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Marselli, L.* ; Piron, A.* ; Suleiman, M.* ; Colli, M.L.* ; Yi, X.* ; Khamis, A.* ; Carrat, G.R.* ; Rutter, G.A.* ; Bugliani, M.* ; Giusti, L.* ; Ronci, M.* ; Ibberson, M.* ; Turatsinze, J.V.* ; Boggi, U.* ; De Simone, P.* ; De Tata, V.* ; Lopes, M.* ; Nasteska, D.* ; De Luca, C.* ; Tesi, M.* ; Bosi, E.* ; Singh, P.* ; Campani, D.* ; Schulte, A.M.* ; Solimena, M. ; Hecht, P.* ; Rady, B.* ; Bakaj, I.* ; Pocai, A.* ; Norquay, L.* ; Thorens, B.* ; Canouil, M.* ; Froguel, P.* ; Eizirik, D.L.* ; Cnop, M.* ; Marchetti, P.*

Persistent or transient human β cell dysfunction induced by metabolic stress: Specific signatures and shared gene expression with type 2 diabetes.

Cell Rep. 33:108466 (2020)

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	Open Access Gold

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Pancreatic β cell failure is key to type 2 diabetes (T2D) onset and progression. Here, we assess whether human β cell dysfunction induced by metabolic stress is reversible, evaluate the molecular pathways underlying persistent or transient damage, and explore the relationships with T2D islet traits. Twenty-six islet preparations are exposed to several lipotoxic/glucotoxic conditions, some of which impair insulin release, depending on stressor type, concentration, and combination. The reversal of dysfunction occurs after washout for some, although not all, of the lipoglucotoxic insults. Islet transcriptomes assessed by RNA sequencing and expression quantitative trait loci (eQTL) analysis identify specific pathways underlying β cell failure and recovery. Comparison of a large number of human T2D islet transcriptomes with those of persistent or reversible β cell lipoglucotoxicity show shared gene expression signatures. The identification of mechanisms associated with human β cell dysfunction and recovery and their overlap with T2D islet traits provide insights into T2D pathogenesis, fostering the development of improved β cell-targeted therapeutic strategies.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Beta Cells ; Damage ; Endoplasmic Reticulum Stress ; Eqtl ; Glucolipotoxicity ; Human Pancreatic Islets ; Lipoglucotoxicity ; Recovery ; Transcriptome ; Type 2 Diabetes

ISSN (print) / ISBN 2211-1247

e-ISSN 2211-1247

Journal Cell Reports

Quellenangaben Volume: 33, Issue: 9, Article Number: 108466

Publisher Cell Press

Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Pancreatic Islet Research (IPI)

Grants Wellcome Investigator Award
Leona M. and Harry B. Helmsley Charitable Trust
JDRF
EFPIA
Union's Horizon 2020 research and innovation programme
Innovative Medicines Initiative 2 Joint Undertaking
Swiss State Secretariat for Education, Research, and Innovation (SERI)
European Union's Horizon 2020 research and innovation programme, EFPIA
Innovative Medicines Initiative 2 Joint Undertaking Rhapsody
European Union's Horizon 2020 research and innovation programme, project T2DSystems
Italian Ministry of University and Research (PRIN 2017)
MRC (UK) Programme grant
Agence Nationale de la Recherche (ANR EQUIPEX Ligan), France
Agence Nationale de la Recherche, France
Societe Francophone du Diabete
Centre National de la Recherche Scientifique
Brussels Region Innoviris project DiaType, Belgium
Welbio
Fonds National de la Recherche Scientifique (FNRS)
Janssen Research & Development, Philadelphia, PA