The eukaryotic translation initiation factor 2, a hero turned
villain in β cells
By
Baroj Abdulkarim
Université libre de Bruxelles
Faculty of Medicine
ULB Center for Diabetes Research
Academic year 2016-2017
Jury Members:
Dr. Ingrid Langer (President)
Dr. Miriam Cnop (Promoter and secretary) Dr. Mariana Igoillo Esteve (Co-Promoter) Dr. Daniel Christophe
3
Contents
Papers constituting this thesis ... 4
Abbreviations ... 5
Abstract ... 8
Résumé ... 9
Introduction ... 10
Diabetes mellitus ... 10
How β cells work ... 11
Type 2 and monogenic diabetes ... 12
Free fatty acids and diabetes ... 14
Acute exposure to FFAs: enhanced β cell function ... 15
Prolonged exposure to saturated FFAs: Lipotoxicity-induced ER stress ... 17
The unfolded protein response ... 17
Dysregulation of PERK/eIF2α pathway in diabetes ... 22
β cell apoptosis ... 24
The extrinsic pathway ... 26
The intrinsic pathway ... 26
Aims of this thesis ... 29
Results... 30
PAPER I ... 30
PAPER II ... 48
PAPER III ... 62
Discussion ... 84
Diseases caused by dysregulated ER stress signaling ... 88
Not only β cells ... 88
Models of PERK/eIF2α pathway ... 90
Treating ER stress ... 91
Conclusions and perspectives ... 92
Acknowledgements ... 95
References ... 96
4
Papers constituting this thesis
1. Cnop M, Abdulkarim B, Bottu G, Cunha DA, Masini M, Turatsinze JV, Griebel T, Igoillo-Esteve M, Bugliani M, Villate O, Ladriere L, Marselli L, Marchetti P, McCarthy MI, Sammeth M, Eizirik DL; RNA-sequencing identifies dysregulation of the human pancreatic islet transcriptome by the saturated fatty acid palmitate. Diabetes, 2013, 63, 6, 1978-1993
2. Abdulkarim B, Nicolino M, Igoillo-Esteve M, Daures M, Romero S, Philippi A, Senée V, Lopes M, Cunha DA, Harding HP, Derbois C, Bendelac N, Hattersley AT, Eizirik DL, Ron D, Cnop M, Julier C; A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly. Diabetes. 2015, 64, 11, 3951-3962.
