scholarly journals The Glucagon-Like Peptide-1 Receptor Agonist Exendin-4 Inhibits Lipopolysaccharide-Induced Osteoclast Formation and Bone Resorption via Inhibition of TNF-αExpression in Macrophages

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Wei-Ren Shen ◽  
Keisuke Kimura ◽  
Masahiko Ishida ◽  
Haruki Sugisawa ◽  
Akiko Kishikawa ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Mrna Expression ◽  
Receptor Agonist ◽  
Type I Collagen ◽  
Osteoclast Formation ◽  
Type I ◽  
Receptor Agonists ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) receptor agonists are an effective treatment approach for type 2 diabetes. Recently, anti-inflammatory effects of GLP-1 receptor agonists have also been reported. Lipopolysaccharide (LPS) induces inflammation and osteoclast formation. In this study, we investigated the effect of exendin-4, a widely used GLP-1 receptor agonist, in LPS-induced osteoclast formation and bone resorption. LPS with or without exendin-4 was administered on mouse calvariae by daily subcutaneous injection. The number of osteoclasts, the ratio of bone resorption pits, and the level of C-terminal cross-linked telopeptide of type I collagen (CTX) were significantly lower in LPS- and exendin-4-coadministered mice than in mice administered with LPS alone. RANKL and TNF-αmRNA expression levels were lower in the exendin-4- and LPS-coadministered group than in the LPS-administered group. Ourin vitroresults showed no direct effects of exendin-4 on RANKL-induced osteoclast formation, TNF-α-induced osteoclast formation, or LPS-induced RANKL expression in stromal cells. Conversely, TNF-αmRNA expression was inhibited in the exendin-4- and LPS-cotreated macrophages compared with cells treated with LPS alone. These results indicate that the GLP-1 receptor agonist exendin-4 may inhibit LPS-induced osteoclast formation and bone resorption by inhibiting LPS-induced TNF-αproduction in macrophages.

Synthesis and in vitro biological evaluation of new pyrimidines as glucagon-like peptide-1 receptor agonists

2017 ◽  
Vol 27 (22) ◽  
pp. 5071-5075 ◽  
Author(s):  
Shaikha S. AlNeyadi ◽  
Abdu Adem ◽  
Naheed Amer ◽  
Alaa A. Salem ◽  
Ibrahim M. Abdou
Keyword(s):  
Biological Evaluation ◽  
Receptor Agonists ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like Peptide 1 Receptor Agonists, Diabetic Retinopathy and Angiogenesis: The AngioSafe Type 2 Diabetes Study

2019 ◽  
Vol 105 (4) ◽  
pp. e1549-e1560 ◽  
Author(s):  
Bénédicte Gaborit ◽  
Jean-Baptiste Julla ◽  
Samaher Besbes ◽  
Matthieu Proust ◽  
Clara Vincentelli ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
Fundus Photography ◽  
Endothelial Cell Proliferation ◽  
Receptor Agonists ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Aims Recent trials provide conflicting results on the association between glucagon-like peptide 1 receptor agonists (GLP-1RA) and diabetic retinopathy (DR). The aim of the AngioSafe type 2 diabetes (T2D) study was to determine the role of GLP-1RA in angiogenesis using clinical and preclinical models. Methods We performed two studies in humans. In study 1, we investigated the effect of GLP-1RA exposure from T2D diagnosis on the severity of DR, as diagnosed with retinal imaging (fundus photography). In study 2, a randomized 4-week trial, we assessed the effect of liraglutide on circulating hematopoietic progenitor cells (HPCs), and angio-miRNAs. We then studied the experimental effect of Exendin-4, on key steps of angiogenesis: in vitro on human endothelial cell proliferation, survival and three-dimensional vascular morphogenesis; and in vivo on ischemia-induced neovascularization of the retina in mice. Results In the cohort of 3154 T2D patients, 10% displayed severe DR. In multivariate analysis, sex, disease duration, glycated hemoglobin (HbA1c), micro- and macroangiopathy, insulin therapy and hypertension remained strongly associated with severe DR, while no association was found with GLP-1RA exposure (o 1.139 [0.800–1.622], P = .47). We further showed no effect of liraglutide on HPCs, and angio-miRNAs. In vitro, we demonstrated that exendin-4 had no effect on proliferation and survival of human endothelial cells, no effect on total length and number of capillaries. Finally, in vivo, we showed that exendin-4 did not exert any negative effect on retinal neovascularization. Conclusions The AngioSafe T2D studies provide experimental and clinical data confirming no effect of GLP-1RA on angiogenesis and no association between GLP-1 exposure and severe DR.

