{"id":120,"date":"2022-05-24T11:37:55","date_gmt":"2022-05-24T11:37:55","guid":{"rendered":"https:\/\/web.ucdr.be\/wordpress\/\/?page_id=120"},"modified":"2024-05-08T10:55:16","modified_gmt":"2024-05-08T08:55:16","slug":"molecular-mechanisms-of-polygenic-and-monogenic-diabetes","status":"publish","type":"page","link":"https:\/\/www.ucdr.be\/index.php\/molecular-mechanisms-of-polygenic-and-monogenic-diabetes\/","title":{"rendered":"MOLECULAR MECHANISMS OF POLYGENIC AND MONOGENIC DIABETES"},"content":{"rendered":"\t\t
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Molecular mechanisms of polygenic and monogenic diabetes<\/h2>\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t
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GROUP LEADER: PROF. MARIANA IGOILLO-ESTEVE<\/h2>\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t
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Mariana Igoillo-Esteve\u2019s research is focused on the study of the molecular mechanisms of \u03b2-cell dysfunction and death in type 2 diabetes and monogenic forms of diabetes, with the ultimate goal to identify novel strategies to prevent \u03b2-cell demise.<\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t

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Group Leader, Prof. Mariana Igoillo-Esteve<\/h2>\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t
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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. She is currently Associate Professor at the ULB Center for Diabetes Research, Medical Faculty, Universit\u00e9 Libre de Bruxelles (ULB), Belgium. She has published 46 full papers and reviews in peer-reviewed international journals that have been cited more than 3800 times. She has an h-index of 27 and has received several honors and awards.<\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t

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Research Interests<\/h2>\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t
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Pathogenic mutations in a large number of genes cause diabetes and neuronal demise, pointing to shared critical pathways between pancreatic \u03b2-cells and neurons that are needed for their proper function and survival. Mariana Igoillo-Esteve studies the molecular mechanisms of \u03b2-cell and neuronal dysfunction and death in monogenic forms of diabetes with syndromic presentations, with the ultimate goal to identify novel strategies to prevent \u03b2-cell and neuronal demise. The monogenic forms of diabetes can be considered as \u201chuman knockout\u201d models for specific pathways\/functions. The elucidation of disease mechanisms in these rare forms of diabetes contributes to further the understanding of \u03b2-cell failure in polygenic type 1 and type 2 diabetes, and to propose tailored therapeutic strategies. Specifically, Igoillo-Esteve studies the loss of functional \u03b2-cell mass related to endoplasmic reticulum stress and altered tRNA modifications, two biological pathways contributing to \u03b2-cell failure in monogenic, type 1 and type 2 diabetes. She also studies the impact of these altered pathways in neuronal differentiation, function and survival.\u00a0<\/p>

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Of note, the Igoillo-Esteve\u2019s group studies potential therapeutic approaches, based on drug repurposing, for diabetes and neurodegeneration in Wolfram syndrome, a monogenic form of diabetes caused by mutations in the endoplasmic reticulum stress gene WFS1. This project involves drug testing in\u00a0in vitro<\/em>\u00a0and\u00a0in vivo<\/em>models of WFS1 deficiency including RNAi-mediated gene silencing in human \u03b2-cells, WFS1 knockout mice, and a humanized mouse model for the disease generated by transplanting iPSC-derived \u03b2-cells from WFS1-deficient patients under the kidney capsule of immunodeficient mice. The latter approach allows us to evaluate the impact of prolonged treatments in human \u03b2-cells. The group is also currently testing the impact of selected repurposed drugs in iPSC-derived neuronal models of Wolfram syndrome.<\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t

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Insulin (green) and glucagon (red) staining of a pancreatic islet from a wildtype mouse.<\/div><\/div><\/div><\/div>
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Beta tubulin III staining of induced pluripotent stem cell-derived cerebellar neurons from a person with Wolfram syndrome.<\/div><\/div><\/div><\/div>
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Insulin (green) and glucagon (red) staining of a pancreatic islet from a WFS1 knockout mouse, a mouse model of Wolfram syndrome.<\/div><\/div><\/div><\/div>\t\t\t\t<\/div>\n\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t
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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 \u03b2-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 \u03b2-cell apoptosis under TRMT10A deficiency. This constitutes a completely novel mechanism of pancreatic \u03b2-cell demise in diabetes. Through high quality, innovative and disease-relevant research Dr Igoillo-Esteve is expanding knowledge on tRNA biology in pancreatic \u03b2-cells and shedding light on this new pathway of \u03b2-cell failure, relevant to monogenic and polygenic forms of diabetes. Currently she is also studying the association between TRMT10A deficiency and microcephaly aiming to shed light on the impact of tRNA hypomethylation and fragmentation on neuronal differentiation, function and survival.\u00a0<\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t

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Honours & Awards<\/h2>\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t
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  • 2018<\/strong> Young Investigator Award of the Belgian Endocrine society<\/p><\/li>

