scholarly journals The Interplay of Glucagon-Like Peptide-1 Receptor Trafficking and Signalling in Pancreatic Beta Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Amaara Marzook ◽  
Alejandra Tomas ◽  
Ben Jones
Keyword(s):  
Pancreatic Beta Cells ◽  
Metabolic Effects ◽  
Physiological Importance ◽  
Intracellular Signals ◽  
Class B ◽  
The Central Nervous System ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
G Protein Coupled

The glucagon-like peptide 1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) which mediates the effects of GLP-1, an incretin hormone secreted primarily from L-cells in the intestine and within the central nervous system. The GLP-1R, upon activation, exerts several metabolic effects including the release of insulin and suppression of appetite, and has, accordingly, become an important target for the treatment for type 2 diabetes (T2D). Recently, there has been heightened interest in how the activated GLP-1R is trafficked between different endomembrane compartments, controlling the spatial origin and duration of intracellular signals. The discovery of “biased” GLP-1R agonists that show altered trafficking profiles and selective engagement with different intracellular effectors has added to the tools available to study the mechanisms and physiological importance of these processes. In this review we survey early and recent work that has shed light on the interplay between GLP-1R signalling and trafficking, and how it might be therapeutically tractable for T2D and related diseases.

Bile-induced secretion of glucagon-like peptide-1: pathophysiological implications in type 2 diabetes?

2010 ◽  
Vol 299 (1) ◽  
pp. E10-E13 ◽  
Author(s):  
Filip K. Knop
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Intestinal Secretion ◽  
Postprandial Glucose ◽  
Glucose Lowering ◽  
Incretin Hormone ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
G Protein Coupled

During the last decades it has become clear that bile acids not only act as simple fat solubilizers, but additionally represent complex hormonal metabolic integrators. Bile acids activate both nuclear receptors (controlling transcription of genes involved in for example bile acid, cholesterol, and glucose metabolism) and the cell surface G protein-coupled receptor TGR5 (modulating energy expenditure in brown fat and muscle cells). It has been shown that TGR5 is expressed in enteroendocrine L cells, which secrete the potent glucose-lowering incretin hormone glucagon-like peptide-1 (GLP-1). Recently it was shown that bile acid-induced activation of TGR5 results in intestinal secretion of GLP-1 and that enhanced TGR5 signaling improves postprandial glucose tolerance in diet-induced obese mice. This Perspectives article presents these novel findings in the context of prior studies on nutrient-induced GLP-1 secretion and outlines the potential implications of bile acid-induced GLP-1 secretion in physiological, pathophysiological, and pharmacological perspectives.

scholarly journals The effects of yam gruel on lowering fasted blood glucose in T2DM rats

2020 ◽  
Vol 15 (1) ◽  
pp. 763-773
Author(s):  
Xinjun Lin ◽  
Zongting Luo ◽  
Shuqin Pang ◽  
Carol Chunfeng Wang ◽  
Li Ge ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Gut Microbiota ◽  
Peptide Yy ◽  
Short Chain Fatty Acids ◽  
Scientific Basis ◽  
Probiotic Bacteria ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
G Protein Coupled

AbstractThere is increasing evidence of the linkage between type 2 diabetes mellitus (T2DM) and gut microbiota. Based on our previous studies, we investigated the hypoglycemic mechanisms of yam gruel to provide a scientific basis for its popularization and application. Wistar rats were randomly divided into control and T2DM model groups. Rats in the model group were stimulated by a high-sugar/high-fat diet combined with an intraperitoneal injection of streptozotocin to induce T2DM. The T2DM rats were further subdivided randomly into three groups: (1) DM, (2) DM + yam gruel, and (3) DM + metformin. After 4 weeks of intervention, the changes in gut microbiota, short-chain fatty acids (SCFAs) (acetic acid, propionic acid, and butyric acid), the expression of G protein-coupled receptor 43 (GPR43), glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and fasted blood glucose (FBG) levels were observed. Yam gruel intervention elevated the abundance of probiotic bacteria and increased the expression of SCFAs, GPR43 receptor, GLP-1, and PYY. It also reduced FBG levels. We conclude that yam gruel can lower FBG by promoting the growth of probiotic bacteria, increasing the content of SCFAs, and enhancing the expression of GPR43 receptor to increase the content of GLP-1 and PYY in serum.

scholarly journals Evaluation of efficacy- versus affinity-driven agonism with biased GLP-1R ligands P5 and exendin-F1

2021 ◽  
Author(s):  
Amaara Marzook ◽  
Shiqian Chen ◽  
Phil Pickford ◽  
Maria Lucey ◽  
Yifan Wang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
G Protein ◽  
Early Endosomes ◽  
Important Regulator ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
G Protein Coupled