Glucagon-Like Peptide 1 Receptor Agonist ZP10A Increases Insulin mRNA Expression and Prevents Diabetic Progression in db/db Mice

2003 ◽  
Vol 307 (2) ◽  
pp. 490-496 ◽  
Author(s):  
Christian Thorkildsen ◽  
Søren Neve ◽  
Bjarne Due Larsen ◽  
Eddi Meier ◽  
Jørgen Søberg Petersen
Keyword(s):  
Mrna Expression ◽  
Receptor Agonist ◽  
Insulin Mrna ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Carboxyterminal telopeptide of type I collagen, ICTP, as a marker of matrix degradation in neonatal mouse calvarial bones, in vitro

1992 ◽  
Vol 12 (5) ◽  
pp. 407-411 ◽  
Author(s):  
Östen Ljunggren ◽  
Sverker Ljunghall
Keyword(s):  
Parathyroid Hormone ◽  
Bone Resorption ◽  
Type I Collagen ◽  
Bone Matrix ◽  
Neonatal Mouse ◽  
Type I ◽  
Matrix Degradation ◽  
Dose Responses ◽  
Carboxyterminal Telopeptide

Bone resorption, in vitro, is often measured as the release of prelabelled45Ca from neonatal mouse calvarial bones, or from fetal rat long bones. In this report we describe a technique to measure the breakdown of bone-matrix, in vitro. We also describe a new way to dissect neonatal mouse calvarial bones, in order to obtain large amounts of bone samples. Twelve bone fragments were dissected out from each mouse calvaria and were thereafter cultured in CMRL 1066 culture medium in serum-free conditions in 0.5 cm2 multiwell culture dishes. Matrix degradation after treatment with parathyroid hormone was assessed by measuring the amount of carboxyterminal telopeptide of type I collagen (ICTP) by RIA. The data on matrix degradation was compared to the release of prelabelled45Ca from neonatal mouse calvarial bones. We found that the dose-responses for parathyroid hormone-induced release of prelabelled45Ca and ICTP were identical. In conclusion: RIA-analysis of the ICTP-release is an easy and accurate method to measure degradation of bone-matrix, in vitro. Furthermore, the new dissection technique, described in this report, makes it easy to obtain large amounts of bone samples and thus to perform extensive experiments, e.g. dose-responses for agents that enhance bone resorption.

scholarly journals Fusion Potential of Human Osteoclasts In Vitro Reflects Age, Menopause, and In Vivo Bone Resorption Levels of Their Donors—A Possible Involvement of DC-STAMP

2020 ◽  
Vol 21 (17) ◽  
pp. 6368
Author(s):  
Anaïs M. J. Møller ◽  
Jean-Marie Delaissé ◽  
Jacob B. Olesen ◽  
Luisa M. Canto ◽  
Silvia R. Rogatto ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Type I Collagen ◽  
Transmembrane Protein ◽  
Type I ◽  
Contributing Factors ◽  
Expression Levels ◽  
Procollagen Type ◽  
Age Related

