Preventive treatment with liraglutide protects against development of glucose intolerance in a rat model of Wolfram syndrome

Toots, Maarja; Seppa, Kadri; Jagomäe, Toomas; Koppel, Tuuliki; Pallase, Maia; Heinla, Indrek; Terasmaa, Anton; Plaas, Mario; Vasar, Eero

doi:10.1038/s41598-018-28314-z

Cited by 40 publications

(57 citation statements)

References 42 publications

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“…The Wfs1 KO rats were already glucose intolerant at the beginning of the experiment (Fig. 1a,b) (F(1, 30) = 38.69, p < 0.001 (genotype)), which agrees with our previous studies 6,8 . As expected, 13-month-old KO animals were still glucose intolerant (Fig.…”

Section: Resultssupporting

confidence: 91%

“…For that reason, it is important to find not only antidiabetic treatments but also therapies that could delay the progression of neurodegeneration and thereby extend the quality of life and lifespan of WS patients. We have shown that the GLP-1 receptor agonist liraglutide has the ability to slow down the progression of the diabetic phenotype in our validated Wfs1-deficient rat model 8 . Wfs1 and GLP-1 receptor are both expressed in the inferior olive and in the retina, and therefore treatment with the GLP-1 receptor agonist may have a direct neuroprotective effect on those structures 6,12–14 .…”

Section: Discussionmentioning

confidence: 76%

“…Recently, our group has demonstrated in Wfs1 knock-out (KO) rats that 19-week-long treatment with Glucagon-like-peptide-1 (GLP-1) receptor agonist liraglutide decreases ER stress, inflammation, and proliferation in Langerhans islets and thereby prevents or delays the development of a diabetic phenotype 8 . Moreover, treatment with the GLP-1 receptor agonist exenatide has shown a promising anti-diabetic effect in Wfs1 knock-out mice both after acute 9 and in chronic administration 10 .…”

Section: Introductionmentioning

confidence: 99%

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GLP-1 receptor agonist liraglutide has a neuroprotective effect on an aged rat model of Wolfram syndrome

Seppa

Toots

Reimets

et al. 2019

Sci Rep

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Wolfram syndrome (WS) is a rare neurodegenerative disorder that is mainly characterized by diabetes mellitus, optic nerve atrophy, deafness, and progressive brainstem degeneration. Treatment with GLP-1 receptor agonists has shown a promising anti-diabetic effect in WS treatment in both animal models and in human patients. Since previous research has tended to focus on investigation of the WS first symptom, diabetes mellitus, the aim of the present study was to examine liraglutide effect on WS-associated neurodegeneration. We took 9-month-old Wfs1 knock-out (KO) animals that already had developed glucose intolerance and treated them with liraglutide for 6 months. Our research results indicate that 6-month liraglutide treatment reduced neuroinflammation and ameliorated endoplasmic reticulum (ER) stress in the inferior olive of the aged WS rat model. Liraglutide treatment also protected retinal ganglion cells from cell death and optic nerve axons from degeneration. According to this, the results of the present study provide novel insight that GLP-1 receptor agonist liraglutide has a neuroprotective effect in the WS rat model.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

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GLP-1 receptor agonist liraglutide has a neuroprotective effect on an aged rat model of Wolfram syndrome

Seppa

Toots

Reimets

et al. 2019

Sci Rep

Self Cite

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“…Mutations in WFS1 , the wolframin gene, are responsible for the development of Wolfram syndrome, an autosomal recessive disease characterized by a variety of disorders including diabetes mellitus [ 167 ]. In a mice study researchers have demonstrated that treatment with GLP1RA may improve beta cell function, show a neuroprotective effect and even preserve from glucose intolerance in case of preventive therapy [ 168 , 169 , 170 , 171 ]. As GLP1RA may be considered as a potential therapy for wolfram syndrome treatment, analysis of association between WFS1 gene polymorphism and GLP1RA efficacy becomes reasonable.…”

Section: Genes Associated With Dpp4-inhibitors and Glp1 Receptor Amentioning

confidence: 99%

Pharmacogenetics of Type 2 Diabetes—Progress and Prospects

Nasykhova

Tonyan

Михайлова

et al. 2020

IJMS

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Type 2 diabetes mellitus (T2D) is a chronic metabolic disease resulting from insulin resistance and progressively reduced insulin secretion, which leads to impaired glucose utilization, dyslipidemia and hyperinsulinemia and progressive pancreatic beta cell dysfunction. The incidence of type 2 diabetes mellitus is increasing worldwide and nowadays T2D already became a global epidemic. The well-known interindividual variability of T2D drug actions such as biguanides, sulfonylureas/meglitinides, DPP-4 inhibitors/GLP1R agonists and SGLT-2 inhibitors may be caused, among other things, by genetic factors. Pharmacogenetic findings may aid in identifying new drug targets and obtaining in-depth knowledge of the causes of disease and its physiological processes, thereby, providing an opportunity to elaborate an algorithm for tailor or precision treatment. The aim of this article is to summarize recent progress and discoveries for T2D pharmacogenetics and to discuss the factors which limit the furthering accumulation of genetic variability knowledge in patient response to therapy that will allow improvement the personalized treatment of T2D.

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“…Treatment tests do not actually require expertise in pathogenesis, although it certainly helps. Treatments for Niemann-Pick C1 (Fan et al, 2013), Wilson's disease (Muller et al, 2018), Wolfram's disease (Toots et al, 2018), cyclin-dependent kinase-like 5 deficiency disorder (Yennawar et al, 2019), and many others have been tested. However, in these studies systems biology methods are infrequently used and the treatment efficacy is judged by symptomatic relief or individual biomarkers.…”

Section: Figmentioning

confidence: 99%

Metabolomics for Animal Models of Rare Human Diseases: An Expert Review and Lessons Learned

Kilk

2019

OMICS: A Journal of Integrative Biology

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Rare diseases occur with a frequency £1:1500-1:2500 depending on the location and applicable definitions across countries. Although individually rare, they collectively affect as much as 4-8% of population imposing a large burden on public health. Rarity in prevalence means prolonged path to accurate diagnosis, lack of treatment options, and also limited chances for preclinical studies of pathogenesis. I discuss in this expert review (1) what metabolomics, as a high throughput systems sciences technology, offers for rare disease studies, (2) why animal models are important for the study of rare human diseases and what should be kept in mind while using animal models, and finally, (3) provide examples of recent research to highlight how metabolomics on animal models of rare diseases perform, and how these results can lead to the knowhow, which raises genome, metabolome, and phenotype integration to a whole new level. In sum, metabolomics has been for years in clinical use for diagnosis of certain types of rare diseases. Determination of pathogenesis of more complex diseases and testing of treatment strategies is where animal models and systems biology analytical approaches are necessary. From gathered data, it is possible to go back to diagnostic and prognostic markers for rare diseases, which so far lack reliable and robust diagnosis and therapeutic options. In the future, a major challenge is to reveal the links between genotype, metabolism, and phenotype. Rare diseases could be the key in that process.

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Preventive treatment with liraglutide protects against development of glucose intolerance in a rat model of Wolfram syndrome

Cited by 40 publications

References 42 publications

GLP-1 receptor agonist liraglutide has a neuroprotective effect on an aged rat model of Wolfram syndrome

GLP-1 receptor agonist liraglutide has a neuroprotective effect on an aged rat model of Wolfram syndrome

Pharmacogenetics of Type 2 Diabetes—Progress and Prospects

Metabolomics for Animal Models of Rare Human Diseases: An Expert Review and Lessons Learned

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