Neurturin and a GLP-1 Analogue Act Synergistically to Alleviate Diabetes in Zucker Diabetic Fatty Rats

Trevaskis, James L.; Sacramento, Chester Bittencourt; Jouihan, Hani; Ali, Safina; Lay, John Le; Oldham, Stephanie; Bhagroo, Nicholas; Boland, Brandon B.; Cann, Jennifer A.; Chang, Yuan; O’Day, Terrence; Howard, Victor; Reers, Christina; Winzell, Maria Sörhede; Smith, David M.; Feigh, Michael; Barkholt, Pernille; Schreiter, Kay; Austen, Matthias; Andag, Uwe; Thompson, Simon G.; Jermutus, Lutz; Coghlan, Matthew P.; Grimsby, Joseph; Dohrmann, Cord; Rhodes, Christopher J.; Rondinone, Cristina M.; Sharma, Arun

doi:10.2337/db16-0916

Cited by 12 publications

(10 citation statements)

References 37 publications

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“…The injection of NRTN in a diabetic rat model prevents the development of hyperglycemia, and reduces fasting glucose levels and the deterioration of metabolic parameters. However, it is not clear how NRTN mediates its metabolic activity to prevent hyperglycemia [75]. Diabetes can also result in the loss of enteric neurons leading to gastrointestinal dysfunction.…”

Section: In Diabetesmentioning

confidence: 99%

Revisiting the Role of Neurotrophic Factors in Inflammation

Morel

Domingues

Zimmer

et al. 2020

Cells

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The neurotrophic factors are well known for their implication in the growth and the survival of the central, sensory, enteric and parasympathetic nervous systems. Due to these properties, neurturin (NRTN) and Glial cell-derived neurotrophic factor (GDNF), which belong to the GDNF family ligands (GFLs), have been assessed in clinical trials as a treatment for neurodegenerative diseases like Parkinson’s disease. In addition, studies in favor of a functional role for GFLs outside the nervous system are accumulating. Thus, GFLs are present in several peripheral tissues, including digestive, respiratory, hematopoietic and urogenital systems, heart, blood, muscles and skin. More precisely, recent data have highlighted that different types of immune and epithelial cells (macrophages, T cells, such as, for example, mucosal-associated invariant T (MAIT) cells, innate lymphoid cells (ILC) 3, dendritic cells, mast cells, monocytes, bronchial epithelial cells, keratinocytes) have the capacity to release GFLs and express their receptors, leading to the participation in the repair of epithelial barrier damage after inflammation. Some of these mechanisms pass on to ILCs to produce cytokines (such as IL-22) that can impact gut microbiota. In addition, there are indications that NRTN could be used in the treatment of inflammatory airway diseases and it prevents the development of hyperglycemia in the diabetic rat model. On the other hand, it is suspected that the dysregulation of GFLs produces oncogenic effects. This review proposes the discussion of the biological understanding and the potential new opportunities of the GFLs, in the perspective of developing new treatments within a broad range of human diseases.

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Section: In Diabetesmentioning

confidence: 99%

Revisiting the Role of Neurotrophic Factors in Inflammation

Morel

Domingues

Zimmer

et al. 2020

Cells

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“…Experiments utilize human neuroblastoma cell line, TGW (TGW-SRE-Luc, clone 42, JCRB0618, originally from the Japanese Collection of Research Bioresources), stably expressing a reporter gene construct containing a luciferase gene under control of repetitive Serum Response Elements as descibed earlier (34). The assay is carried out in Collagen I coated 96 well plates (Becton Dickinson Labware) using Neolite High Sensitivity Luminescence Reporter Gene Assay System (PerkinElmer).…”

