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ABSTRACT Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone secreted from L cells in the distal small intestine and proximal colon after a meal that acts as an incretin to augment

the insulin response, while also inhibiting glucagon and slowing gastric emptying. These characteristics of GLP-1, as well as its ability to reduce islet beta cell apoptosis and expand beta

cell mass and its cardioprotective and neuroprotective effects, provide a broad spectrum of actions potentially useful for the management of type-2 diabetes mellitus. GLP-1 also has the

added advantage of having its incretin effects dependent on the level of serum glucose, only acting in the presence of hyperglycaemia, and thereby preventing hypoglycemic responses. Although

natural GLP-1 has a very short half-life, limiting its therapeutic usefulness, a variety of analogues and formulations have been developed to provide extended actions and to limit side

effects. However, all of these peptides require parenteral administration. Potentially orally active small-molecule agonists acting at the GLP-1 receptor are also being developed, but have

not yet been approved for clinical use. Recent insights into the molecular nature of the class B G-protein-coupled GLP-1 receptor has provided insights into the modes of binding these types

of ligands, as well as providing opportunities for rational enhancement. The advantages and disadvantages of each of these agents and their possible clinical utility will be explored. Access

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Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS GLUCAGON-LIKE PEPTIDE-1 RECEPTOR: MECHANISMS AND ADVANCES

IN THERAPY Article Open access 18 September 2024 DEVELOPMENT OF AN ORALLY DELIVERED GLP-1 RECEPTOR AGONIST THROUGH PEPTIDE ENGINEERING AND DRUG DELIVERY TO TREAT CHRONIC DISEASE Article Open

access 18 November 2021 THE INCRETIN CO-AGONIST TIRZEPATIDE REQUIRES GIPR FOR HORMONE SECRETION FROM HUMAN ISLETS Article Open access 05 June 2023 REFERENCES * Hu FB . Globalization of

diabetes: the role of diet, lifestyle, and genes. _Diabetes Care_ 2011; 34: 1249–1257. Article  PubMed  PubMed Central  Google Scholar  * Creutzfeldt W . The incretin concept today.

_Diabetologia_ 1979; 16: 75–85. Article  CAS  PubMed  Google Scholar  * Elrick H, Stimmler L, Hlad Jr CJ, Arai Y . Plasma insulin response to oral and intravenous glucose administration. _J

Clin Endocrinol Metab_ 1964; 24: 1076–1082. Article  CAS  PubMed  Google Scholar  * Nauck M, Stockmann F, Ebert R, Creutzfeldt W . Reduced incretin effect in type 2 (non-insulin-dependent)

diabetes. _Diabetologia_ 1986; 29: 46–52. Article  CAS  PubMed  Google Scholar  * Adelhorst K, Hedegaard BB, Knudsen LB, Kirk O . Structure-activity studies of glucagon-like peptide-1. _J

Biol Chem_ 1994; 269: 6275–6278. CAS  PubMed  Google Scholar  * Neidigh JW, Fesinmeyer RM, Prickett KS, Andersen NH . Exendin-4 and glucagon-like-peptide-1: NMR structural comparisons in the

solution and micelle-associated states. _Biochemistry_ 2001; 40: 13188–13200. Article  CAS  PubMed  Google Scholar  * Hoare SR . Mechanisms of peptide and nonpeptide ligand binding to class

B G-protein-coupled receptors. _Drug Discov Today_ 2005; 10: 417–427. Article  CAS  PubMed  Google Scholar  * Dong M, Lam PC, Pinon DI, Hosohata K, Orry A, Sexton PM _et al_. Molecular

basis of secretin docking to its intact receptor using multiple photolabile probes distributed throughout the pharmacophore. _J Biol Chem_ 2011; 286: 23888–23899. Article  CAS  PubMed 

PubMed Central  Google Scholar  * White JW, Saunders GF . Structure of the human glucagon gene. _Nucleic Acids Res_ 1986; 14: 4719–4730. Article  CAS  PubMed  PubMed Central  Google Scholar

  * Mortensen K, Christensen LL, Holst JJ, Orskov C . GLP-1 and GIP are colocalized in a subset of endocrine cells in the small intestine. _Regul Pept_ 2003; 114: 189–196. Article  CAS 

PubMed  Google Scholar  * Mayo KE, Miller LJ, Bataille D, Dalle S, Goke B, Thorens B _et al_. International union of pharmacology. XXXV. The glucagon receptor family. _Pharmacol Rev_ 2003;

55: 167–194. Article  CAS  PubMed  Google Scholar  * Shoichet BK, Kobilka BK . Structure-based drug screening for G-protein-coupled receptors. _Trends Pharmacol Sci_ 2012; 33: 268–272.

