Brain Endothelial Cells Regulate Glucagon-Like Peptide 1 Entry Into the Brain via a Receptor-Mediated Process

Fu, Zhuo; Gong, Liying; Liu, Jia; Wu, Jing; Barrett, Eugene J.; Aylor, Kevin W.; Liu, Zhenqi

doi:10.3389/fphys.2020.00555

Cited by 19 publications

(14 citation statements)

References 44 publications

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“…Considering the mechanisms involved in weight loss, the GLP‐1RA–induced weight effect appears to be mediated in part by its actions on the brain 18 . Specifically, there are studies showing effects mediated by the hindbrain 19 and hypothalamus, 20 and recently, GLP‐1 facilitated transport over the blood‐brain barrier (BBB) was discovered 21 . GLP‐1 RAs with large molecular weights, such as albiglutide (~73 kDa), may hardly cross the BBB; thus, they may have a weak effect on weight loss 22 .…”

Section: Discussionmentioning

confidence: 99%

“…18 Specifically, there are studies showing effects mediated by the hindbrain 19 and hypothalamus, 20 and recently, GLP-1 facilitated transport over the blood-brain barrier (BBB) was discovered. 21 GLP-1 RAs with large molecular weights, such as albiglutide (73 kDa), may hardly cross the BBB; thus, they may have a weak effect on weight loss. 22 Nevertheless, dulaglutide (63 kDa) has displayed a clear weight-loss effect in T2D patients.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy and safety of polyethylene glycol loxenatide monotherapy in type 2 diabetes patients: A multicentre, randomized, double‐blind, placebo‐controlled phase 3a clinical trial

Shi

Yang

Zhang

et al. 2020

Diabetes Obesity Metabolism

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Aim To evaluate the efficacy and safety of polyethylene glycol loxenatide (PEX168) monotherapy in type 2 diabetes (T2D) patients in China. Materials and Methods In a multicentred, randomized, double‐blinded, placebo‐controlled phase 3a clinical trial, 361 patients with inadequate glycaemic control (HbA1c 7.0%‐10.5%, fasting plasma glucose <13.9 mmol/L) were randomized (1:1:1) for weekly subcutaneous injections: placebo, PEX168/100 μg or PEX168/200 μg. The 24‐week treatment was followed by a 28‐week extension, during which placebo‐treated patients were randomly assigned to PEX168/100 μg or PEX168/200 μg. The primary efficacy endpoint was the HbA1c change from baseline to week 24. Results The three groups had similar demographics and baseline characteristics. The HbA1c least‐square mean (95% CI) change from baseline to week 24 was greater for PEX168/100 μg (−1.02% [−1.21%, −0.83%]) and PEX168/200 μg (−1.34% [−1.54%, −1.15%]) than for placebo (−0.17% [−0.36%, 0.02%]); (superiority: P < .0001). The proportions of patients with less than 7% HbA1c in the placebo, PEX168/100 μg and PEX168/200 μg groups were 15.7%, 34.7% and 46.6%, respectively. Common gastrointestinal adverse events (AEs) were nausea (5.6%, 10.0% and 0% for PEX168/100 μg, PEX168/200 μg and placebo, respectively) and vomiting (2.4%, 8.3% and 0% for PEX168/100 μg, PEX168/200 μg and placebo, respectively). Six (1.6%) patients (PEX168/100 μg: N = 2 [1.6%], PEX168/200 μg: N = 3 [2.5%] and placebo: N = 1 [0.8%]) discontinued treatment because of AEs. Four (1.2%) patients (PEX168/100 μg: N = 3 [2.5%] and PEX168/200 μg: N = 1 [0.9%]) developed PEX168 antidrug antibodies. Conclusion PEX168 monotherapy significantly improved glycaemic control in T2D patients with a safety profile resembling that of other glucagon‐like peptide‐1 receptor agonists.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of polyethylene glycol loxenatide monotherapy in type 2 diabetes patients: A multicentre, randomized, double‐blind, placebo‐controlled phase 3a clinical trial

