in paragangliomas, medullary thyroid carcinomas, meningiomas, astrocytomas, and medulloblastomas. GLP-1 binding was not observed in breast carcinomas, gastrocolic adenocarcinomas, pancreatic ductal carcinomas, cholangiocellular carcinomas, hepatocellular carcinomas, non–small cell and small cell lung carcinomas, and renal cell carcinomas. In regard to normal tissues, the highest density of binding was observed in the posterior pituitary. In the pancreas, binding was most abundant in islets but detectable binding sites were also localized to the acini in the exocrine pancreas. No binding of GLP-1 ligand was detected in liver, spleen, lymph nodes, thymus, adrenal gland, adenohypophysis, prostate, heart, skeletal muscle, and fat.  GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting. J Nucl Med. 2007;48:736–743.

Consistent with localization of Glp1r expression to the mouse and human exocrine pancreas, Hou et al demonstrated that Glp1r expression was identified in isolated pancreatic acini, and GLP-1R agonists directly stimulated amylase release, findings abolished in experiments using pancreatic tissue from Glp1r-/- mice.

The Glucagon-Like Peptide-1 Receptor is Present in Pancreatic Acinar Cells and Regulates Amylase Secretion through cyclic AMP Am J Physiol Gastrointest Liver Physiol. 2015 Nov 5:ajpgi.00293.2015. doi: 10.1152/ajpgi.00293.2015

A combination of in situ hybridization and immunocytochemical localization experiments was used to determine the cells expressing the GLP-1R in the mouse, rat and human pancreas. The GLP-1R was localized to pancreatic duct cells and to b-cells, with little to no expression found on other islet cell types. Furthermore, human cells exhibit heterogeneity in the extent of GLP-1R expression. There was little evidence to support the expression of GLP-1R on a-cells, although a few cells in the rat pancreas that contained both insulin and glucagon expressed the GLP-1R. Similarly, very few d-cells expressed the GLP-1R. See Expression of the GLP-1 Receptor in Mouse, Rat, and Human Pancreas. J Histochem Cytochem. 2008 Jun 9. [Epub ahead of print]

Richards and colleagues have indirectly assessed the expression of the mouse GLP-1 receptor indirectly through the development and analysis of a reporter mouse that expresses Cre recombinase under the control of endogenous murine Glp1r regulatory elements. This mouse was then bred to lines of reporter mice to activate reporter gene expression within tissues permission for Glp1r promoter expression. Principal sites of reporter gene expression included pancreatic β- and δ-cells, vascular smooth muscle, cardiac atrium, gastric antrum/pylorus, enteric neurones, and vagal and dorsal root ganglia. A few positive cells were also detected within pancreatic ducts. Within the CNS, positive cells were detected within area postrema, arcuate nucleus, paraventricular nucleus and ventromedial hypothalamus. See Identification and characterization of GLP-1 receptor-expressing cells using a new transgenic mouse model Diabetes. 2014 Apr;63(4):1224-33

A second more detailed analysis of reporter gene exprssion within the mouse brain, using the same transgenic lines, concluded that many regions of the mouse brain expressed the Glp1r-directed reporter genes, including the circumventricular organs, amygdala, hypothalamic nuclei and the ventrolateral medulla, as well as the NTS, thalamic paraventricular nucleus, hippocampus and cortex  Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain Mol Metab. 2015 Aug 5;4(10):718-73

 

GLP-1R Desensitization

Considerable evidence accumulated using islet cell lines, rodent islets and rodent studies, provides evidence for acute and sustained GLP-1R desensitization on b-cells Desensitization and phosphorylation of the glucagon-like peptide-1 (GLP-1) receptor by GLP-1 and 4-phorbol 12-myristate 13-acetate Mol Endocrinol. 1996 Jan;10(1):62-75. and Heterologous desensitization of the glucagon-like peptide-1 receptor by phorbol esters requires phosphorylation of the cytoplasmic tail at four different sites J Biol Chem. 1996 Aug 16;271(33):19957-63. and Internalization and homologous desensitization of the GLP-1 receptor depend on phosphorylation of the receptor carboxyl tail at the same three sites Mol Endocrinol. 1997 Jul;11(8):1094-102. Nevertheless, these classic pharmacological studies invoking the importance of PKA, and PKC, for receptor phosphorylation, internalization, and desensitization, need to be interpreted in the context of experimental animal and clinical in vivo data demonstrating that sustained GLP-1R activation for years continues to lower glucose, stimulate insulin secretion, and reduce appetite and body weight, in rodents. Chronic exposure to GLP-1R agonists promotes homologous GLP-1 receptor desensitization in vitro but does not attenuate GLP-1R-dependent glucose homeostasis in vivo Diabetes. 2004 Dec;53 Suppl 3:S205-14.and Repeated intracerebroventricular administration of glucagon-like peptide-1-(7-36) amide or exendin-(9-39) alters body weight in the rat Endocrinology. 1999 Jan;140(1):244-50 and in human subjects with diabetes and/or obesity. The one pharmacodynamic exception to this concept appears to be gastric emptying, where even a few hours of constant GLP-1R agonism produces tachyphylaxis in the extent of gastric emptying inhibition in normal human subjects Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans Diabetes. 2011 May;60(5):1561-5 with similar findings of attenuated inhibition of gastric emptying detected in diabetic human subjects chronically treated with exenatide Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study Lancet. 2008 Oct 4;372(9645):1240-50

