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lördag 24 juni 2017

Betasolujen endokannabinoidisysteemi(11) Tulevaiset suunnat. Yhteenveto. Viitteet


Diabetes Obes Metab. 2016 Jun;18(6):549-57. doi: 10.1111/dom.12646. Epub 2016 Mar 31.  Betasolufunktioiden endokannabinoidisäätely: sovellutusta glykemiseen kontrolliin ja diabetekseen
 LÄHDE: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045244/
 

Tulevaiset suunnat (11)

Future Directions

Nykynäyttö endokannabinoidien ja niiden reseptorien osuudesta glykemisessä kontrollissa on perustunut suurimmaksi osaksi jyrsijöitten diabetes ja obesitasmallien käyttöön
  • Current evidence for the involvement of endocannabinoids and their receptors in the control of glycaemic functions has been based largely on studies using rodent models of diabetes and obesity.

Vaikkakin varhaiset kliiniset tutkimukset CB1-reseptoriantagonistilla (rimonabantti)
antoivat tukea käsitykselle CB1- reseptorin osuudesta insuliiniresistenssissä ja Tyypin 2 diabeteksessa sekä lihavilla janylipainoisilla, rimonabantin vetäminen pois lääkemarkkinoilta neuropsykiatristen sivuvaikutusten vuoksi aiheutti viivästystä tämän reseptorisignaloinnin taustamekanismien jatkotutkimuksiin ihmisessä. (Rimonabantti oli aikanaan ensimmäinen CB1R antagonisti ja sitä alettiin käyttää lihavuuden hoitoon. Se kiellettiin Suomessa 2008)

  • Although early clinical studies with the CB1R antagonist rimonabant supported the role of CB1R in insulin resistance and T2D in obese/overweight individuals, the withdrawal of rimonabant from the market because of neuropsychiatric side effects has hampered further exploration of the underlying mechanisms in humans.
Nykyinen näyttö jyrsijämallien tyypin 2 diabeteksesta ja lihavuudesta viittaa siihen, että periferiaan rajoittuneet CB1 R-antagonistit omaavat metabolisia etuja ( joihin kuuluu betasolua suojaava vaikutus); globaalisti vaikuttavista yhdistyksistä- ilman niistä aiheuttuvaa neuropsykiatrista altistusta saattaa olla kehitettävissä diabetekseen potentiellia CB1- reseptoriblokadiin perustuvaa terapiaa. Eräs sellainen yhdiste on JD-5037 ja se on parhaillaan toksikologisessa seulonnassa.

Yhteenveto ja Viitteet (12)

Conclusions

Kertyvä näyttö osoittaa, että yliaktiivinen endokannabinoidiysteemi osallistuu diabeteksen kehittymiseen ja insuliiniresistenssiin ja hallitsevasti mukana on CB1- kannabinoidireseptori monissa perifeerisissä elimissä. Haiman betasolut on insuliinin påälähde kehossa ja niillä on täysin funktionaalinen endokannabinoidisysteemi; on myös näyttöä in vitro ja in vivo tutkimuksista, että endokannabinoidit moduloivat basaalia insuliinin eritystä ja myös glukoosin stimuloimaa insuliinin eritystä (GSIS) sekä betasolujen elossapysymistä ja proliferoitumista.
Useinkin eristetyistä haimasaarekkeista tehdyt tutkimukset ovat antaneet ristiriitaista tietoa CB1 reseptorin solutyyppispesifisestä sijainnista saarekkeessa ja basaali-insuliinin tai glukoosin stimuloiman insuliinin erityksen lisääntymän ja vähenemän muutoksen suunnasta- CB1-resptoriaktivatiosta

  • Mounting evidence indicates that an overactive ECS is involved in the development of diabetes and insulin resistance, with the prominent involvement of CB1R in multiple peripheral organs. Pancreatic β-cells, the major source of insulin in the body, have a fully functional ECS, and there is both in vitro and in vivo evidence of endocannabinoid modulation of basal insulin secretion and GSIS as well as the survival and proliferation of β-cells.
  • Studies using isolated pancreatic islets have often provided conflicting information as to the cell-type specific localization CB1R in the islet and the direction of change – increase or decrease – elicited by CB1R activation in basal insulin secretion and GSIS.
Sitä vastoin on yksiselitteistä näyttöä siitä, että pitkäaikainen CB1R blokadi lieventää ihmisen diabetesta ja insuliiniresistenssiä ja suojaa betasolukadolta sekä ihmisen diabeteksessa ja obesitaksessa/ /metabolisessa oireyhtymässä että vastaavissa kokeellisissa tutkimuksissa. Jälkimmäiset löydöt ovat yhtäpitäviä endokannabinoidien dokumentoidun osuuden kanssa mitä tulee apoptoosin edistämiseen ja betasolujen proliferaation estoon.

  • In contrast, there is unambiguous evidence that chronic CB1R blockade attenuates diabetes and insulin resistance and protects against β-cell loss in both human and experimental diabetes and obesity/metabolic syndrome. These latter findings are consistent with the documented role of endocannabinoids in promoting the apoptosis and inhibiting the proliferation of β-cells.
In vitro tutkimukset ovat yhtäpitäviä autokriinin mallin suhteen, missä betasoluista peräisin oleva endokannabinoidit edistävät solukuolemaa CB1R-välitteisen apoptoosin induktion ja inflammatoristen geenien ilmenemisen kautta.
In vivo-tutkimuksista saatu näyttö tukee vaihtoehtoista parakriinia mallia , jossa CB1R aktivaatio proinflammtorisessa makrofagissa edistää niiden ilmenemää Nlrp3 inflammasomissa ja niiden infiltroitumista diabeettisiin haimasaarekkeisiin, jossa ne vapauttavat sytotoksisia IL-1beta ja IL-18 sytokiinejä, jotka aiheuttavat betasolujen kuolemaa. Tämän prosessin ehkäisy periferiaan rajoitetusti vaikuttavilla CB1R-antagonisteilla antaa viitettä tämän luokan yhdisteiden terapeuttisesta potentiaalista.

  • The results of in vitro studies are compatible with an autocrine model whereby β-cell-derived endocannabinoids promote apoptosis via CB1R-mediated induction of apoptotic and inflammatory gene expression. Evidence from in vivo studies supports an alternative paracrine model whereby activation of CB1R on proinflammatory macrophages promotes their expression of the Nlrp3 inflammasome and their infiltration into diabetic islets, where they release cytotoxic IL-1β and IL-18 that cause β-cell death. Prevention of this process by peripherally restricted CB1R antagonists highlights the therapeutic potential of this class of compounds.

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