Monogenetische Formen des juvenil sich manifestierenden Diabetes: neue Schritte in Richtung β-Zellentwicklung, -funktion und -überleben.
Gastroenterologie
Zusammenfassung der Projektergebnisse
Multifactorial diabetes, as an age-related disease, is characterized by a large clinical and biological variability. At the same time, current therapy is only based on treatment of symptomatic insulin resistance and hyperglycemia but not prevention of declining mass and function of insulin-producing beta-cells. Therefore, a worrying trend of increasing prevalence urges not only for better understanding of early stage pathomechanisms but also for developing of more specific drugs and amelioration of associated comorbidities. In an international team effort, we could show that mutations in ONECUT1 play an important role during development of monogenic as well as multifactorial diabetes. Whereas mutations in ONECUT1 lead to a neonatal diabetes syndrome in homozygous patients, heterozygous carriers develop early-onset diabetes. Additionally, we demonstrated that common regulatory variants are associated with an increased risk of multifactorial T2D. In a next step, we succeeded in characterizing the possible pathomechanism by employing pluripotent stem cells featuring ONECUT1 loss-of-function and state-of-the-art in vitro pancreatic stem cell differentiation. Extensive molecular and functional analyses revealed that ONECUT1 gene mutations disturbed formation of pancreatic progenitors and initiation of the endocrine developmental program. Mechanistically, this defect originated from reduced protein binding of ONECUT1 with pancreas-specific transcription factors thereby hampering normal gene regulation and disrupting the well-controlled transcriptional network. In addition to ONECUT1, other possible candidates are currently characterized using this well-established pipeline. Our staged approach allowing genetic and functional analysis of novel diabetes genes helped us to model patient-specific genotypes and to identify novel molecular mechanisms involved in diabetes. In turn, better understanding of the transcriptional landscape in pancreatic development and disease will provide the basis for developing personalized therapy options. Identification and characterization of ONECUT1 and other candidates as novel diabetes genes are therefore particularly of clinical relevance. In addition to publications in the prestigious journals of Nature Medicine and Communications Biology, a lay summary of our work “Mutations and variants of ONECUT1 in diabetes” has been communicated in newspaper articles (Südwestpresse, 19.10.2021) and on medical webpages e.g. medwireNews (Springer Nature Group, 08.11.2021), Journal Med (20.10.2021), Biopharma Cluster (19.10.2021) and Biermann Medizin (19.10.2021). Moreover, results of our work have been acknowledged by societies such as Diabetiker Niedersachsen e.V. (06.01.2022) and other institutes such as the “Institut für Humangenetik” in Göttingen (10.2021) and the RWTH Aachen (27.10.2021).
Projektbezogene Publikationen (Auswahl)
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Human Pluripotent Stem Cells Go Diabetic: A Glimpse on Monogenic Variants. Frontiers in Endocrinology, 12.
Heller, Sandra; Melzer, Michael Karl; Azoitei, Ninel; Julier, Cécile & Kleger, Alexander
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Mutations and variants of ONECUT1 in diabetes. Nature Medicine, 27(11), 1928-1940.
Philippi, Anne; Heller, Sandra; Costa, Ivan G.; Senée, Valérie; Breunig, Markus; Li, Zhijian; Kwon, Gino; Russell, Ronan; Illing, Anett; Lin, Qiong; Hohwieler, Meike; Degavre, Anne; Zalloua, Pierre; Liebau, Stefan; Schuster, Michael; Krumm, Johannes; Zhang, Xi; Geusz, Ryan; Benthuysen, Jacqueline R. ... & Kleger, Alexander
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Transcriptional changes and the role of ONECUT1 in hPSC pancreatic differentiation. Communications Biology, 4(1).
Heller, Sandra; Li, Zhijian; Lin, Qiong; Geusz, Ryan; Breunig, Markus; Hohwieler, Meike; Zhang, Xi; Nair, Gopika G.; Seufferlein, Thomas; Hebrok, Matthias; Sander, Maike; Julier, Cécile; Kleger, Alexander & Costa, Ivan G.