Rajan and colleagues demonstrated that both high glucose and sustained exposure to GLP-1R agonists resulted in loss of responsivity to subsequent rechallenge with GLP-1R agonists both in islet cell lines in vitro and in mice in vivo. Desensitization was cyclic AMP-PKA-dependent, and associated with rapid loss of cell surface GLP-1R expression, assessed using binding of fluorescein-tagged exendin-4 and cellular localization of a transfected GLP-1R-GFP cDNA. Consistent with previous studies, serine 301 was critical for glucose-dependent receptor internalization, mediated by interactions with the small ubiquitin-related receptor modifier (SUMO). See Chronic hyperglycemia downregulates GLP-1 receptor signaling in pancreatic β-cells via protein kinase A Mol Metab. 2015 Feb 3;4(4):265-76

The effectiveness of combination therapy using metformin and GLP-1RR agonists or DPP-4 inhibitors appears to due a combination of actions of metformin on both enhancement of GLP-1 secretion and on induction of islet GLP-1R receptor expression. Although metformin exerts potent actions on suppresion of hepatic glucose production, meformin acutely stimulates GLP-1 secretion even in the absence of glucose loading in mice, and rapidly induces the expression of both GIP and to a greater exstent, GLP-1 receptor expression in muirne islet cells. The actions of metformin to increase GLP-1 receptor expression appear direct, and are mediated through a Ppara-dependent pathway. Metformin treatment of islet b-cells thus directly enhances the insulinotropic actions of incretin hormones. See Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-α in mice DOI:10.1007/s00125-010-1937-z and the commentary New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser Diabetologia. 2010 Nov 30. [Epub ahead of print]

Although considerable effort has been expended in searching for a second GLP-1 receptor, only a single receptor coupled to control of glucose homeostasis and food intake/body weight has been isolated to date.

There appears to be an element of species-specificity in GLP-1R expression, as illustrated in studies from Giacca, Wheeler and colleagues Diabetes 1999 48(5):1045-53. For example, in the dog, GLP-1R mRNA transcripts were identified in muscle and adipose tissue, whereas these tissues do not express the pancreatic islet GLP-1 receptor in rodents and humans.

There is some controversy as to whether the GLP-1R is expressed in islet α cells. For example, studies from the laboratory of Frans Schuit, Diabetes 1996;45(2):257-61 using isolated populations of α and β cells, did not detect GLP-1R expression in α cells. In contrast, studies from the Habener laboratory Insulinotropic glucagon-like peptide I receptor expression in glucagon-producing alpha-cells of the rat endocrine pancreas. Diabetes. 1997 May;46(5):785-91 of cell lines and dispersed rat islet cells, using single cell RT-PCR or a GLP-1R antibody, detected GLP-1R expression in a subpopulation of islet α cells.

The GLP-1R is negatively regulated, in pancreatic islets by glucose and dexamethasone but GLP-1R expression does not appear to be significantly affected by the PKA-dependent pathway Regulation of glucagon and glucagon-like peptide-1 receptor messenger ribonucleic acid expression in cultured rat pancreatic islets by glucose, cyclic adenosine 3',5'-monophosphate, and glucocorticoids. Endocrinology. 1995 Apr;136(4):1572-8.

The impact of hyperglycemia on GLP-1 receptor expression has been examined in studies using rats with partial pancreatectomy, (Ppx rats) and db/db mice. GLP-1 receptor mRNA transcripts and immunoreactive GLP-1R protein was reduced in hyperglycemic Ppx rats, and levels of GLP-1R RNA and protein were restored towards normal following normalization of glycemia with phlorizin. Similar findings were observed for the GIP receptor. In contrast, short term hyperglycemia either in vitro or in vivo reduced GLP-1R expression but paradoxically increased GIPR expression. The effect of glucose on GLP-1R expression was dependent on PKCa. See Downregulation of GLP-1 and GIP Receptor Expression by Hyperglycemia: Possible Contribution to Impaired Incretin Effects in Diabetes. Diabetes. 2007 Mar 14; [Epub ahead of print].

Analysis of incretin receptor expression in human islets isolated from subjects with T2DM revealed decreased levels of both Gipr and Glp1r mRNA transcripts, and reduced protein levels of TCF7L2, and knock down of TCF7L2 in human islets was also associated with reduced levels of incretin receptors and diminished responsivity to exogenous GIP and GLP-1 Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell function Hum Mol Genet. 2009 Jul 1;18(13):2388-99.

