scholarly journals Minireview: Signal Bias, Allosterism, and Polymorphic Variation at the GLP-1R: Implications for Drug Discovery

2013 ◽  
Vol 27 (8) ◽  
pp. 1234-1244 ◽  
Author(s):  
Cassandra Koole ◽  
Emilia E. Savage ◽  
Arthur Christopoulos ◽  
Laurence J. Miller ◽  
Patrick M. Sexton ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Cell Mass ◽  
Current Understanding ◽  
Receptor Protein ◽  
Insulin Biosynthesis ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Downstream Signaling ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The glucagon-like peptide-1 receptor (GLP-1R) controls the physiological responses to the incretin hormone glucagon-like peptide-1 and is a major therapeutic target for the treatment of type 2 diabetes, owing to the broad range of effects that are mediated upon its activation. These include the promotion of glucose-dependent insulin secretion, increased insulin biosynthesis, preservation of β-cell mass, improved peripheral insulin action, and promotion of weight loss. Regulation of GLP-1R function is complex, with multiple endogenous and exogenous peptides that interact with the receptor that result in the activation of numerous downstream signaling cascades. The current understanding of GLP-1R signaling and regulation is limited, with the desired spectrum of signaling required for the ideal therapeutic outcome still to be determined. In addition, there are several single-nucleotide polymorphisms (used in this review as defining a natural change of single nucleotide in the receptor sequence; clinically, this is viewed as a single-nucleotide polymorphism only if the frequency of the mutation occurs in 1% or more of the population) distributed within the coding sequence of the receptor protein that have the potential to produce differential responses for distinct ligands. In this review, we discuss the current understanding of GLP-1R function, in particular highlighting recent advances in the field on ligand-directed signal bias, allosteric modulation, and probe dependence and the implications of these behaviors for drug discovery and development.

Glucagon-like peptide-1: a major regulator of pancreatic beta-cell function

2000 ◽  
pp. 717-725 ◽  
Author(s):  
R Perfetti ◽  
P Merkel
Keyword(s):  
Beta Cell ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Glucagon Secretion ◽  
Insulin Biosynthesis ◽  
Gut Hormone ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) is a gut hormone synthesized by post-translational processing in intestinal L-cells, and it is released in response to food ingestion. GLP-1 stimulates insulin secretion during hyperglycemia, suppresses glucagon secretion, stimulates (pro)-insulin biosynthesis and decreases the rate of gastric emptying and acid secretion. GLP-1 has also been shown to have a pro-satiety effect. In addition, it has been demonstrated that a long-term infusion with GLP-1, or exendin-4, a long-acting analog of human GLP-1, increases beta-cell mass in rats. In conclusion, GLP-1 appears to regulate plasma glucose levels via various and independent mechanisms. GLP-1 is an excellent candidate option for the treatment of patients with type 2 diabetes mellitus.

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

2013 ◽  
Vol 41 (1) ◽  
pp. 172-179 ◽  
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.

Molecular mechanisms underlying nutrient-stimulated incretin secretion

2010 ◽  
Vol 12 ◽  
Author(s):  
Helen E. Parker ◽  
Frank Reimann ◽  
Fiona M. Gribble
Keyword(s):  
Drug Discovery ◽  
Molecular Mechanisms ◽  
Fat Metabolism ◽  
Potential Range ◽  
Incretin Hormones ◽  
Appetite Control ◽  
K Cells ◽  
Incretin Secretion ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from enteroendocrine cells in the intestinal epithelium in response to nutrient ingestion. The actions of GLP-1 and GIP – not only on local gut physiology but also on glucose homeostasis, appetite control and fat metabolism – have made these hormones an attractive area for drug discovery programmes. The potential range of strategies to target the secretion of these hormones therapeutically has been limited by an incomplete understanding of the mechanisms underlying their release. The use of organ and whole-animal perfusion techniques, cell line models and primary L- and K-cells has led to the identification of a variety of pathways involved in the sensing of carbohydrate, fat and protein in the gut lumen. This review focuses on our current understanding of these signalling mechanisms that might underlie nutrient responsiveness of L- and K-cells.

scholarly journals Single Nucleotide Polymorphisms That Cause Structural Changes in the Cyclic AMP Receptor Protein Transcriptional Regulator of the Tuberculosis Vaccine Strain Mycobacterium bovis BCG Alter Global Gene Expression without Attenuating Growth

2008 ◽  
Vol 76 (5) ◽  
pp. 2227-2234 ◽  
Author(s):  
Debbie M. Hunt ◽  
José W. Saldanha ◽  
John F. Brennan ◽  
Pearline Benjamin ◽  
Molly Strom ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hydrogen Bond ◽  
Cyclic Amp ◽  
Single Nucleotide Polymorphisms ◽  
Mycobacterium Bovis ◽  
Transcriptional Regulator ◽  
Receptor Protein ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

