Open Access Articles- Top Results for Glucagon-like peptide 1 receptor

Glucagon-like peptide 1 receptor

SymbolsGLP1R ; MGC138331
External IDsOMIM138032 MGI99571 HomoloGene1558 IUPHAR: 249 ChEMBL: 1784 GeneCards: GLP1R Gene
RNA expression pattern
File:PBB GE GLP1R 208401 s at tn.png
File:PBB GE GLP1R 208390 s at tn.png
File:PBB GE GLP1R 208391 s at tn.png
More reference expression data
RefSeq (mRNA)NM_002062NM_021332
RefSeq (protein)NP_002053NP_067307
Location (UCSC)Chr 6:
39.02 – 39.06 Mb
Chr 17:
30.9 – 30.94 Mb
PubMed search[1][2]

The glucagon-like peptide 1 receptor (GLP1R) is a human gene which resides on chromosome 6.[1][2] The protein encoded by this gene is a member of the glucagon receptor family of G protein-coupled receptors.[3]

Ligand specificity

GLP1R binds specifically the glucagon-like peptide-1 (GLP1) and has much lower affinity for related peptides such as the gastric inhibitory polypeptide and glucagon.[4]

Function and therapeutic potential

GLP1R is known to be expressed in pancreatic beta cells. Activated GLP1R stimulates the adenylyl cyclase pathway which results in increased insulin synthesis and release of insulin.[5] Consequently GLP1R has been suggested as a potential target for the treatment of diabetes.[6]

GLP1R is also expressed in the brain where it is involved in the control of appetite.[7] Furthermore, mice which over express GLP1R display improved memory and learning.[8]

Huntington's disease

The diabetic, pancreatic, and neuroprotection implications of GLP1R are also thought to be potential therapies for treating the diabetes and energy metabolism abnormalities associated with Huntington's disease affecting the brain and periphery. Exendin-4, an FDA-approved antidiabetic glucagon-like peptide 1 (GLP-1) receptor agonist, has been tested in mice with the mutated human huntingtin protein showing neurodegenerative changes, motor dysfunction, poor energy metabolism, and high blood glucose levels. Exendin-4 (Ex-4) treatment reduced the accumulation of mhtt protein aggregates, improved motor function, extended the survival time, improved glucose regulation, and decreased brain and pancreas pathology.[9]

Exendin-4 increases beta cell mass in the pancreatic islets to improve the release of insulin to ultimately increase glucose uptake. The mechanism regarding this insulin increase involves Ex-4 and GLP-1. When the islets in the pancreas are exposed to GLP-1, there is an increased expression of the anti-apoptotic gene bcl-2 and decreased expression of pro-apoptotic genes bax and caspase-3, which leads to greater cell survival. GLP-1 binding to its G protein-coupled receptor activates various different pathways including the growth factor receptor and is coupled to pathways stimulating mitogenesis. Some of these pathways include Rap, Erk1/2, MAPK, B-RAF, PI3-K, cAMP, PKA, and TORC2 that are activated to initiate exocytosis, proinsulin gene expression and translation, increase insulin biosynthesis, and genetically increase beta cell proliferation and neogenesis. The GLP-1R is a G protein-coupled receptor that is dependent on glucose and GLP-1 is a peptide hormone that acts directly on the beta cell to stimulate insulin secretion by activating signal transduction when glucose is present. When glucose is not present, this receptor no longer couples to stimulate insulin secretion in order to prevent hypoglycemia.[10]

Relating glucose metabolism and insulin sensitivity back to Huntington's disease, increased insulin release and beta cell proliferation by a GLP-1 agonist, Ex-4, helps combat the damage done by mutant htt in peripheral tissues. Htt aggregation decreases beta cell mass and thus impairs insulin release and increases blood glucose levels. Disruption of glycemic homeostasis then affects nutrient availability to neurons and alters neuron function contributing to neurodegeneration and motor problems seen in Huntington's disease. The health of the nervous system is related to metabolic health, thus a diabetes medication as a Huntington's disease treatment is a potential treatment. Ex-4 easily crosses the blood-brain barrier and GLP-1 and Ex-4 have been shown to act on neurons in the brain by exerting neuroprotective actions.[9]

