ULB Center for Diabetes Research

Pathogenesis of Type 2 Diabetes and Monogenic Forms of Diabetes

Group Leader: Prof Miriam Cnop

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In the Endocrine Division of the Erasmus Hospital Miriam Cnop has an active endocrine outpatient clinic, with a particular focus on clinical care of diabetic patients.

 

Group Leader, Prof. Miriam Cnop

Miriam Cnop obtained her MD degree at the Vrije Universiteit Brussel in 1995, was trained in Internal Medicine and Endocrinology in Brussels and obtained a PhD degree at the Vrije Universiteit Brussel in 2002 for her work on the effects of lipoproteins and free fatty acids on pancreatic β cells. She worked as a postdoctoral fellow with Steven Kahn at the University of Washington, Seattle, studying the relative contribution of insulin resistance and β cell dysfunction in the pathogenesis of type 2 diabetes. She currently holds appointments as Professor and Clinical Director of the Erasmus Hospital, and Chargé de Cours/Associate Professor of the Faculty of Medicine, Université Libre de Bruxelles.

 

Research Interests

In the Endocrine Division of the Erasmus Hospital Miriam Cnop has an active endocrine outpatient clinic, with a particular focus on clinical care of diabetic patients. Her interests lie in the early and accurate diagnosis of type 1 diabetes, type 2 diabetes and monogenic forms of diabetes, in order to tailor treatment choices. Using phenotyping and genotyping approaches, personalized treatment is proposed as a function of diabetes etiology. The clinical work and observations provide a basis for her translational research. She also co-directs the obesity clinic that provides comprehensive patient phenotyping and lifestyle, endoscopic and surgical treatment choices.

The principle research interests of the Cnop group are the role of pancreatic β cell dysfunction and apoptosis in the pathogenesis of type 2 diabetes and monogenic forms of diabetes, in order to develop novel strategies to improve functional β cell mass. The Cnop group has identified endoplasmic reticulum (ER) stress as an important cellular response contributing to free fatty acid-induced β cell apoptosis. The monogenic forms of diabetes under study in her group include diseases due to mutations in genes with a role in ER stress, mitochondrial function and tRNA biology. The Cnop group demonstrated that β cell dysfunction and death are central in the pathogenesis of diabetes in Friedreich ataxia, a mitochondrial neurodegenerative disease. She identified new forms of diabetes caused by mutations in TRMT10A, a tRNA methyl transferase, PPP1R15B, a regulator of ER stress signaling, and RFX6, a transcription factor regulating incretin secretion and β cell function. To gain further insight into the pathways of β cell failure in diabetes and to test novel therapies, she has recently established an induced pluripotent stem cell facility: the differentiation of patient-derived stem cells into human pancreatic β cells provides a highly relevant disease-in-a-dish model, opening a range of new research avenues.

Honours & Awards

  • 2003 Endocrinology Research Prize by the Royal Academy of Science of Belgium
  • 2004 Novo Nordisk Prize for Diabetology, Belgium
  • 2005 Rising Star of the European Association for the Study of Diabetes
  • 2010 Belgian Endocrine Society Annual Award
  • 2010 GB Morgagni Young Investigator Award, awarded under the auspices of the School of Medicine of the University of Padua, Italy
  • 2013 Oskar Minkowski Award of the European Association for the Study of Diabetes, the most important award for a European diabetes researcher under the age of 45 years
  • 2014 Auguste Loubatieres Prize of the French Diabetes Society
  • 2017 Associate Member of the Royal Academy of Medicine of Belgium

Selected Publications

  1. Cnop M, Havel PJ, Utzschneider KM, Carr DB, Sinha MK, Boyko EJ, Retzlaff BM, Knopp RH, Brunzell JD and Kahn SE. Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia 2003, 46:459-469. [Impact factor (IF) 5.7; NIH Relative Citation Ratio (RCR) 24.3]
  2. Cnop M, Vidal J, Hull RL, Utzschneider KM, Carr DB, Schraw T, Scherer PE, Boyko EJ, Fujimoto WY and Kahn SE. Progressive loss of β-cell function leads to worsening glucose tolerance in first-degree relatives of subjects with type 2 diabetes. Diabetes Care 2007, 30:677-682. [IF 7.9; RCR 2.7]
  3. Cunha DA, Hekerman P, Ladrière L, Bazarra-Castro A, Ortis F, Wakeham MC, Moore F, Rasschaert J, Cardozo AK, Bellomo E, Overbergh L, Mathieu C, Lupi R, Hai T, Herchuelz A, Marchetti P, Rutter GA, Eizirik DL and Cnop M. Initiation and execution of lipotoxic ER stress in pancreatic beta cells. J Cell Sci 2008, 121:2308-2318. [IF 6.2; RCR 9.1]
  4. Cnop M, Hughes SJ, Igoillo-Esteve M, Hoppa MB, Sayyed F, van de Laar L, Gunter JH, de Koning EJP, Walls GV, Gray DWG, Johnson PRV, Hansen BC, Morris JF, Pipeleers-Marichal M, Cnop I and Clark A. The long lifespan and low turnover of human islet beta cells estimated by mathematical modelling of lipofuscin accumulation. Diabetologia 2010, 53:321-330. [IF 7.0; RCR 3.5]
  5. Volkmar M, Dedeurwaerder S, Cunha DA, Ndlovu MN, Defrance M, Deplus R, Calonne E, Volkmar U, Igoillo-Esteve M, Naamane N, Del Guerra S, Masini M, Bugliani M, Marchetti P, Cnop M, Eizirik DL and Fuks F. DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients. EMBO J 2012, 31:1405-1426. [IF 9.8; RCR 8.6]
  6. Cnop M, Igoillo-Esteve M, Rai M, Begu A, Serroukh Y, Depondt C, 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. Ann Neurol 2012, 72:971-982. [IF 11.2; RCR 1.4]
  7. Igoillo-Esteve M, Genin A, Lambert N, Desir 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 and Cnop M. tRNA methyltransferase homolog gene TRMT10A mutation in young onset diabetes and primary microcephaly in humans. PLoS Genet 2013, 9:e1003888. [IF 8.2; RCR 1.4]
  8. 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 and Eizirik DL. RNA sequencing identifies dysregulation of the human pancreatic islet transcriptome by the saturated fatty acid palmitate. Diabetes 2014, 63:1978-1993. [IF 8.1; RCR 5.6]
  9. Fjeld K, Weiss FU, Lasher D, Rosendahl J, Chen JM, Johansson BB, Kirsten H, Ruffert C, Masson E, Steine SJ, Bugert P, Cnop M, Grützmann R, Mayerle J, Mössner J, Ringdal M, Schulz HU, Sendler M, Simon P, Sztromwasser P, Torsvik J, Scholz M, Tjora E, Férec C, Witt H, Lerch MM, Njølstad PR, Johansson S and Molven A. A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis. Nat Genet 2015, 47:518-522. [IF 31.6; RCR 5.1]
  10. Patel KA, Kettunen J, Laakso M, Stančáková A, Laver TW, Colclough K, Johnson MB, Abramowicz M, Groop L, Miettinen PJ, Sheppard MH, Flanagan SE, Ellard S, Inagaki N, Hattersley AT, Tuomi T, Cnop M* and Weedon MN*. Heterozygous RFX6 protein truncating variants are associated with Maturity-Onset Diabetes of the Young (MODY) with reduced penetrance. Nat Commun 2017, 8:888. *shared last/corresponding author