AbstractThe glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of glucose homeostasis and has been successfully targeted for the treatment of type 2 diabetes. Recently described biased GLP-1R agonists with selective reductions in β-arrestin versus G protein coupling show improved metabolic actions in vivo. However, two prototypical G protein-favouring GLP-1R agonists, P5 and exendin-F1, are reported to show divergent effects on insulin secretion. In this study we aimed to resolve this discrepancy by performing a side-by-side characterisation of these two ligands across a variety of in vitro and in vivo assays. Exendin-F1 showed reduced acute efficacy versus P5 for several readouts, including recruitment of mini-G proteins, G protein-coupled receptor kinases (GRKs) and β-arrestin-2. Maximal responses were also lower for both GLP-1R internalisation and the presence of active GLP-1R-mini-Gs complexes in early endosomes with exendin-F1 treatment. In contrast, prolonged insulin secretion in vitro and sustained anti-hyperglycaemic efficacy in mice were both greater with exendin-F1 than with P5. We conclude that the particularly low acute efficacy of exendin-F1 and associated reductions in GLP-1R downregulation appear to be more important than preservation of endosomal signalling to allow sustained insulin secretion responses. This has implications for the ongoing development of affinity- versus efficacy-driven biased GLP-1R agonists as treatments for metabolic disease.

scholarly journals Intestinal SGLT1 in metabolic health and disease

2016 ◽  
Vol 310 (11) ◽  
pp. G887-G898 ◽  
Author(s):  
Anders Lehmann ◽  
Pamela J. Hornby
Keyword(s):  
Metabolic Diseases ◽  
Apical Membrane ◽  
Peptide Yy ◽  
Metabolic Effects ◽  
New Class ◽  
Health And Disease ◽  
Glucose Exposure ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The Na+-glucose cotransporter 1 (SGLT1/SLC5A1) is predominantly expressed in the small intestine. It transports glucose and galactose across the apical membrane in a process driven by a Na+ gradient created by Na+-K+-ATPase. SGLT2 is the major form found in the kidney, and SGLT2-selective inhibitors are a new class of treatment for type 2 diabetes mellitus (T2DM). Recent data from patients treated with dual SGLT1/2 inhibitors or SGLT2-selective drugs such as canagliflozin (SGLT1 IC50 = 663 nM) warrant evaluation of SGLT1 inhibition for T2DM. SGLT1 activity is highly dynamic, with modulation by multiple mechanisms to ensure maximal uptake of carbohydrates (CHOs). Intestinal SGLT1 inhibition lowers and delays the glucose excursion following CHO ingestion and augments glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) secretion. The latter is likely due to increased glucose exposure of the colonic microbiota and formation of metabolites such as L cell secretagogues. GLP-1 and PYY secretion suppresses food intake, enhances the ileal brake, and has an incretin effect. An increase in colonic microbial production of propionate could contribute to intestinal gluconeogenesis and mediate positive metabolic effects. On the other hand, a threshold of SGLT1 inhibition that could lead to gastrointestinal intolerability is unclear. Altered Na+ homeostasis and increased colonic CHO may result in diarrhea and adverse gastrointestinal effects. This review considers the potential mechanisms contributing to positive metabolic and negative intestinal effects. Compounds that inhibit SGLT1 must balance the modulation of these mechanisms to achieve therapeutic efficacy for metabolic diseases.

scholarly journals The putative signal peptide of glucagon-like peptide-1 receptor is not required for receptor synthesis but promotes receptor expression

2014 ◽  
Vol 34 (6) ◽  
Author(s):  
Yunjun Ge ◽  
Dehua Yang ◽  
Antao Dai ◽  
Caihong Zhou ◽  
Yue Zhu ◽  
...  
Keyword(s):  
Signal Peptide ◽  
Receptor Expression ◽  
Hek293 Cells ◽  
Putative Signal Peptide ◽  
293 Cells ◽  
Class B ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
G Protein Coupled