  • 2016<\/strong> Laureate of the Funds for Health Research, King Baudouin Foundation<\/p><\/li>

  • 2013<\/strong> Young Investigator Award of the Belgian Endocrine Society<\/p><\/li>

  • 2011<\/strong> Young Investigator Award of the Belgian Endocrine Society<\/p><\/li><\/ul>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t

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    Selected Publications<\/h2>\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t
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    1. Shah S, Dooms M.M, Amaral-Garcia S, Igoillo-Esteve M<\/strong>. Current drug repurposing strategies for rare neurodegenerative disorders. Frontiers in Pharmacology. 2021. Vol 12. doi:10.3389\/fphar.2021.768023. IF: 4.4.<\/p><\/li>

    2. Sanchez-Caballero, Gorgogietas V, Arroyo MN, Igoillo-Esteve M<\/strong>. Molecular mechanisms of \u03b2-cell dysfunction and death in monogenic forms of diabetes. Int Rev Cell Mol Biol. 2021<\/strong>. Vol 359.139-256. doi:10.1016\/bs.ircmb.2021.02.005 (Book Chapter). IF: 3.79.<\/p><\/li>

    3. Arroyo MN, Green JA, Cnop M, Igoillo-Esteve M<\/strong>. tRNA Biology in the Pathogenesis of Diabetes: Role of Genetic and Environmental Factors. Int. J Mol Sci. 2021<\/strong>. 22, 1-27, 496.<\/strong> doi: 10.3390\/ijms22020496. IF: 4.07<\/p><\/li>

    4. \u00a0Lytrivi M, Sen\u00e9e V, Salpea P, Fantuzzi F, Philippi A, Abdulkarim B, Sawatani T, Mar\u00edn-Ca\u00f1as S, Pachera N, Degavre A, Singh P, Derbois C, Lechner D, Ladri\u00e8re L, Igoillo-Esteve M<\/strong>, Cosentino C, Marselli L, Deleuze JF, Marchetti P, Eizirik DL, Nicolino M, Chaussenot A, Julier C, Cnop M. DNAJC3 deficiency induces \u03b2-cell mitochondrial apoptosis and causes syndromic young-onset diabetes. Eur J Endocrinol.<\/em> 2021<\/strong> 184(3):459-472. doi: 10.1530\/EJE-20-0636. IF. 5.107.<\/p><\/li>

    5. De Franco E, Lytrivi M, Ibrahim H, Montaser H, Wakeling M, Fantuzzi F, Patel K, Demarez C, Cai Y,\u00a0Igoillo-Esteve M<\/strong>, Cosentino C, Lithovius V, Vihinen H, Jokitalo E, Laver TH, Johnson MB, Sawatani T, Shakeri H, Pachera N, Halioglu B, Ozbek MN, Unal E, Yildirim R, Godbole T, Yildiz M, Aydin B, Bilheu A, Suzuki I, Flanagan SE, Vanderhaeghen P, Senee V, Julier C, Marchetti P, Eizirik DL, Ellard S, Saarimaki-Vire J, Otonkoski T, Cnop M, Hattersley AT YIPF5 mutations cause diabetes and microcephaly through disrupted ER-to-Golgi trafficking. J Clin Invest,\u00a02020<\/strong>. \u201cin press\u201d. IF: 11.86<\/p><\/li>

    6. Igoillo-Esteve M<\/strong>, Oliveira AF, Cosentino C, Fantuzzi F, Demarez C, Toivonen S, Hu A, Chintawar S, Lopes M, Pachera N, Cai Y, Abdulkarim B, Rai M, Marselli L, Marchetti P, Tariq M, Jonas JC, Boscolo M, Pandolfo M, Eizirik DL, Cnop M. Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia. JCI Insight. 2020 Jan 30;5(2):e134221. doi: 10.1172\/jci.insight.134221. IF: 6.01.<\/p><\/li>

    7. Cosentino C, Cnop M,\u00a0Igoillo-Esteve, M<\/strong>. The tRNA epitranscriptome and diabetes: emergence of tRNA hypomodifications as a cause of pancreatic \u03b2-cell failure. Endocrinology. Accepted for publication March 15th\u00a0\u00a02019<\/strong>. doi: 10.1210\/en.2019-00098 IF: 3.961, Q2. Cited 4 times.<\/p><\/li>

    8. Cosentino C, Toivonen S, Diaz Villamil E, Atta M, Ravanat JL, Demine S, Schiavo A, Pachera N, Deglasse JP, Jonas JC, Balboa D, Otonkoski T, Pearson ER, Marchetti P, Eizirik DL, Cnop M and\u00a0Igoillo-Esteve M.<\/strong>\u00a0Pancreatic\u00a0\u03b2-cell tRNA hypomethylation and fragmentation link TRMT10A deficiency with diabetes. Nucleic Acids Res.\u00a02018<\/strong>; 46(19):10302-10318. doi: 10.1093\/nar\/gky839. IF:11.561, Q1. Cited 15 times.<\/p><\/li>

