scholarly journals Caveolin-1 Regulates Cellular Trafficking and Function of the Glucagon-Like Peptide 1 Receptor

2006 ◽  
Vol 20 (12) ◽  
pp. 3400-3411 ◽  
Author(s):  
Colin A. Syme ◽  
Lei Zhang ◽  
Alessandro Bisello
Keyword(s):  
Cell Membrane ◽  
Cell Function ◽  
Fluorescent Protein ◽  
Dominant Negative ◽  
Cellular Trafficking ◽  
Cellular Mechanisms ◽  
Caveolin 1 ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Signaling Activity

Abstract The glucagon-like peptide 1 receptor (GLP-1R) mediates important effects on β-cell function and glucose homeostasis and is one of the most promising therapeutic targets for type 2, and possibly type 1, diabetes. Yet, little is known regarding the molecular and cellular mechanisms that regulate its function. Therefore, we examined the cellular trafficking of the GLP-1R and the relation between receptor localization and signaling activity. In resting human embryonic kidney 293 and insulinoma MIN6 cells, a fully functional green fluorescent protein-tagged GLP-1R was localized both at the cell membrane and in highly mobile intracellular compartments. Real-time confocal fluorescence microscopy allowed direct visualization of constitutive cycling of the receptor. Overexpression of K44A-dynamin increased the number of functional receptors at the cell membrane. Immunoprecipitation, sucrose sedimentation, and microscopy observations demonstrated that the GLP-1R localizes in lipid rafts and interacts with caveolin-1. This interaction is necessary for membrane localization of the GLP-1R, because overexpression of a dominant-negative form of caveolin-1 (P132L-cav1) or specific mutations within the putative GLP-1R’s caveolin-1 binding domain completely inhibited GLP-1 binding and activity. Upon agonist stimulation, the GLP-1R underwent rapid and extensive endocytosis independently from arrestins but in association with caveolin-1. Finally, GLP-1R-stimulated activation of ERK1/2, which involves transactivation of epidermal growth factor receptors, required lipid raft integrity. In summary, the interaction of the GLP-1R with caveolin-1 regulates subcellular localization, trafficking, and signaling activity. This study provides further evidence of the key role of accessory proteins in specifying the cellular behavior of G protein-coupled receptors.

scholarly journals Spatial expression of glucagon-like peptide 1 receptor and caveolin-1 in hepatocytes with macrovesicular steatosis in non-alcoholic steatohepatitis

2020 ◽  
Vol 7 (1) ◽  
pp. e000370
Author(s):  
Hiroaki Yokomori ◽  
Wataru Ando
Keyword(s):  
Cell Function ◽  
Caveolin 1 ◽  
Alcoholic Steatohepatitis ◽  
Cellular Localisation ◽  
Β Cell Function ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
End Stage ◽  
Small Clusters ◽  
Macrovesicular Steatosis

ObjectiveNon-alcoholic steatohepatitis (NASH) can progress to fibrosis, cirrhosis and end-stage liver disease. Glucagon-like peptide 1 receptor (GLP-1R) mediates β cell function. Its receptor agonists, currently used to treat type 2 diabetes mellitus, might be effective against NASH. GLP-1R, a G protein-coupled receptor family member, preferentially localises to caveolae. Therefore, we ascertained the cellular localisation of GLP-1R and caveolin (CAV)-1 in NASH liver.MethodsLiver biopsies were obtained from three patients with NASH and were compared with those of four normal patients. Immunohistochemistry (IHC) and immunoelectron microscopy (IEM) were used to compare GLP-1R and CAV-1 expression in the livers of patients with metastatic liver cancer and normal patients.ResultsIHC showed that GLP-1R localised to basolateral membranes of hepatocytes with macrovesicular steatosis and was expressed in monocytes infiltrating hepatic sinusoids. CAV-1 was minimally associated with low-electron density lipid droplets (LDs) in hepatocytes. IEM showed small clusters of GLP-1R molecules on the peripheral rims of LDs and on cytoplasmic leaflets of endoplasmic reticulum membranes and vesicles, whereas CAV-1 molecules were found in LD caveolae.ConclusionsGLP-1R is present in the lipid microdomains of hepatocytes with macrovesicular steatosis. These results may help inform future studies about the liver-specific mechanisms of GLP-1 modulation in NASH therapy.