Fasting and re-feeding modulate CNS GLP-1 receptor expression in the rat hypothalamus and brainstem, as described in Short-term food restriction and refeeding alter expression of genes likely involved in brain glucosensing. Exp Biol Med (Maywood). 2003 Sep;228(8):943-50. A high fat diet alone reduced hindbrain Glp1r expression in rats High-fat diet changes the temporal profile of GLP-1 receptor-mediated hypophagia in rats Am J Physiol Regul Integr Comp Physiol. 2013 Jul 1;305(1):R68-77.

In high fat fed mice, liraglutide alone significantly reduced hypothalamic Glp1r RNA transcripts, whereas co-administration of the MCR4 agonist RM-493 and liraglutide normalized relative levels of hypothalamic Glp1r RNA transcripts. Dual melanocortin-4 receptor and GLP-1 receptor agonism amplifies metabolic benefits in diet-induced obese mice EMBO Mol Med. 2015 Feb 4. pii: e201404508

Although little is known about the control of GLP-1R gene transcription, promoter analysis Gene expression of the human glucagon-like peptide-1 receptor is regulated by Sp1 and Sp3. Endocrinology. 1999 Feb;140(2):624-31 has demonstrated the presence of binding sites for Sp1 and Sp3 which appear to be functionally important for GLP-1R promoter activity in transfection studies.

The Glp1r gene is a target for both isl-1 and its co-regulator, Ldb1, as mice with pancreas-specific inactivation of either isl-1 or Ldb1 exhibit reduced levels of Glp1r mRNA transcripts and CHIP experimenst revealed evidence for Glp1r promoter binding using antisera directed against either isl-1 or Ldb1. Islet α-, β-, and δ-cell development is controlled by the Ldb1 coregulator, acting primarily with the islet-1 transcription factor Diabetes. 2013 Mar;62(3):875-86

The Brussels group of Frans Schuit et al have identified an essential role for the GLP-1R in regulation of both islet cAMP and glucose-stimulated cytosolic Ca2+, using both +/+ islets and exendin (9-39) and GLP-1R-/- islets. For the complete story, see Altered cAMP and Ca2+ signaling in mouse pancreatic islets with glucagon-like peptide-1 receptor null phenotype. Diabetes. 1999 Oct;48(10):1979-86

Does GLP-1 modulate insulin binding? A study in Am J Physiol Endocrinol Metab 2000 Jul;279(1):E88-E94 suggests that GLP-1 treatment of RIN cells and monocytes significantly increased insulin binding, with the greatest increase seen in high capacity binding sites. In contrast, glucagon or GIP did not exert similar effects despite the findings that increased adenylate cyclase mimicked the GLP-1 effect on insulin binding sites.

A major goal of diabetes therapeutics would be the development of orally active GLP-1 receptor non-peptide agonists. Although the patent literature contains a few suggestions that this may be possible, progress to date has been slow. Beinborn and colleagues report that the non-peptide molecule T0632, originally identified as a CCK receptor ligand, is also a GLP-1 receptor ligand that preferentially binds to the human versus the rat receptor, due to the presence of the Trp 33 residue in the human but not the rat receptor. T0632 functions as a GLP-1 receptor antagonist and blocks GLP-1-  stimulated cAMP accumulation. See A small molecule ligand of the glucagon-like peptide 1 receptor targets its amino-terminal hormone binding domain. J Biol Chem. 2001 Oct 12;276(41):37787-93

Novel GLP-1 Receptors

GLP-1 may not be the only ligand for the known GLP-1 receptor. For example, several studies indicated that the related PGDP oxyntomodulin also exerts many of its actions through the GLP-1 receptor Oxyntomodulin inhibits food intake in the rat. Endocrinology. 2001 142(10):4244-50 and Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. Gastroenterology. 2004 Aug;127(2):546-58

Intriguingly, obestatin, a 23 amino acid amidated peptide derived from the ghrelin gene, has also been shown to bind weakly to GLP-1 receptors on insulinoma cell lines but not in human islets. Moreover, exogenous obestatin increased the levels of GLP-1 receptor mRNA transcripts in INS1E cells and human islets, and the GLP-1 receptor antagonist exendin(9-39) blocked the anti-apoptotic actions of obestatin in INS-1E cells following serum starvation or cytokine exposure. Obestatin and exendin-4 had similar effects on induction of IRS-2 expression in islet cells. See OBESTATIN PROMOTES SURVIVAL OF PANCREATIC b-CELLS AND HUMAN ISLETS AND INDUCES EXPRESSION OF GENES INVOLVED IN THE REGULATION OF b-CELL MASS AND FUNCTION Diabetes. 2007 Dec 27; [Epub ahead of print]

Is there a second GLP-1 receptor? This question continues to resonate largely due to the results of several studies demonstrating GLP-1 effects that are either "non-classical" in terms of binding, signal transduction, or the actions of GLP-1 may not be blocked by known GLP-1 receptor antagonists such as exendin(9-39). See "GLP-1 actions and a second GLP-1 receptor"