ABSTRACT Single nucleotide polymorphisms (SNPs) are present in the global transcriptional regulator cyclic AMP (cAMP) receptor protein (CRP) of the attenuated vaccine strain Mycobacterium bovis, bacillus Calmette-Guérin (BCG). We have found that these SNPs resulted in small but significant changes in the expression of a number of genes in M. tuberculosis when a deletion of the Rv3676 CRP was complemented by the BCG allele, compared to complementation by the M. tuberculosis allele. We can explain these changes in gene expression by modeling the structure of the mycobacterial protein on the known structure of CRP from Escherichia coli. Thus, the SNP change in the DNA-binding domain, Lys178, is predicted to form a hydrogen bond with the phosphate backbone of the DNA, as does the equivalent residue in E. coli, whereas Glu178 in M. tuberculosis/M. bovis does not, thus explaining the stronger binding reported for CRP of BCG to CRP-binding sites in mycobacterial DNA. In contrast, the SNP change in the nucleotide binding domain (Leu47Pro) is predicted to result in the loss of one hydrogen bond, which is accommodated by the structure, and would not therefore be expected to cause any change in function relating to cAMP binding. The BCG allele fully complemented the growth defect caused by the deletion of the Rv3676 protein in M. tuberculosis, both in vitro and in macrophage and mouse infections, suggesting that these SNPs do not play any role in the attenuation of BCG. However, they may have allowed BCG to grow better under the in vitro-selective conditions used in its derivation from the M. bovis wild type.

Incretins: pathophysiological and therapeutic implications of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1

2008 ◽  
Vol 61 (4) ◽  
pp. 401-409 ◽  
Author(s):  
L R Ranganath
Keyword(s):  
B Cell ◽  
Cell Mass ◽  
Therapeutic Agents ◽  
Glycosidase Inhibitors ◽  
Therapeutic Implications ◽  
Obesity And Diabetes ◽  
Control Of Diabetes ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
High Doses

Incretins such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are intestinal postprandial hormones that stimulate insulin release from the pancreas as long as circulating glucose concentrations are raised. In addition to their effect on insulin secretion and consequent glucose lowering, GIP and GLP-1, especially the latter, have a number of physiological effects such as inhibition of glucagon release, gastric emptying and food intake, as well as a tropic action on pancreatic B-cell mass. There is currently a pandemic of obesity and diabetes, and existing treatments are largely inadequate both in regard to efficacy as well as their ability to tackle important factors in the pathogenesis of type 2 diabetes (T2D). There is increasing evidence that current treatments do not address the issue of progressive B-cell failure in T2D. Since obesity is the engine that is driving the epidemic of diabetes, it is disappointing that most treatments that succeed in lowering plasma glucose are also associated with weight gain. It is now well established that intensively treated T2D has a better outcome than standard treatment. Consequently, achieving better control of diabetes with lower HbA1c is the goal of optimal treatment. Despite the use of usual therapeutic agents in T2D, often in high doses and as combinations, such as metformin, sulphonylurea, α-glycosidase inhibitors, thiazolidinediones and a number of animal and human insulin preparations, optimal control of glycaemia is not achieved. The use of incretins as therapeutic agents offers a new approach to the treatment of T2D.

scholarly journals Glucagon receptor family (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Dominique Bataille ◽  
Susan L. Chan ◽  
Philippe Delagrange ◽  
Daniel J. Drucker ◽  
Burkhard Göke ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Gastric Inhibitory Polypeptide ◽  
Current Understanding ◽  
Glucagon Receptor ◽  
Endogenous Peptide ◽  
Common Precursor ◽  
Signaling Events ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Receptor Family

The glucagon family of receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on the Glucagon receptor family [159]) are activated by the endogenous peptide (27-44 aa) hormones glucagon, glucagon-like peptide 1, glucagon-like peptide 2, glucose-dependent insulinotropic polypeptide (also known as gastric inhibitory polypeptide), GHRH and secretin. One common precursor (GCG) generates glucagon, glucagon-like peptide 1 and glucagon-like peptide 2 peptides [116]. For a recent review on review the current understanding of the structures of GLP-1 and GLP-1R, the molecular basis of their interaction, and the signaling events associated with it, see de Graaf et al., 2016 [87].

scholarly journals Incretin System: Recent Advances in Glucagon Like Peptide-1 and Dipeptidyl Peptidase-4 Inhibitors

2015 ◽  
Vol 1 (1) ◽  
pp. 36-42
Author(s):  
Rameshwar Mahaseth
Keyword(s):  
Cell Mass ◽  
Dipeptidyl Peptidase ◽  
Common Adverse Event ◽  
Haemoglobin A1c ◽  
Incretin Mimetics ◽  
Dipeptidyl Peptidase 4 ◽  
Wide Range ◽  
Dipeptidyl Peptidase 4 Inhibitors ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The endogenous incretins, glucose-dependent insulinotropic polypeptide and Glucagon-like peptide, are peptide hormones secreted from endocrine cells in the small intestine. Glucagon-like peptide-1 stimulates insulin and suppresses glucagon secretion, delays gastric emptying, and reduces appetite and food intake, which explains the positive effect of incretin mimetics on weight. The incretins have also been shown to have a sustained improvement in glycemic control over three years. A wide range of cardiovascular benefits have also been claimed, such as lowering of blood pressure and postprandial lipids. Clinical trials with the incretin mimetic exenatide and liraglutide show reductions in fasting and postprandial glucose concentrations, and haemoglobin A1c (1–2%), associated with weight loss (2–5 kg). The most common adverse event associated with Glucagon-like peptide-1 receptor agonists is nausea, which lessens over time. Orally administered Dipeptidyl Peptidase-4 inhibitors reduce hemoglobin A1c by 0·5–1·0%, with few adverse effects and no weight gain. These new classes of anti-diabetic agents also expand β-cell mass in preclinical studies. However, long-term clinical studies are still needed to determine the benefits of incretin for the treatment of type 2 diabetes. DOI: http://dx.doi.org/10.3126/jpahs.v1i1.13015 Journal of Patan Academy of Health Sciences. 2014 Jun;1(1):36-42 

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