2106-P: Glucagon-Like Peptide-1 Receptor Agonist Exenatide Promotes ß-Cell Function via Activation of PPARd/UCP-2 Pathway

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 2106-P
Author(s):  
YANNA SU ◽  
WEN XU ◽  
BEISI LIN ◽  
ZIYU LIU ◽  
YALAN CHEN ◽  
...  
Keyword(s):  
Receptor Agonist ◽  
Cell Function ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals Optical reconstruction of murine colorectal mucosa at cellular resolution

2015 ◽  
Vol 308 (9) ◽  
pp. G721-G735 ◽  
Author(s):  
Cambrian Y. Liu ◽  
Philip E. Dubé ◽  
Nandini Girish ◽  
Ajay T. Reddy ◽  
D. Brent Polk
Keyword(s):  
Cell Function ◽  
Fluorescent Protein ◽  
Confocal Imaging ◽  
Host Cells ◽  
Cellular Mechanisms ◽  
Colorectal Mucosa ◽  
Cellular Resolution ◽  
Volume Imaging ◽  
Mucosal Layer ◽  
Optical Reconstruction

The mucosal layer of the colon is a unique and dynamic site where host cells interface with one another and the microbiome, with major implications for physiology and disease. However, the cellular mechanisms mediating colonic regeneration, inflammation, dysplasia, and dysbiosis remain undercharacterized, partly because the use of thin tissue sections in many studies removes important volumetric context. To address these challenges in visualization, we have developed the deep mucosal imaging (DMI) method to reconstruct continuous extended volumes of mouse colorectal mucosa at cellular resolution. Use of ScaleA2 and SeeDB clearing agents enabled full visualization of the colonic crypt, the fundamental unit of adult colon. Confocal imaging of large colorectal expanses revealed epithelial structures involved in repair, inflammation, tumorigenesis, and stem cell function, in fluorescent protein-labeled, immunostained, paraffin-embedded, or human biopsy samples. We provide freely available software to reconstruct and explore on computers with standard memory allocations the large DMI datasets containing in toto representations of distal colonic mucosal volume. Extended-volume imaging of colonic mucosa through the novel, extensible, and readily adopted DMI approach will expedite mechanistic investigations of intestinal physiology and pathophysiology at intracrypt to multicrypt length scales.

GLP-1 response to sequential mixed meals: influence of insulin resistance

2017 ◽  
Vol 131 (24) ◽  
pp. 2901-2910 ◽  
Author(s):  
Eleni Rebelos ◽  
Brenno Astiarraga ◽  
Roberto Bizzotto ◽  
Andrea Mari ◽  
Maria Laura Manca ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Release ◽  
Cell Function ◽  
Fasting Glucose ◽  
Insulin Resistant ◽  
Esterified Fatty Acids ◽  
Β Cell Function ◽  
Glucose Sensitivity ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Previous work has shown that potentiation of insulin release is impaired in non-diabetic insulin resistance; we tested the hypothesis that this defect may be related to altered glucagon-like peptide-1 (GLP-1) release. On consecutive days, 82 non-diabetic individuals, classified as insulin sensitive (IS, n=41) or insulin resistant (IR, n=41) by the euglycaemic clamp, were given two sequential mixed meals with standard (75 g, LCD) or double (150 g, HCD) carbohydrate content. Plasma glucose, insulin, C-peptide, non-esterified fatty acids (NEFA) and GLP-1 concentrations were measured; β-cell function (glucose sensitivity and potentiation) was resolved by mathematical modelling. Fasting GLP-1 levels were higher in IR than IS (by 15%, P=0.006), and reciprocally related to insulin sensitivity after adjustment for sex, age, fat mass, fasting glucose or insulin concentrations. Mean postprandial GLP-1 responses were tightly correlated with fasting GLP-1, were higher for the second than the first meal, and higher in IR than IS subjects but only with LCD. In contrast, incremental GLP-1 responses were higher during (i) the second than the first meal, (ii) on HCD than LCD, and (iii) significantly smaller in IR than IS independently of meal and load. Potentiation of insulin release was markedly reduced in IR vs IS across meal and carbohydrate loading. In the whole dataset, incremental GLP-1 was directly related to potentiation, and both were inversely related to mean NEFA concentrations. We conclude that (a) raised GLP-1 tone may be inherently linked with a reduced GLP-1 response and (b) defective post-meal GLP-1 response may be one mechanism for impaired potentiation of insulin release in insulin resistance.