Article  CAS  PubMed  PubMed Central  Google Scholar  * Parthier C, Reedtz-Runge S, Rudolph R, Stubbs MT . Passing the baton in class B GPCRs: peptide hormone activation via helix induction?

_Trends Biochem Sci_ 2009; 34: 303–310. Article  CAS  PubMed  Google Scholar  * Lisenbee CS, Dong M, Miller LJ . Paired cysteine mutagenesis to establish the pattern of disulfide bonds in

the functional intact secretin receptor. _J Biol Chem_ 2005; 280: 12330–12338. Article  CAS  PubMed  Google Scholar  * Miras AD, Jackson RN, Jackson SN, Goldstone AP, Olbers T, Hackenberg T

_et al_. Gastric bypass surgery for obesity decreases the reward value of a sweet-fat stimulus as assessed in a progressive ratio task. _Am J Clin Nutr_ 2012; 96: 467–473. Article  CAS 

PubMed  Google Scholar  * Eng J, Kleinman WA, Singh L, Singh G, Raufman JP . Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further

evidence for an exendin receptor on dispersed acini from guinea pig pancreas. _J Biol Chem_ 1992; 267: 7402–7405. CAS  PubMed  Google Scholar  * Donnelly D . The structure and function of

the glucagon-like peptide-1 receptor and its ligands. _Br J Pharmacol_ 2012; 166: 27–41. Article  CAS  PubMed  PubMed Central  Google Scholar  * Kendall DM, Riddle MC, Rosenstock J, Zhuang

D, Kim DD, Fineman MS _et al_. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. _Diabetes Care_

2005; 28: 1083–1091. Article  CAS  PubMed  Google Scholar  * Buse JB, Klonoff DC, Nielsen LL, Guan X, Bowlus CL, Holcombe JH _et al_. Metabolic effects of two years of exenatide treatment on

diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled

trials. _Clin Ther_ 2007; 29: 139–153. Article  CAS  PubMed  Google Scholar  * Christensen M, Knop FK, Holst JJ, Vilsboll T . Lixisenatide, a novel GLP-1 receptor agonist for the treatment

of type 2 diabetes mellitus. _IDrugs_ 2009; 12: 503–513. CAS  PubMed  Google Scholar  * Knudsen LB . Liraglutide: the therapeutic promise from animal models. _Int J Clin Pract Suppl_ 2010;

64: 4–11. Article  CAS  Google Scholar  * Nauck MA, Meier JJ . Glucagon-like peptide 1 and its derivatives in the treatment of diabetes. _Regul Pept_ 2005; 128: 135–148. Article  CAS  PubMed

  Google Scholar  * Meier JJ . GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. _Nat Rev Endocrinol_ 2012; 8: 728–742. Article  CAS  PubMed  Google Scholar 

* Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H . Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes

mellitus. _Diabetologia_ 2006; 49: 2564–2571. Article  CAS  PubMed  Google Scholar  * Baggio LL, Huang Q, Brown TJ, Drucker DJ . Oxyntomodulin and glucagon-like peptide-1 differentially

regulate murine food intake and energy expenditure. _Gastroenterology_ 2004; 127: 546–558. Article  CAS  PubMed  Google Scholar  * Chen D, Liao J, Li N, Zhou C, Liu Q, Wang G _et al_. A

nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice. _Proc Natl Acad Sci USA_ 2007; 104: 943–948. Article  CAS  PubMed  PubMed Central  Google

Scholar  * Irwin N, Flatt PR, Patterson S, Green BD . Insulin-releasing and metabolic effects of small molecule GLP-1 receptor agonist

6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline. _Eur J Pharmacol_ 2010; 628: 268–273. Article  CAS  PubMed  Google Scholar  * Knudsen LB, Kiel D, Teng M, Behrens C, Bhumralkar

D, Kodra JT _et al_. Small-molecule agonists for the glucagon-like peptide 1 receptor. _Proc Natl Acad Sci USA_ 2007; 104: 937–942. Article  CAS  PubMed  PubMed Central  Google Scholar  *

