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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)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
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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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Publication type Article: Journal article
Document type Scientific Article
Keywords 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
Language english
Publication Year 2023
Prepublished in Year 2022
HGF-reported in Year 2022
ISSN (print) / ISBN 1934-5909
e-ISSN 1875-9777
Journal Cell Stem Cell
Quellenangaben Volume: 30, Issue: 1, Pages: 38-51.e8 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge, Mass.
Reviewing status Peer reviewed
Institute(s) Institute of Transl. Stem Cell Research (ITS)
POF-Topic(s) 30201 - Metabolic Health
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-506800-001
Grants 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
DOI 10.1016/j.stem.2022.12.001
WOS ID 000918714500001
Scopus ID 85145229760
PubMed ID 36563694
Erfassungsdatum 2023-01-17
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