scholarly journals The Clinical Efficacy and Safety of Glucagon-Like Peptide-1 (GLP-1) Agonists in Adults with Type 2 Diabetes Mellitus

2011 ◽  
Vol 4 ◽  
pp. CMED.S4086 ◽  
Author(s):  
Kira R. Brice ◽  
Maria K. Tzefos
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Cell Function ◽  
Efficacy And Safety ◽  
Medline Search ◽  
Study Selection ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Objective To review the efficacy and safety of glucagon-like peptide-1 (GLP-1) agonists to determine their role in type 2 diabetes mellitus (T2DM). Data Sources A Medline search was conducted using the keywords exenatide, liraglutide, glucagon-like peptide-1, type 2 diabetes mellitus, hyperglycemia, pharmacokinetics, pharmacology and safety. Study Selection All identified articles written in English were evaluated with priority given to controlled, randomized trials including human data. References of identified published trials were reviewed for additional trials to be included in the review. Data Synthesis Exenatide and liraglutide are GLP-1 agonists approved for the treatment of T2DM. Several randomized, active and placebo controlled trials examining the efficacy and safety of exenatide and liraglutide both as monotherapy and in combination therapy have been conducted. Both agents have demonstrated improved glycemic control in addition to weight loss and increased beta-cell function. The most common adverse effects are gastrointestinal in nature and appear to be transient. Conclusion It appears exenatide and liraglutide are safe and effective in the treatment of T2DM and may exhibit effects that make them preferred over other anti-diabetic medications.

M1713 Mechanisms of Crosstalk Between Intestinal EC and L Cells: the Roles of Serotonin and Glucagon-Like Peptide 1 in Regulating Neuroendocrine Cell Function

2010 ◽  
Vol 138 (5) ◽  
pp. S-403-S-404 ◽  
Author(s):  
Alexander D. Kazberouk ◽  
Francesco Giovinazzo ◽  
Andrew Timberlake ◽  
Betty De Smet ◽  
Roswitha Pfragner ◽  
...  
Keyword(s):  
Cell Function ◽  
Neuroendocrine Cell ◽  
L Cells ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals GPR142 prompts glucagon-like Peptide-1 release from islets to improve β cell function

2018 ◽  
Vol 11 ◽  
pp. 205-211 ◽  
Author(s):  
Hua V. Lin ◽  
Jingru Wang ◽  
Jie Wang ◽  
Weiji Li ◽  
Xuesong Wang ◽  
...  
Keyword(s):  
Cell Function ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals The Mechanism of Metabolic Influences on the Endogenous GLP-1 by Oral Antidiabetic Medications in Type 2 Diabetes Mellitus

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Thiquynhnga Nguyen ◽  
Min Gong ◽  
Song Wen ◽  
Xinlu Yuan ◽  
Chaoxun Wang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Cell Function ◽  
Cellular Mechanisms ◽  
Distal Intestine ◽  
Oral Antidiabetic ◽  
Dpp Iv ◽  
Glucagon Like Peptide 1

Incretin-based therapy is now a prevalent treatment option for patients with type 2 diabetes mellitus (T2DM). It has been associated with considerably good results in the management of hyperglycemia with cardiac or nephron-benefits. For this reason, it is recommended for individuals with cardiovascular diseases in many clinical guidelines. As an incretin hormone, glucagon-like peptide-1 (GLP-1) possesses multiple metabolic benefits such as optimizing energy usage, maintaining body weight, β cell preservation, and suppressing neurodegeneration. However, recent studies indicate that oral antidiabetic medications interact with endogenous or exogenous GLP-1. Since these drugs are transported to distal intestine portions, there are concerns whether these oral drugs directly stimulate intestinal L cells which release GLP-1, or whether they do so via indirect inhibition of the activity of dipeptidyl peptidase-IV (DPP-IV). In this review, we discuss the metabolic relationships between oral antihyperglycemic drugs from the aspect of gut, microbiota, hormones, β cell function, central nervous system, and other cellular mechanisms.

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