It is well established that multinucleation is central for osteoclastic bone resorption. However, our knowledge on the mechanisms regulating how many nuclei an osteoclast will have is limited. The objective of this study was to investigate donor-related variations in the fusion potential of in vitro-generated osteoclasts. Therefore, CD14+ monocytes were isolated from 49 healthy female donors. Donor demographics were compared to the in vivo bone biomarker levels and their monocytes’ ability to differentiate into osteoclasts, showing that: (1) C-terminal telopeptide of type I collagen (CTX) and procollagen type I N-terminal propeptide (PINP) levels increase with age, (2) the number of nuclei per osteoclast in vitro increases with age, and (3) there is a positive correlation between the number of nuclei per osteoclast in vitro and CTX levels in vivo. Furthermore, the expression levels of the gene encoding dendritic cell-specific transmembrane protein (DCSTAMP) of osteoclasts in vitro correlated positively with the number of nuclei per osteoclast, CTX levels in vivo, and donor age. Our results furthermore suggest that these changes in gene expression may be mediated through age-related changes in DNA methylation levels. We conclude that both intrinsic factors and age-induced increase in fusion potential of osteoclasts could be contributing factors for the enhanced bone resorption in vivo, possibly caused by increased expression levels of DCSTAMP.

scholarly journals Anaphylactic Reaction to Dulaglutide: A Glucagon Like Peptide- 1 Receptor Agonist

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A367-A368
Author(s):  
Hamza Quadri ◽  
Basma Ataallah ◽  
Gregory Haggerty
Keyword(s):  
Allergic Reaction ◽  
Anaphylactic Reaction ◽  
Receptor Agonist ◽  
The Body ◽  
Lower Lip ◽  
Receptor Agonists ◽  
Type 2 Dm ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Introduction: The development of Glucagon like peptide-1 (GLP-1) receptors agonists represents an important advancement in the management of type 2 diabetes. The long-acting GLP-1 receptor agonists improve glycemic control, promote weight loss. Anaphylaxis to GLP-1 receptor agonists and mainly Dulaglutide is a rare but serious side effect. We report a patient with Type 2 DM who was recently started on Dulaglutide and started to experience systemic hypersensitivity reactions that required discontinuing the medication and inpatient hospitalization. Case: A 53-Year-old Caucasian female with past medical history of type 2 DM on Metformin presented to the ED with sudden onset of sporadic itchy rash on the lip and chin associated with lip swelling within one hour of her first injection of Dulaglutide. She denied difficulty breathing, rash or pruritus on any other part of the body. She denied any food allergies. The patient used two tablets of Oral Diphenhydramine 25 mg with minimal improvement in her symptoms which warrant her to come to the ED. On arrival, she was Afebrile with a HR 97 beats/minute, a BP of 105/58 mm of Hg and a RR of 17 breaths/minute. The rash was blotchy, non- tender, more evident on the upper lip as compared to the lower lip. Lab results showed WBC count of 11 k/uL with basophils of 2% and HbA1c 8.6%. She was treated for her allergic reaction with Intramuscular injection of Epinephrine 0.3mg, Intravenous Dexamethasone 6mg and Intravenous Diphenhydramine 25mg. She was then transferred to the observation unit for monitoring. Her home metformin 500mg two times a day was continued. After 48 hours, the patient’s symptoms were improved and she was discharged home. She was advised to follow up with her PCP and endocrinologist and stop Dulaglutide. Discussion: GLP-1 receptor agonists are commonly used currently in the management of DM due to their beneficial effect in controlling blood glucose as compared to other diabetic medications. Rarely, a potentially life-threatening reaction, such as anaphylactic reactions have been documented with GLP-1 receptor agonist. Systemic allergic reaction to GLP-1 Agonist Exenatide has been reported in the literature. Our patient had anaphylactic reaction after using Dulaglutide. The mechanism of action of anaphylaxis in GLP-1 receptor agonists is thought to be related to IgE mediated and the immune response was demonstrated by basophil activation.

scholarly journals A brief review on newer Glucagon like Peptide-1 analogues

2020 ◽  
Vol 1 (1) ◽  
pp. 26-34
Author(s):  
B Dharmaraj ◽  
Keyword(s):  
Receptor Agonist ◽  
The United States ◽  
The European Union ◽  
Release Formulation ◽  
Duration Of Action ◽  
Receptor Agonists ◽  
Extended Release Formulation ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Year 2000

