Search: WFRF:(Olsen Lars Rønn)
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An insulin hypersec...
An insulin hypersecretion phenotype precedes pancreatic β cell failure in MODY3 patient-specific cells
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- Hermann, Florian M. (author)
- University of Copenhagen
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- Kjærgaard, Maya Friis (author)
- University of Copenhagen
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- Tian, Chenglei (author)
- University of Copenhagen,Helmholtz Zentrum München
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- Tiemann, Ulf (author)
- University of Copenhagen
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- Jackson, Abigail (author)
- University of Copenhagen
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- Olsen, Lars Rønn (author)
- Technical University of Denmark
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- Kraft, Maria (author)
- Lund University,Lunds universitet,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine,Faculty of Medicine
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- Carlsson, Per Ola (author)
- Uppsala University
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- Elfving, Iina M. (author)
- Folkhälsan Research Center
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- Kettunen, Jarno L.T. (author)
- Helsinki University Central Hospital,Folkhälsan Research Center,University of Helsinki
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- Tuomi, Tiinamaija (author)
- Helsinki University Central Hospital,University of Helsinki,Folkhälsan Research Center
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- Novak, Ivana (author)
- University of Copenhagen
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- Semb, Henrik (author)
- Helmholtz Zentrum München,University of Copenhagen
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(creator_code:org_t)
- Elsevier BV, 2023
- 2023
- English.
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In: Cell Stem Cell. - : Elsevier BV. - 1934-5909. ; 30:1, s. 8-51
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Abstract
Subject headings
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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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
Keyword
- calcium signaling
- congenital hyperinsulinemia
- disease modeling
- HNF1A
- HNF4A
- K channel
- membrane potential
- MODY3
- pancreatic β cell
- patient-specific hiPSCs
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Hermann, Florian ...
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Kjærgaard, Maya ...
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Tian, Chenglei
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Tiemann, Ulf
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Jackson, Abigail
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Olsen, Lars Rønn
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Kraft, Maria
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Carlsson, Per Ol ...
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Elfving, Iina M.
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Kettunen, Jarno ...
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Tuomi, Tiinamaij ...
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Novak, Ivana
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Semb, Henrik
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Endocrinology an ...
- Articles in the publication
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Cell Stem Cell
- By the university
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Lund University