Shi

Yang

Zhang

et al. 2020

Diabetes Obesity Metabolism

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“…Finally, translating the study of the mechanisms governing GLP-1R trafficking to other cellular systems beyond the pancreas represents a further frontier in our understanding of the importance of these processes in GLP-1R biology. For example, it is postulated that GLP-1Rmediated endocytic carriage across tanycytes or endothelial cells is a specific mechanism by which GLP-1RAs access the brain (55,(113)(114)(115), although non-receptor-mediated mechanisms such as adsorptive transcytosis are also suggested to be important (116).…”

Section: Discussionmentioning

confidence: 99%

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

2021

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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.

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“…One potential route of insulin secretion in the brain is via glucagon-like peptide 1 (GLP-1) and protein kinase [37]. During a hyperglycemic state, GLP-1 in the brain is able to cross the blood-brain barrier [38] and inhibit glucose utilisation and cause insulin secretion [39,40]. In this study, P. gingivalis induction resulted in a higher mRNA abundance of GLP1R and several kinases and their receptors and lower mRNA abundance of G6P, a key glucose utilisation marker.…”

Section: Discussionmentioning

confidence: 99%

Porphyromonas gingivalis (W83) Infection Induces Alzheimer’s Disease-Like Pathophysiology in Obese and Diabetic Mice

Bahar

Kanagasingam

Tambuwala

et al. 2021

JAD

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Background: Periodontal disease(s) and metabolic illnesses negatively impact the quality of life and, eventually mental health. Objective: This study investigated the effect of Porphyromonas gingivalis (W83) oral infection on the development of Alzheimer’s disease (AD) pathophysiology in a wild-type obese, diabetic (db/db) mouse model. Methods: The db/db mice were either orally infected with P. gingivalis and Fusobacterium nucleatum or sham infected for 16 weeks. The presence of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) were assessed using a silver impregnation technique and subsequently by immunohistochemistry for tau and neuroinflammation. The mRNA abundance of a panel of 184 genes was performed using quantitative real-time PCR, and the differentially expressed genes were analyzed by Ingenuity Pathway Analysis. Results: While no Aβ plaques and NFTs were evident by silver impregnation, immunohistochemistry (glial cell markers) of the P. gingivalis-infected mice tissue sections exhibited neuroinflammation in the form of reactive microglia and astrocytes. Anti-tau immunopositivity, in addition to cells, was prominent in thickened axons of hippocampal CA neurons. The mRNA abundance of crucial genes in the insulin signaling pathway (INSR, IGF1, IRS, IDE, PIK3R, SGK1, GYS, GSK3B, AKT1) were upregulated, potentially exacerbating insulin resistance in the brain by P. gingivalis oral infection. Increased mRNA abundance of several kinases, membrane receptors, transcription factors, and pro-inflammatory mediators indicated hyperactivation of intracellular cascades with potential for tau phosphorylation and Aβ release in the same infection group. Conclusion: P. gingivalis W83 infection of db/db mice provides a disease co-morbidity model with the potential to reproduce AD pathophysiology with induced periodontal disease.

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Brain Endothelial Cells Regulate Glucagon-Like Peptide 1 Entry Into the Brain via a Receptor-Mediated Process

Cited by 19 publications

References 44 publications

Efficacy and safety of polyethylene glycol loxenatide monotherapy in type 2 diabetes patients: A multicentre, randomized, double‐blind, placebo‐controlled phase 3a clinical trial

Efficacy and safety of polyethylene glycol loxenatide monotherapy in type 2 diabetes patients: A multicentre, randomized, double‐blind, placebo‐controlled phase 3a clinical trial

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

Porphyromonas gingivalis (W83) Infection Induces Alzheimer’s Disease-Like Pathophysiology in Obese and Diabetic Mice

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