In studies with Huntington's disease mice, daily treatments of Ex-4 significantly reduced glucose levels compared to those mice treated with saline. It also increased insulin sensitivity by about 50%, improved insulin-stimulated glucose uptake, and protect pancreatic beta cell function. Huntington's disease has also been linked to imbalances in leptin and ghrelin levels. Ex-4 restored ghrelin levels and also lowered leptin levels allowing Huntington's disease mice to eat more and counteract symptomatic weight loss. This treatment restored beta cell cells and islet structure, reduce mhtt aggregates in the brain and pancreas, and also improve motor function seen by the increased activity level of the mice. Improvements were found in the areas of the body that expressed GLP-1R. In addition to its other effects on the Huntington's disease mouse model, daily treatment of Ex-4, the GLP-1R agonist, significantly delayed the onset of mortality and extended the lifespan by approximately one month.[9]

See also


  1. ^ Thorens B (September 1992). "Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1". Proc. Natl. Acad. Sci. U.S.A. 89 (18): 8641–5. PMC 49976. PMID 1326760. doi:10.1073/pnas.89.18.8641. 
  2. ^ Dillon JS, Tanizawa Y, Wheeler MB, Leng XH, Ligon BB, Rabin DU, Yoo-Warren H, Permutt MA, Boyd AE 3rd (October 1993). "Cloning and functional expression of the human glucagon-like peptide-1 (GLP-1) receptor". Endocrinology 133 (4): 1907–10. PMID 8404634. doi:10.1210/en.133.4.1907. 
  3. ^ Brubaker PL, Drucker DJ (2002). "Structure-function of the glucagon receptor family of the G protein-coupled receptors: the glucagon, GIP, GLP-1, and GLP-2 receptors" (PDF). Recept. Channels 8 (3-4): 179–88. PMID 12529935. doi:10.1080/10606820213687. Retrieved 2008-07-14. 
  4. ^ Fehmann HC, Jiang J, Schweinfurth J, Dörsch K, Wheeler MB, Boyd AE 3rd, Göke B (April 1994). "Ligand-specificity of the rat GLP-I receptor recombinantly expressed in Chinese hamster ovary (CHO-) cells". Z Gastroenterol 32 (4): 203–7. PMID 8017094. 
  5. ^ Drucker DJ, Philippe J, Mojsov S, Chick WL, Habener JF (May 1987). "Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line". Proc. Natl. Acad. Sci. U.S.A. 84 (10): 3434–8. PMC 304885. PMID 3033647. doi:10.1073/pnas.84.10.3434. 
  6. ^ Holst JJ (May 2004). "Treatment of type 2 diabetes mellitus with agonists of the GLP-1 receptor or DPP-IV inhibitors". Expert Opin Emerg Drugs 9 (1): 155–66. PMID 15155141. doi:10.1517/eoed. 
  7. ^ Kinzig KP, D'Alessio DA, Seeley RJ (1 December 2002). "The diverse roles of specific GLP-1 receptors in the control of food intake and the response to visceral illness". J. Neurosci. 22 (23): 10470–6. PMID 12451146. 
  8. ^ During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, Bland RJ, Klugmann M, Banks WA, Drucker DJ, Haile CN (September 2003). "Glucagon-like peptide-1 receptor is involved in learning and neuroprotection". Nat. Med. 9 (9): 1173–9. PMID 12925848. doi:10.1038/nm919. 
  9. ^ a b c Martin B, Golden E, Carlson OD, Pistell P, Zhou J, Kim W, Frank BP, Thomas S, Chadwick WA, Greig NH, Bates GP, Sathasivam K, Bernier M, Maudsley S, Mattson MP, Egan JM (February 2009). "Exendin-4 improves glycemic control, ameliorates brain and pancreatic pathologies, and extends survival in a mouse model of Huntington's disease". Diabetes 58 (2): 318–28. PMC 2628604. PMID 18984744. doi:10.2337/db08-0799. 
  10. ^ Drucker DJ. "Resurrecting the Beta Cell in Type 2 Diabetes: Beta-cell Function, Preservation, and Neogenesis". PowerPoint slides. Medscape. 

Further reading


External links