Section: Activity Assessment Of Neurturin Mutantsmentioning

confidence: 99%

“…NRTN induced signalling has been shown to provide trophic support to neurons (5) and is especially important in guiding the development and distribution of parasympathetic, sensory and enteric innervations (32). The effects on cell survival have also indicated the potential of NRTN in treatment of asthma (33) and, recently, in diabetes, as it has been shown to prevent the development of hyperglycemia and increase β-cell mass in diabetic rats (34). Despite the therapeutic relevance of NRTN and other members of the GDNF protein family, it is still not clear how the receptor complexes are formed, how selectivity between the co-receptors is achieved and how RET is activated.…”

mentioning

confidence: 99%

Structure and biophysical characterization of the human full-length neurturin–GFRa2 complex: A role for heparan sulfate in signaling

Sandmark¹,

Dahl²,

Öster³

et al. 2018

Journal of Biological Chemistry

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Neurturin (NRTN) provides trophic support to neurons and is considered a therapeutic agent for neurodegenerative diseases, such as Parkinson's disease. It binds to its co-receptor GFRa2 and the resulting NRTN:GFRa2 complex activates the transmembrane receptors RET or NCAM. We report the crystal structure of NRTN, alone and in complex with GFRa2. This is the first crystal structure of a GFRa with all three domains and shows that domain 1 does not interact directly with NRTN, but may support an interaction with RET and/or NCAM, via a highly conserved surface. In addition, biophysical results show that the relative concentration of GFRa2 on cell surfaces can affect the functional affinity of NRTN through avidity effects. We have identified a heparan sulfate binding site on NRTN and a putative binding site in GFRa2, suggesting that heparan sulfate has a role in assembly of the signalling complex. We further show that mutant NRTN with reduced affinity for heparan sulfate may provide a route forward for delivery of NRTN with increased exposure in preclinical in vivo models and ultimately to Parkinson's patients.

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“…All the later data suggest the important role of the neuronal gut brain axis in the efficiency of anti-diabetic treatments. Furthermore, a recent study demonstrated that a co-treatment with neurturin, a glial cell-line derived neurotrophic factor, with a GLP-1 analogue improved the diabetic state of Zucker fatty rats [144].…”

Section: Current Treatment Of Type 2 Diabetes: How Can We Improve Thementioning

confidence: 99%

The gut microbiota to the brain axis in the metabolic control

Grasset

Burcelin

2019

Rev Endocr Metab Disord

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The regulation of glycemia is under a tight neuronal detection of glucose levels performed by the gut-brain axis and an efficient efferent neuronal message sent to the peripheral organs, as the pancreas to induce insulin and inhibit glucagon secretions. The neuronal detection of glucose levels is performed by the autonomic nervous system including the enteric nervous system and the vagus nerve innervating the gastro-intestinal tractus, from the mouth to the anus. A dysregulation of this detection leads to the one of the most important current health issue around the world i.e. diabetes mellitus. Furthemore, the consequences of diabetes mellitus on neuronal homeostasis and activities participate to the aggravation of the disease establishing a viscious circle. Prokaryotic cells as bacteria, reside in our gut. The strong relationship between prokaryotic cells and our eukaryotic cells has been established long ago, and prokaryotic and eukaryotic cells in our body have evolved synbiotically. For the last decades, studies demonstrated the critical role of the gut microbiota on the metabolic control and how its shift can induce diseases such as diabetes. Despite an important increase of knowledge, few is known about 1) how the gut microbiota influences the neuronal detection of glucose and 2) how the diabetes mellitus-induced gut microbiota shift observed participates to the alterations of autonomic nervous system and the gut-brain axis activity.

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Neurturin and a GLP-1 Analogue Act Synergistically to Alleviate Diabetes in Zucker Diabetic Fatty Rats

Cited by 12 publications

References 37 publications

Revisiting the Role of Neurotrophic Factors in Inflammation

Revisiting the Role of Neurotrophic Factors in Inflammation

Structure and biophysical characterization of the human full-length neurturin–GFRa2 complex: A role for heparan sulfate in signaling

The gut microbiota to the brain axis in the metabolic control

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