Pharmacological challenge in rodent models of Wolfram syndrome with emphasis on diabetic phenotype
Date
2018-10-26
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Abstract
Wolframi sündroom (WS) on autosomaalne retsessiivne haigus, mida põhjustavad mutatsioonid Wolframin1 (WFS1) geenis. Sündroomi põhisümptomiks on varajane suhkrudiabeet, millele järgneb optilise närvi atroofia, kurtus, psühhiaatrilised häired ja neurodegeneratsioon. Patsientid surevad 30-40 aastaselt piklikaju degeneratsioonist tingitud hingamise seiskumise tagajärjel. WS sagedus populatsioonis on 0.001% ja heterosügootsette WFS1 mutatsiooni kandjate sagedus 0.3-1%. On leitud, et heterosügootsetel WFS1 mutatsiooni kandjatel on suurenenud risk teist tüüpi diabeedi tekkeks.
Täna puudub WS ravi, mis aitaks haiguse progressiooni efektiivselt pidurdada. Sellest tulenevalt üritasime leida uusi ravimikandidaate, mis võiksid aidata WS patsiente. Uurimistööks kasutasime transgeenseid Wfs1 puudulikke hiiri ja rotte.
Esmalt leidsime, et muskariini 3 ja glükagooni-sarnase peptiidi-1 (GLP1) retseptorite akuutne stimulatsioon võimendas insuliini sekretsiooni ja normaliseeris veresuhkru taseme glükoositolerantsi testis Wfs1 puudulikel närilistel. Edasi uurisime GLP-1 retseptor agonisti liraglutiidi võimalikku WS kulgu pidurdavat toimet geeni puudulikus rotis. Erinevalt Wfs1 puudulikust hiirest arenes antud rottidel välja insuliinist sõltuv diabeet.
Kahe kuu vanustel transgeensetel rottidel, kellel puudub Wfs1 geeni 5. kodeeriv ekson, on normaalne glükoositaluvus ja insuliini sekretsioon. Vanemaks saades hävinevad neil järk-järgult pankrease Langerhansi saarte beeta-rakud, süveneb glükoositalumatus ja 13 kuu vanuselt ilmneb neil insuliinist sõltuv diabeet. Alustades Wfs1 puudulike rottide ravi liraglutiidiga 2 kuu vanuselt (enne esimesi haiguse sümptomeid) leidsime 4.5 kuu möödudes, et ravimit saanud transgeensete rottide glükoositaluvus ei erinenud metsiktüüpi rottide omast. Näitasime, et liraglutiidi manustamine parandas insuliini ja glükagooni sekretsiooni ning vähendas Langerhansi saartes endoplasmaatilise retiikulumi stressi ja põletikumarkerite geeniekspressioone. Ravi tulemusena ei vähenenud rottide pankrease Langerhansi saarte mass, mis oli täheldatav ravi mittesaanud loomadel.
Käesolevas töös leidsime esmakordselt, et ennetaval ravil GLP-1 agonistiga võib olla tugev WS vastane toime.
Wolfram syndrome (WS) is an autosomal recessive disorder, caused by mutations in Wolframin1 (WFS1) gene. Main initial symptom is non-autoimmune diabetes mellitus, followed by optic nerve atrophy, deafness, psychiatric disorders, and neural degeneration. Patients usually die in their 30- and 40-s due to central apnea caused by brain stem atrophy. WS prevalence is estimated up to 0.001%, the carrier frequency is approximately 0.3-1%. Carriers of heterozygous WFS1 mutation have been shown to have increased risk for development of type 2 diabetes. Currently there is no cure to delay the progression of WS. Therefore, in current thesis, we aimed to identify new drug candidates for the treatment of WS. For this purpose, transgenic Wfs1 deficient mice and rats were used. Our first findings showed that stimulating muscarinic 3 and glucagon-like peptide-1 (GLP-1) receptors on Langerhans islets beta cells was able to stimulate insulin secretion in Wfs1 deficiency and to normalize blood glucose levels in glucose tolerance test. Next we aimed to study whether repeated treatment with GLP-1 receptor agonist liraglutide was able to delay disease progression in the rat model of WS. Unlike Wfs1 deficient mice these transgenic rats developed insulin dependent diabetes. Rats, missing 5th exon in Wfs1 gene, had normal glucose tolerance and insulin secretion at 2 months of age. After that they started to lose their pancreatic Langerhans islets beta cells and develop progressive glucose intolerance, resulting in insulin dependent diabetes at 13 months of age. Starting the chronic treatment of Wfs1 deficient rats at 2 months of age, before onset of disease symptoms, we established no changes in glucose tolerance of rats receiving medication for 4.5 months. We showed that liraglutide improved insulin and glucagon secretion and decreased endoplasmic reticulum stress and inflammatory markers gene expression in Langerhans islets. Due to these improvements liraglutide receiving rats did not lose Langerhans islet mass, as did untreated animals. In current study we established for the first time the potential therapeutic effect of preventive treatment with GLP-1 analogue against the progression of WS.
Wolfram syndrome (WS) is an autosomal recessive disorder, caused by mutations in Wolframin1 (WFS1) gene. Main initial symptom is non-autoimmune diabetes mellitus, followed by optic nerve atrophy, deafness, psychiatric disorders, and neural degeneration. Patients usually die in their 30- and 40-s due to central apnea caused by brain stem atrophy. WS prevalence is estimated up to 0.001%, the carrier frequency is approximately 0.3-1%. Carriers of heterozygous WFS1 mutation have been shown to have increased risk for development of type 2 diabetes. Currently there is no cure to delay the progression of WS. Therefore, in current thesis, we aimed to identify new drug candidates for the treatment of WS. For this purpose, transgenic Wfs1 deficient mice and rats were used. Our first findings showed that stimulating muscarinic 3 and glucagon-like peptide-1 (GLP-1) receptors on Langerhans islets beta cells was able to stimulate insulin secretion in Wfs1 deficiency and to normalize blood glucose levels in glucose tolerance test. Next we aimed to study whether repeated treatment with GLP-1 receptor agonist liraglutide was able to delay disease progression in the rat model of WS. Unlike Wfs1 deficient mice these transgenic rats developed insulin dependent diabetes. Rats, missing 5th exon in Wfs1 gene, had normal glucose tolerance and insulin secretion at 2 months of age. After that they started to lose their pancreatic Langerhans islets beta cells and develop progressive glucose intolerance, resulting in insulin dependent diabetes at 13 months of age. Starting the chronic treatment of Wfs1 deficient rats at 2 months of age, before onset of disease symptoms, we established no changes in glucose tolerance of rats receiving medication for 4.5 months. We showed that liraglutide improved insulin and glucagon secretion and decreased endoplasmic reticulum stress and inflammatory markers gene expression in Langerhans islets. Due to these improvements liraglutide receiving rats did not lose Langerhans islet mass, as did untreated animals. In current study we established for the first time the potential therapeutic effect of preventive treatment with GLP-1 analogue against the progression of WS.
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Keywords
animal models, Wolfram syndrome, diabetes, phenotype, secretion of insulin, enteroglucagon