    9. Cnop M, Toivoneen S,\u00a0Igoillo-Esteve M<\/strong>, Salpea P. Endoplasmic reticulum stress and eIF2 alpha phosphorylation: the Achilles heel of pancreatic beta cells. Molecular Metabolism. 2017. 6(9), 1024-1039. doi: 10.1016\/j.molmet.2017<\/strong>.06.001. IF:6.291, Q1. Cited 49 times<\/p><\/li>

    10. Igoillo-Esteve M,\u00a0<\/strong>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 \u03b2-cells and neurons in Friedreich\u2019s ataxia.\u00a0\u00a0Human Mol. Genet.\u00a02015<\/strong>;\u00a024(8): 2274-86. IF: 5.985, Q1. Cited 34 times.<\/p><\/li>

    11. Abdulkarim B, Nicolino M,\u00a0Igoillo-Esteve M<\/strong>, Daures M, Romero S, Philippi A, Sen\u00e9e 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\u00a02015<\/strong>; 64(11): 3951-62. IF:8.784,Q1. Cited 32 times.<\/p><\/li>

    12. Cnop M, Abdulkarim B, Bottu G, Cunha DA,\u00a0Igoillo-Esteve M<\/strong>, 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.\u00a02014<\/strong>; 63:1978-93.\u00a0\u00a0IF:8.095, Q1. Cited 119 times<\/p><\/li>

    13. Igoillo-Esteve M,\u00a0<\/strong>Genin A, Lambert N, D\u00e9sir 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.\u00a02013<\/strong>; 9(10): doi:10.1371. IF: 8.167, Q1. Cited 50 times<\/p><\/li>

    14. Cnop M*,\u00a0Igoillo-Esteve M*<\/strong>, Rai M, Begu A, Serroukh Y, Depondt Ch, Musuaya AE, Marhfour I, Ladri\u00e8re L, Moles Lopez X, Lefkaditis D, Moore F, Brion JP,<\/strong>\u00a0Cooper JM, Schapira AHV, Clark A, Koeppen AH, Marchetti P, Pandolfo M, Eizirik DL, and F\u00e9ry F. Central role and mechanisms of\u00a0\u03b2-cell dysfunction and death in Friedreich ataxia-\u00a0associated diabetes. Annals of Neurology.\u00a02012<\/strong>; 72: 971-82\u00a0*Shared first authorship. IF:11.193, Q1. Cited 44 times.<\/p><\/li>

    15. Cunha DA,\u00a0Igoillo-Esteve M<\/strong>, 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 \u03b2-cell apoptosis. Diabetes. 2012; 61(11):2763-75. IF:7.895, Q1. Cited 41 times<\/p><\/li>

    16. Ladri\u00e8re L*,\u00a0Igoillo-Esteve M*<\/strong>,\u00a0<\/strong>Cunha DA, Brion JP, Bugliani M, Marchetti P, Eizirik DL, Cnop M.\u00a0<\/strong>Enhanced signaling downstream of ribonucleic acid-activated protein kinase-like endoplasmic reticulum kinase potentiates lipotoxic endoplasmic reticulum stress in human islets. The Journal of Clinical Endocrinology and Metabolism.\u00a02010<\/strong>; 95 (3): 1442-9.\u00a0*Shared first authorship. IF:6.495, Q1. Cited 44 times.<\/p><\/li><\/ol>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<\/div>\n\t\t","protected":false},"excerpt":{"rendered":"

      Molecular mechanisms of polygenic and monogenic diabetes GROUP LEADER: PROF. MARIANA IGOILLO-ESTEVE Mariana Igoillo-Esteve\u2019s research is focused on the study of the molecular mechanisms of \u03b2-cell dysfunction and death in type 2 diabetes and monogenic forms of diabetes, with the ultimate goal to identify novel strategies to prevent \u03b2-cell demise. Group Leader, Prof. Mariana Igoillo-Esteve […]<\/p>\n","protected":false},"author":1,"featured_media":0,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"elementor_header_footer","meta":{"footnotes":""},"class_list":["post-120","page","type-page","status-publish","hentry"],"_links":{"self":[{"href":"https:\/\/www.ucdr.be\/index.php\/wp-json\/wp\/v2\/pages\/120","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.ucdr.be\/index.php\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/www.ucdr.be\/index.php\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/www.ucdr.be\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.ucdr.be\/index.php\/wp-json\/wp\/v2\/comments?post=120"}],"version-history":[{"count":29,"href":"https:\/\/www.ucdr.be\/index.php\/wp-json\/wp\/v2\/pages\/120\/revisions"}],"predecessor-version":[{"id":1412,"href":"https:\/\/www.ucdr.be\/index.php\/wp-json\/wp\/v2\/pages\/120\/revisions\/1412"}],"wp:attachment":[{"href":"https:\/\/www.ucdr.be\/index.php\/wp-json\/wp\/v2\/media?parent=120"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}