GLP-1 (Glucagon like Peptide-1) receptor agonists have been shown to be effective in the treatment of type 2 diabetes mellitus (T2DM). Although the first GLP-1 receptor agonist, Exenatide, was approved in the year 2000, other agents with a longer duration of action that do not require twice-daily dosing are now being developed. Indeed, Liraglutide, a once-daily GLP-1 receptor agonist, was approved in 2010, a once-weekly extended-release formulation of Exenatide (Exenatide ER) was approved in 2011 and now more recently Semaglutide, an oral GLP 1 receptor agonist was approved for medical use in the United States in September 2019 and in the European Union in April 2020. The importance of GLP-1 itself and the use of GLP-1 receptor agonists in T2DM are discussed. An overview of the clinical development of the GLP-1 receptor agonists (Exenatide ER, Liraglutide, Lixisenatide, Albiglutide, Taspoglutide and Semaglutide) is provided and their mechanism of action, efficacy in terms of glycaemic control, weight loss and tolerability are reviewed. Keywords: GLP1 receptor agonist; Liraglutide; Exenatide ER; Lixisenatide; Semaglutide

Abstract MP52: Population Health Impact of Sodium Glucose Co-Transporter 2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists in US Adults With Type 2 Diabetes

Circulation ◽  
2018 ◽  
Vol 137 (suppl_1) ◽  
Author(s):  
Girish Nadkarni ◽  
Priti Poojary ◽  
Rocco Ferrandino ◽  
Aparna Saha ◽  
Kinsuk Chauhan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Receptor Agonist ◽  
Health Impact ◽  
Complication Rates ◽  
Potential Health ◽  
Receptor Agonists ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Introduction: Recently, sodium glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 (GLP-1) receptor agonists have been introduced as novel antidiabetic agents, but their potential health impact in the US is unknown. We assessed the number of potentially eligible type 2 diabetes (T2D) patients, as well as projected changes in death and complication rates for nationwide use. Methods: Based on inclusion criteria of SGLT2i and GLP-1 receptor agonist RCTs, we determined eligibility in a weighted sample of 69.2M T2D patients from 2007-2014 National Health and Nutrition Examination Survey (NHANES) data. We employed a validated microsimulation model based on the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial to simulate virtual life courses of eligible US patients. Pooled hazard ratios from meta-analyses of published RCTs were applied to model death and non-fatal adverse event rates with SGLT2i and GLP-1 receptor agonist use. Results: The proportion eligible in NHANES was 9.2% (95% CI 7.3-11.1), which translates into ~6.4M US adults. Simulated 10-year mortality (32.5%) decreased by 4.6% (95% CI 2.7-7.3) with SGLT2i and by 2.9% (95% CI 1.6-4.8) with GLP-1 receptor agonists. Mean life expectancy was 16.5 y, and increased by 1.3 y (95% CI 0.6-2.2) with SGLT2i and by 0.8 y (95% CI 0.4-1.5) with GLP-1 receptor agonists. With SGLT2i, lifetime heart failure risk decreased by 7.4% (95% CI 4.1-12.3) and end-stage renal disease (ESRD) risk decreased by 0.4% (95% CI -0.1-0.9). Improvements in these event risks were uncertain with GLP-1 receptor agonist use (Figure). With lifetime SGLT2i use, fracture risk increased from 16.9 to 22.4% (95% CI of Δ 2.5-9.6) and amputation risk rose from 5.7 to 11.2% (95% CI of Δ 2.3-9.5). Conclusions: Nationwide use of SGLT2i or GLP-1 receptor agonists may save over 8 or 5M life years, respectively. Moreover, SGLT2i may avoid over 470K new cases of heart failure and over 28K ESRD cases. Further research should illuminate whether these benefits outweigh additional costs and harms.

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