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Experimental Diabetes Research
Volume 2012, Article ID 470851, 12 pages
Review Article

Physiology and Emerging Biochemistry of the Glucagon-Like Peptide-1 Receptor

1Translational Science and Technologies, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
2Endocrine Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA

Received 31 December 2011; Accepted 25 January 2012

Academic Editor: Matteo Monami

Copyright © 2012 Francis S. Willard and Kyle W. Sloop. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


The glucagon-like peptide-1 (GLP-1) receptor is one of the best validated therapeutic targets for the treatment of type 2 diabetes mellitus (T2DM). Over several years, the accumulation of basic, translational, and clinical research helped define the physiologic roles of GLP-1 and its receptor in regulating glucose homeostasis and energy metabolism. These efforts provided much of the foundation for pharmaceutical development of the GLP-1 receptor peptide agonists, exenatide and liraglutide, as novel medicines for patients suffering from T2DM. Now, much attention is focused on better understanding the molecular mechanisms involved in ligand induced signaling of the GLP-1 receptor. For example, advancements in biophysical and structural biology techniques are being applied in attempts to more precisely determine ligand binding and receptor occupancy characteristics at the atomic level. These efforts should better inform three-dimensional modeling of the GLP-1 receptor that will help inspire more rational approaches to identify and optimize small molecule agonists or allosteric modulators targeting the GLP-1 receptor. This article reviews GLP-1 receptor physiology with an emphasis on GLP-1 induced signaling mechanisms in order to highlight new molecular strategies that help determine desired pharmacologic characteristics for guiding development of future nonpeptide GLP-1 receptor activators.