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Hermann, F.M.* ; Kjærgaard, M.F.* ; Tian, C. ; Tiemann, U.* ; Jackson, A.* ; Olsen, L.R.* ; Kraft, M.* ; Carlsson, P.O.* ; Elfving, I.M.* ; Kettunen, J.L.T.* ; Tuomi, T.* ; Novak, I.* ; Semb, H.

An insulin hypersecretion phenotype precedes pancreatic β cell failure in MODY3 patient-specific cells.

Cell Stem Cell 30, 38-51.e8 (2023)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
MODY3 is a monogenic hereditary form of diabetes caused by mutations in the transcription factor HNF1A. The patients progressively develop hyperglycemia due to perturbed insulin secretion, but the pathogenesis is unknown. Using patient-specific hiPSCs, we recapitulate the insulin secretion sensitivity to the membrane depolarizing agent sulfonylurea commonly observed in MODY3 patients. Unexpectedly, MODY3 patient-specific HNF1A+/R272C β cells hypersecrete insulin both in vitro and in vivo after transplantation into mice. Consistently, we identified a trend of increased birth weight in human HNF1A mutation carriers compared with healthy siblings. Reduced expression of potassium channels, specifically the KATP channel, in MODY3 β cells, increased calcium signaling, and rescue of the insulin hypersecretion phenotype by pharmacological targeting ATP-sensitive potassium channels or low-voltage-activated calcium channels suggest that more efficient membrane depolarization underlies the hypersecretion of insulin in MODY3 β cells. Our findings identify a pathogenic mechanism leading to β cell failure in MODY3.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Hnf1a ; Hnf4a ; K(atp) Channel ; Mody3 ; Calcium Signaling ; Congenital Hyperinsulinemia ; Disease Modeling ; Membrane Potential ; Pancreatic β Cell ; Patient-specific Hipscs; Beta-cells; Congenital Hyperinsulinism; Glucose; Hnf1a; Young; Expression; Mutations; Diagnosis; Gene; Hypoglycemia
ISSN (print) / ISBN 1934-5909
e-ISSN 1875-9777
Zeitschrift Cell Stem Cell
Quellenangaben Band: 30, Heft: 1, Seiten: 38-51.e8 Artikelnummer: , Supplement: ,
Verlag Cell Press
Verlagsort Cambridge, Mass.
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Transl. Stem Cell Research (ITS)
Förderungen Helmholtz Zentrum Munchen
Danmarks Frie Forskningsfond
Novo Nordisk Foundation Center for Stem Cell Biology , University of Copenhagen
Medical Sciences
Lund Stem Cell Center , Stem Therapy , Lund University