GLP-1R (glucagon-like peptide-1 receptor) mediates the ‘incretin effect’ and many other anti-diabetic actions of its cognate ligand, GLP-1 (glucagon-like peptide-1). It belongs to the class B family of GPCRs (G protein-coupled receptors) and possesses an N-terminal putative SP (signal peptide). It has been reported that this sequence is required for the synthesis of GLP-1R and is cleaved after receptor synthesis. In the present study, we conducted an in-depth exploration towards the role of the putative SP in GLP-1R synthesis. A mutant GLP-1R without this sequence was expressed in HEK293 cells (human embryonic kidney 293 cells) and displayed normal functionality with respect to ligand binding and activation of adenylate cyclase. Thus the putative SP does not seem to be required for receptor synthesis. Immunoblotting analysis shows that the amount of GLP-1R synthesized in HEK293 cells is low when the putative SP is absent. This indicates that the role of the sequence is to promote the expression of GLP-1R. Furthermore, epitopes tagged at the N-terminal of GLP-1R are detectable by immunofluorescence and immunoblotting in our experiments. In conclusion, the present study points to different roles of SP in GLP-1R expression which broadens our understanding of the functionality of this putative SP of GLP-1R and possibly other Class B GPCRs.

scholarly journals Differential GLP-1R binding and activation by peptide and non-peptide agonists

2020 ◽  
Author(s):  
Xin Zhang ◽  
Matthew J. Belousoff ◽  
Peishen Zhao ◽  
Albert J. Kooistra ◽  
Tin T. Truong ◽  
...  
Keyword(s):  
Binding Mode ◽  
Peptide Drugs ◽  
Hydrogen Bond Networks ◽  
Class B ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Peptide Agonist ◽  
Substantial Interest ◽  
Receptor Conformation

SUMMARYPeptide drugs targeting class B1 GPCRs can treat multiple diseases, however there remains substantial interest in the development of orally delivered non-peptide drugs. Here we reveal unexpected overlap between signalling and regulation of the glucagon-like peptide-1 (GLP-1) receptor by the non-peptide agonist, PF 06882961, and GLP-1 that was not observed for another compound, OWL-833. Both compounds are currently in clinical trials for treatment of type 2 diabetes. High resolution cryo-EM structures reveal the binding sites for PF-06882961 and GLP-1 substantially overlap, whereas OWL-833 adopts a unique binding mode with a more open receptor conformation at the extracellular face. Structural differences involving extensive water-mediated hydrogen bond networks could be correlated to functional data to understand how PF 06882961, but not OWL-833, can closely mimic the pharmacological properties of GLP-1. These findings will facilitate rational structure-based discovery of non-peptide agonists targeting class B GPCRs.

scholarly journals Choosing between GLP-1 Receptor Agonists and DPP-4 Inhibitors: A Pharmacological Perspective

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Dominique Xavier Brown ◽  
Marc Evans
Keyword(s):  
Pancreatic Beta Cells ◽  
Competitive Inhibition ◽  
Insulin Synthesis ◽  
Receptor Agonists ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
New Treatment ◽  
Incretin Therapies ◽  
Pharmacological Basis

In recent years the incretin therapies have provided a new treatment option for patients with type 2 diabetes mellitus (T2DM). The incretin therapies focus on the increasing levels of the two incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This results in increased glucose dependent insulin synthesis and release. GLP-1 receptor agonists such as liraglutide and exenatide exert an intrinsic biological effect on GLP-1 receptors directly stimulating the release of insulin from pancreatic beta cells. DPP-4 inhibitors such as sitagliptin and linagliptin prevent the inactivation of endogenous GLP-1 and GIP through competitive inhibition of the DPP-4 enzyme. Both incretin therapies have good safety and tolerability profiles and interact minimally with a number of medications commonly prescribed in T2DM. This paper focuses on the pharmacological basis by which the incretin therapies function and how this knowledge can inform and benefit clinical decisions. Each individual incretin agent has benefits and pitfalls relating to aspects such as glycaemic and nonglycaemic efficacy, safety and tolerability, ease of administration, and cost. Overall, a personalized medicine approach has been found to be favourable, tailoring the incretin agent to benefit and suit patient's needs such as renal impairment (RI) or hepatic impairment (HI).

scholarly journals Glucagon-Like Peptide-1 and Its Class B G Protein–Coupled Receptors: A Long March to Therapeutic Successes

2016 ◽  
Vol 68 (4) ◽  
pp. 954-1013 ◽  
Author(s):  
Chris de Graaf ◽  
Dan Donnelly ◽  
Denise Wootten ◽  
Jesper Lau ◽  
Patrick M. Sexton ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Class B ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
G Protein Coupled

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

2016 ◽  
Vol 44 (2) ◽  
pp. 582-588 ◽  
Author(s):  
Madeleine M. Fletcher ◽  
Michelle L. Halls ◽  
Arthur Christopoulos ◽  
Patrick M. Sexton ◽  
Denise Wootten
Keyword(s):  
Type 2 Diabetes ◽  
Cell Mass ◽  
Peripheral Tissues ◽  
Biased Agonism ◽  
Temporal Aspects ◽  
Class B ◽  
Future Drug ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

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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