Molecular Mechanisms of Polygenic and Monogenic Diabetes
Group Leader: Prof. Mariana Igoillo-Esteve
Group Leader: Prof. Mariana Igoillo-Esteve
Mariana Igoillo-Esteve obtained her Biochemistry degree in 1999 at the Faculty of Pharmacy and Biochemistry, University of Buenos Aires (UBA) Argentina; and her PhD in Molecular Biology and Biotechnology in 2005 at the IIB/INTECH-CONICET, National University of General San Martin, Argentina. During her PhD training and first post-doc at the De Duve Institute, Université Catholique de Louvain, Belgium, she studied the metabolism of trypanosomatid parasites causing Chagas disease, Leishmaniasis, and sleeping sickness. In 2007, she shifted her research interest to human metabolism and joined the ULB Center for Diabetes Research (UCDR), Université Libre de Bruxelles (ULB), headed by Prof. Decio Eizirik where she studied the molecular mechanism of pancreatic β-cell dysfunction and death in monogenic and polygenic forms of diabetes. In 2016 she was appointed Chargé de Cours/Associate Professor of the Faculty of Medicine, Université Libre de Bruxelles.
Mariana Igoillo-Esteve's research is focused on the study of the molecular mechanisms of β-cell dysfunction and death in type 2 diabetes and monogenic forms of diabetes, with the ultimate goal to identify novel strategies to prevent β-cell demise. Specifically, she studies the loss of functional β-cell mass related to endoplasmic reticulum stress and altered tRNA modifications, two biological pathways contributing to β-cell failure in monogenic and type 2 diabetes. The monogenic forms of diabetes can be considered as “human knockout” models for specific pathways/functions. The elucidation of disease mechanisms in these rare forms of diabetes contributes to further the understanding of β-cell failure in polygenic type 1 and type 2 diabetes, and to propose tailored therapeutic strategies.
The Igoillo-Esteve group studies potential therapeutic approaches, based on drug repurposing, for diabetes in Wolfram syndrome, a monogenic form of diabetes caused by mutations in the endoplasmic reticulum stress gene WFS1. This project involves drug testing in in vitro and in vivo models of WFS1 deficiency including RNAi-mediated gene silencing in human β-cells, WFS1 KO mice, and a humanized mouse model generated by transplantation of iPSC-derived β-cells from WFS1-deficient patients under the kidney capsule of immunodeficient mice. This last approach allows to evaluate the impact of prolonged treatments in human β-cells.
Her team also studies the molecular mechanisms underlying cellular demise in a syndrome of young onset diabetes and microcephaly, caused by nonsense mutations in the tRNA methyltransferase TRMT10A. Her recent findings indicate that tRNA methylation is essential for β-cell survival, and that hypomodified tRNAs are prone to enzymatic cleavage leading to tRNA fragment generation. tRNA halves and smaller tRNA fragments are a new class of small non-coding RNAs that modulate a number of cellular processes by inhibiting translation or transcription of specific mRNAs. Dr Igoillo-Esteve showed that tRNA glutamine fragments mediate pancreatic β-cell apoptosis under TRMT10A deficiency. This constitutes a completely novel mechanism of pancreatic β-cell demise in diabetes. Through high quality, innovative and disease-relevant research Dr Igoillo-Esteve is expanding knowledge on tRNA biology in pancreatic β-cells and shedding light on this new pathway of β-cell failure, relevant to monogenic and polygenic forms of diabetes.
2018 Young Investigator Award of the Belgian Endocrine society
2016 Laureate of the Funds for Health Research, King Baudouin Foundation
2013 Young Investigator Award of the Belgian Endocrine Society
2011 Young Investigator Award of the Belgian Endocrine Society
Cosentino C, Toivonen S, Diaz Villamil E, Atta M, Ravanat JL, Demine S, Schiavo AA, Pachera N, Deglasse JP, Jonas JC, Balboa D, Otonkoski T, Pearson ER, Marchetti P, Eizirik DL, Cnop M, Igoillo-Esteve M. Pancreatic β-cell tRNA hypomethylation and fragmentation link TRMT10A deficiency with diabetes. Nucleic Acids Res. 2018; 46(19):10302-10318.
Cnop M, Toivoneen S, Igoillo-Esteve M, Salpea P. Endoplasmic reticulum stress and eIF2 alpha phosphorylation: the Achilles heel of pancreatic beta cells. Molecular Metabolism. 2017; 6(9), 1024-1039.
Abdulkarim B, Nicolino M, Igoillo-Esteve M, Daures M, Romero S, Philippi A, Senée V, Lopes, M, Cunha D, Harding H, Derbois C, Bendelac N, Hattersley A, 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): 3951-62.
Igoillo-Esteve M, Gurgul-Convey, Hu A, Romagueira Bichara Dos Santos L, Abdulkarim B, Chintawar S, Marselli L, Marchetti P, Jonas JC, Eizirik DL, Pandolfo M, Cnop M. Unveiling a common mechanism of apoptosis in β-cells and neurons in Friedreich’s ataxia. Human Mol. Genet. 2015; 24(8): 2274-86.
Cnop M, Abdulkarim B, Bottu G, Cunha DA, Igoillo-Esteve M, Masini M, Turatsinze JV, Griebel T, Villate O, Santin I, Bugliani M, Ladriere L, Marselli L, McCarthy MI, Marchetti P, Sammeth M, Eizirik DL. RNA-sequencing identifies dysregulation of the human pancreatic islet transcriptome by the saturated fatty acid palmitate. Diabetes. 2014; 63:1978-93.
Igoillo-Esteve M, Genin A, Lambert N, Désir J, Pirson I, Abdulkarim B, Simonis N, Drielsma A, Marselli L, Marchetti P, Vanderhaeghen P, Eizirik DL, Wuyts W, Julier C, Chakera AJ, Ellard S, Hattersley AT, Abramowicz M, Cnop M. tRNA methyltransferase homolog gene TRMT10A mutation in young onset diabetes and primary microcephaly in humans. PLoS Genet. 2013; 9(10): doi:10.1371.
Cnop M, Mulder H, Igoillo-Esteve M. Diabetes in Friedreich Ataxia. Journal of Neurochemistry. 2013; 126 (Suppl. 1): 94-102.
Cunha DA, Igoillo-Esteve M, Gurzov EN, Germano CM, Naamane N, Marhfour I, Fukaya M, Vanderwinden JM, Gysemans C, Mathieu Ch, Marselli L, Marchetti P, Eizirik DL, Cnop M. DP5 and Puma mediate the ER stress-mitochondrial dialog triggering lipotoxic rodent and human β-cell apoptosis. Diabetes. 2012; 61(11):2763-75.
Cnop M*, Igoillo-Esteve M*, Rai M, Begu A, Serroukh Y, Depondt Ch, Musuaya AE, Marhfour I, Ladrière L, Moles Lopez X, Lefkaditis D, Moore F, Brion JP, Cooper JM, Schapira AHV, Clark A, Koeppen AH, Marchetti P, Pandolfo M, Eizirik DL, and Féry F. Central role and mechanisms of β-cell dysfunction and death in Friedreich ataxia- associated diabetes. Annals of Neurology. 2012; 72: 971-82 *Shared first authorship.
Igoillo-Esteve M, Marselli L, Cunha DA, Ladrière L, Ortis F, Grieco FA, Dotta F, Weir GC, Marchetti P, Eizirik DL, Cnop M. Palmitate induces a pro-inflammatory response in human pancreatic islets that mimics CCL2 expression by β-cells in type 2 diabetes. Diabetologia. 2010; 53(7): 1395-405.