Sloop KW, Willard FS, Brenner MB, Ficorilli J, Valasek K, Showalter AD _et al_. Novel small molecule glucagon-like peptide-1 receptor agonist stimulates insulin secretion in rodents and from

human islets. _Diabetes_ 2010; 59: 3099–3107. Article  CAS  PubMed  PubMed Central  Google Scholar  * Su H, He M, Li H, Liu Q, Wang J, Wang Y _et al_. Boc5, a non-peptidic glucagon-like

Peptide-1 receptor agonist, invokes sustained glycemic control and weight loss in diabetic mice. _PLoS One_ 2008; 3: e2892. Article  PubMed  PubMed Central  Google Scholar  * Willard FS,

Bueno AB, Sloop KW . Small molecule drug discovery at the glucagon-like peptide-1 receptor. _Exp Diabetes Res_ 2012; 2012: 709893. PubMed  PubMed Central  Google Scholar  * Koole C, Wootten

D, Simms J, Miller LJ, Christopoulos A, Sexton PM . Second extracellular loop of human glucagon-like peptide-1 receptor (GLP-1R) has a critical role in GLP-1 peptide binding and receptor

activation. _J Biol Chem_ 2012; 287: 3642–3658. Article  CAS  PubMed  Google Scholar  * Koole C, Wootten D, Simms J, Savage EE, Miller LJ, Christopoulos A _et al_. Second extracellular loop

of human glucagon-like peptide-1 receptor (GLP-1R) differentially regulates orthosteric but not allosteric agonist binding and function. _J Biol Chem_ 2012; 287: 3659–3673. Article  CAS 

PubMed  Google Scholar  * Koole C, Wootten D, Simms J, Valant C, Sridhar R, Woodman OL _et al_. Allosteric ligands of the glucagon-like peptide 1 receptor (GLP-1R) differentially modulate

endogenous and exogenous peptide responses in a pathway-selective manner: implications for drug screening. _Mol Pharmacol_ 2010; 78: 456–465. Article  CAS  PubMed  PubMed Central  Google

Scholar  * Harikumar KG, Wootten D, Pinon DI, Koole C, Ball AM, Furness SGB _et al_. Glucagon-like peptide-1 receptor dimerization differentially regulates agonist signalling but does not

affect small molecule allostery. _Proc Natl Acad Sci USA_ 2012; 109: 18607–18612. Article  CAS  PubMed  PubMed Central  Google Scholar  * Gao F, Harikumar KG, Dong M, Lam PC, Sexton PM,

Christopoulos A _et al_. Functional importance of a structurally distinct homodimeric complex of the family B G protein- coupled secretin receptor. _Mol Pharmacol_ 2009; 76: 264–274. Article

  CAS  PubMed  PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS This work was supported by a grant from the National Institutes of Health (DK046577). PS has received an

NHMRC Program grant (#519461) and an NHMRC Project grant (#1002180). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Molecular Pharmacology and Experimental Therapeutics, Mayo

Clinic, Scottsdale, AZ, USA L J Miller, M Dong & K G Harikumar * Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Drug Discovery Biology, Monash University,

Parkville, Victoria, Australia, P M Sexton Authors * L J Miller View author publications You can also search for this author inPubMed Google Scholar * P M Sexton View author publications You

can also search for this author inPubMed Google Scholar * M Dong View author publications You can also search for this author inPubMed Google Scholar * K G Harikumar View author

publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to L J Miller. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no

conflict of interest. ADDITIONAL INFORMATION This article is published as part of a supplement sponsored by the Université Laval's Research Chair in Obesity in an effort to inform the

public on the causes, consequences, treatments, and prevention of obesity. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Miller, L., Sexton, P., Dong,

M. _et al._ The class B G-protein-coupled GLP-1 receptor: an important target for the treatment of type-2 diabetes mellitus. _Int J Obes Supp_ 4 (Suppl 1), S9–S13 (2014).

https://doi.org/10.1038/ijosup.2014.4 Download citation * Published: 08 July 2014 * Issue Date: July 2014 * DOI: https://doi.org/10.1038/ijosup.2014.4 SHARE THIS ARTICLE Anyone you share the

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Nature SharedIt content-sharing initiative KEYWORDS * glucagon-like peptide-1, incretin, type-2 diabetes, G-protein-coupled receptor