The GLP-1 receptor was originally isolated from a rat pancreatic islet cDNA library in the laboratory of Dr. B. Thorens 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 clearly linked to an increased risk of diabetes.
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
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]
Although considerable effort has been expended in searching for a second GLP-1 receptor, only a single receptor has been isolated to date.
There appears to be an element of species-specificity in GLP-1R expression, as illustrated in recent studies from Giacca, Wheeler and colleagues in the May issue of 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]
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.
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 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"