The complexity of signalling mediated by the glucagon-like peptide-1 receptor

The glucagon-like peptide-1 receptor (GLP-1R) is a class B GPCR that is a major therapeutic target for the treatment of type 2 diabetes. The receptor is activated by the incretin peptide GLP-1 promoting a broad range of physiological effects including glucose-dependent insulin secretion and biosynthesis, improved insulin sensitivity of peripheral tissues, preservation of β-cell mass and weight loss, all of which are beneficial in the treatment of type 2 diabetes. Despite this, existing knowledge surrounding the underlying signalling mechanisms responsible for the physiological actions downstream of GLP-1R activation is limited. Here, we review the current understanding around GLP-1R-mediated signalling, in particular highlighting recent contributions to the field on biased agonism, the spatial and temporal aspects for the control of signalling and how these concepts may influence future drug development.

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Recent advances in understanding GLP-1R (glucagon-like peptide-1 receptor) function

Biochemical Society Transactions ◽

10.1042/bst20120236 ◽

2013 ◽

Vol 41 (1) ◽

pp. 172-179 ◽

Cited By ~ 42

Author(s):

Cassandra Koole ◽

Kavita Pabreja ◽

Emilia E. Savage ◽

Denise Wootten ◽

Sebastian G.B. Furness ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cell Mass ◽

Insulin Biosynthesis ◽

Ongoing Research ◽

Beneficial Effects ◽

Future Drug ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

New Treatments

Type 2 diabetes is a major global health problem and there is ongoing research for new treatments to manage the disease. The GLP-1R (glucagon-like peptide-1 receptor) controls the physiological response to the incretin peptide, GLP-1, and is currently a major target for the development of therapeutics owing to the broad range of potential beneficial effects in Type 2 diabetes. These include promotion of glucose-dependent insulin secretion, increased insulin biosynthesis, preservation of β-cell mass, improved peripheral insulin sensitivity and promotion of weight loss. Despite this, our understanding of GLP-1R function is still limited, with the desired spectrum of GLP-1R-mediated signalling yet to be determined. We review the current understanding of GLP-1R function, in particular, highlighting recent contributions in the field on allosteric modulation, probe-dependence and ligand-directed signal bias and how these behaviours may influence future drug development.

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Persistent Improvement of Type 2 Diabetes in the Goto-Kakizaki Rat Model by Expansion of the -Cell Mass During the Prediabetic Period With Glucagon-Like Peptide-1 or Exendin-4

Diabetes ◽

10.2337/diabetes.51.5.1443 ◽

2002 ◽

Vol 51 (5) ◽

pp. 1443-1452 ◽

Cited By ~ 214

Author(s):

C. Tourrel ◽

D. Bailbe ◽

M. Lacorne ◽

M.-J. Meile ◽

M. Kergoat ◽

...

Keyword(s):

Type 2 Diabetes ◽

Rat Model ◽

Cell Mass ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Glucagon-Like Peptide-1 as a Treatment Option for Type 2 Diabetes and Its Role in Restoring Beta-Cell Mass

Diabetes Technology & Therapeutics ◽

10.1089/dia.2005.7.651 ◽

2005 ◽

Vol 7 (4) ◽

pp. 651-657 ◽

Cited By ~ 12

Author(s):

B. Gallwitz

Keyword(s):

Type 2 Diabetes ◽

Beta Cell ◽

Treatment Option ◽

Cell Mass ◽

Beta Cell Mass ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Chronic administration of ezetimibe increases active glucagon-like peptide-1 and improves glycemic control and pancreatic beta cell mass in a rat model of type 2 diabetes

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2011.02.129 ◽

2011 ◽

Vol 407 (1) ◽

pp. 153-157 ◽

Cited By ~ 19

Author(s):

Soo Jin Yang ◽

Jung Mook Choi ◽

Lisa Kim ◽

Byung-Joon Kim ◽

Jin Hee Sohn ◽

...

Keyword(s):

Type 2 Diabetes ◽

Glycemic Control ◽

Pancreatic Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Chronic Administration ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Pancreatic Beta Cell Mass

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Glucagon-like peptide 1 agonists and the development and growth of pancreatic β-cells

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00007.2004 ◽

2004 ◽

Vol 286 (6) ◽

pp. E875-E881 ◽

Cited By ~ 65

Author(s):

James F. List ◽

Joel F. Habener

Keyword(s):

Type 2 Diabetes ◽

Progenitor Cells ◽

Β Cells ◽

Pancreatic Β Cells ◽

Peripheral Tissues ◽

New Findings ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Glucose Output

Glucagon-like peptide 1 (GLP-1) is an intestine-derived insulinotropic hormone that stimulates glucose-dependent insulin production and secretion from pancreatic β-cells. Other recognized actions of GLP-1 are to suppress glucagon secretion and hepatic glucose output, delay gastric emptying, reduce food intake, and promote glucose disposal in peripheral tissues. All of these actions are potentially beneficial for the treatment of type 2 diabetes mellitus. Several GLP-1 agonists are in clinical trials for the treatment of diabetes. More recently, GLP-1 agonists have been shown to stimulate the growth and differentiation of pancreatic β-cells, as well as to exert cytoprotective, antiapoptotic effects on β-cells. Recent evidence indicates that GLP-1 agonists act on receptors on pancreas-derived stem/progenitor cells to prompt their differentiation into β-cells. These new findings suggest an approach to create β-cells in vitro by expanding stem/progenitor cells and then to convert them into β-cells by treatment with GLP-1. Thus GLP-1 may be a means by which to create β-cells ex vivo for transplantation into patients with insulinopenic type 1 diabetes and severe forms of type 2 diabetes.

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