Identification of signaling pathways controlling survival of pancreatic beta-cells in diabetes

Lupše, Blaž (author), Kreft, Marko (mentor), Maedler, Kathrin (comentor)

B Both, type 1 (T1D) and type 2 (T2D) diabetes mellitus involve the loss of functional insulin-producing beta-cell mass, where autoimmunity in T1D and apoptotic signalling in T2D are main causes for beta-cell death but their underlying mechanisms are poorly understood. In this thesis, we have investigated several interconnected signaling pathways controlling pancreatic beta-cell function and survival in diabetes. We have found that: (I) small molecule inhibitor of Hippo kinase MST1 improved beta-cell survival in human islets and in an established beta-cell line in vitro. (II) Islet-overexpression of the Hippo terminal effector YAP protects beta-cells from apoptosis triggered by multiple diabetogenic conditions. (III) mTORC1 signaling is activated in isolated islets from diabetic mouse models and its genetic and pharmacological suppression improved beta-cell function. (IV) PHLPP 1 and 2 phosphatases promote beta-cell dysfunction and death, and are regulated by mTORC1 signaling under diabetic conditions in beta-cells. These analyses confirm the importance of Hippo pathway components (MST1 and YAP) for the regulation of β-cell survival in diabetes. Also, mTORC1 has been identified as novel regulator of the PHLPP-MST1 signaling axis, which is highly activated under a diabetic milieu, suggesting a novel Hippo-dependent cellular program, regulated by PHLPP and mTOR1 signaling, which balances beta-cell homeostasis.

• Language: Slovenian
• Keywords: PHLPP1, 2/mTOR, YAP, Hippo pathway, MST1, beta-cells, pancreas, diabetes
• Work type: Master's thesis/paper
• Typology: 2.09 - Master's Thesis
• Organization: BF - Biotechnical Faculty
• Publisher: [B. Lupše]
• Year: 2017
• PID: 20.500.12556/RUL-99016
• UDC: 606:616.379-008.64:591437:577.151(043.2)
• COBISS.SI-ID: 8908665

Note

Univerzitetna Prešernova nagrada / University Prešern Award 2018

• Publication date in RUL: 21.12.2017

Secondary language

• Language: English
• Title: Identifikacija signalnih poti za uravnavanje preživetja beta-celic trebušne slinavke pri sladkorni bolezni

Abstract

I Oba tipa sladkorne bolezni, sladkorna bolezen tipa 1 (SBT1) in tipa 2 (SBT2), sta povezani z izgubo funkcionalne mase beta-celic, ki proizvajajo inzulin. Avtoimunost pri SBT1 in apoptotično signaliziranje pri SBT2 sta glavna vzroka za smrt teh celic, a so osnovni mehanizmi za to slabo poznani. V tem magistrskem delu smo preučevali več medsebojno povezanih signalnih poti, ki nadzorujejo funkcijo beta-celic in njihovo preživetje pri sladkorni bolezni. Ugotovili smo, da: (I) inhibitor Hippo kinaze MST1 izboljša preživetje in delovanje beta-celic v človeški trebušni slinavki in uveljavljeni beta-celični liniji in vitro. (II) povečana ekspresija Hippo terminalnega efektorja YAP ščiti beta-celice pred apoptozo, ki jo sprožijo razmere pri diabetesu. (III) signaliziranje mTORC1 je prekomerno aktivirano v trebušni slinavki diabetičnih miši, njegova genetska in farmakološka inaktivacija pa izboljša funkcijo β-celic. (IV) PHLPP 1 in 2 fosfataze povzročajo zmanjšano funkcijo β-celic in njihovo smrt v diabetičnih razmerah in so pozitivno regulirane preko mTORC1. Te analize potrjujejo pomembnost Hippo signalne poti (MST1 in YAP) za uravnavanje preživetja β-celic pri sladkorni bolezni. Tudi mTORC1 je bil identificiran kot nov regulator PHLPP-MST1 signalne osi, ki je močno aktivirana v diabetičnih razmerah, kar kaže na novo regulacijo Hippo poti regulirane preko PHLPP in mTOR1 signaliziranja, ki uravnava beta-celično homeostazo.

• Keywords: PHLPP1, 2/mTOR, YAP, Hippo signalna pot, MST1, beta-celice, trebušna slinavka, sladkorna bolezen