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An insulin hypersec...
An insulin hypersecretion phenotype precedes pancreatic beta cell failure in MODY3 patient-specific cells
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- Hermann, Florian M. (author)
- Univ Copenhagen, Novo Nordisk Fdn Ctr Stem Cell Biol DanStem, Copenhagen, Denmark.
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- Kjaergaard, Maya Friis (author)
- Univ Copenhagen, Novo Nordisk Fdn Ctr Stem Cell Biol DanStem, Copenhagen, Denmark.
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- Tian, Chenglei (author)
- Univ Copenhagen, Novo Nordisk Fdn Ctr Stem Cell Biol DanStem, Copenhagen, Denmark.;Helmholtz Zent Munchen, Helmholtz Diabet Ctr, Inst Translat Stem Cell Res, Munich, Germany.
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- Tiemann, Ulf (author)
- Univ Copenhagen, Novo Nordisk Fdn Ctr Stem Cell Biol DanStem, Copenhagen, Denmark.
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- Jackson, Abigail (author)
- Univ Copenhagen, Novo Nordisk Fdn Ctr Stem Cell Biol DanStem, Copenhagen, Denmark.
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- Olsen, Lars Ronn (author)
- Tech Univ Denmark, Dept Hlth Technol, Lyngby, Denmark.
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- Kraft, Maria (author)
- Lund Univ, Lund Stem Cell Ctr, Lund, Sweden.
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- Carlsson, Per-Ola (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi,Transplantation och regenerativ medicin
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- Elfving, Iina M. (author)
- Folkhalsan Res Ctr, Helsinki, Finland.
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- Kettunen, Jarno L. T. (author)
- Folkhalsan Res Ctr, Helsinki, Finland.;Univ Finland, Inst Mol Med Finland, Helsinki, Finland.;Helsinki Univ Hosp, Abdominal Ctr, Dept Endocrinol, Helsinki, Finland.
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- Tuomi, Tiinamaija (author)
- Folkhalsan Res Ctr, Helsinki, Finland.;Univ Finland, Inst Mol Med Finland, Helsinki, Finland.;Helsinki Univ Hosp, Abdominal Ctr, Dept Endocrinol, Helsinki, Finland.
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- Novak, Ivana (author)
- Univ Copenhagen, Novo Nordisk Fdn Ctr Stem Cell Biol DanStem, Copenhagen, Denmark.;Univ Copenhagen, Dept Biol, Copenhagen, Denmark.
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- Semb, Henrik (author)
- Univ Copenhagen, Novo Nordisk Fdn Ctr Stem Cell Biol DanStem, Copenhagen, Denmark.;Helmholtz Zent Munchen, Helmholtz Diabet Ctr, Inst Translat Stem Cell Res, Munich, Germany.
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Univ Copenhagen, Novo Nordisk Fdn Ctr Stem Cell Biol DanStem, Copenhagen, Denmark Univ Copenhagen, Novo Nordisk Fdn Ctr Stem Cell Biol DanStem, Copenhagen, Denmark.;Helmholtz Zent Munchen, Helmholtz Diabet Ctr, Inst Translat Stem Cell Res, Munich, Germany. (creator_code:org_t)
- Elsevier, 2023
- 2023
- English.
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In: Cell Stem Cell. - : Elsevier. - 1934-5909 .- 1875-9777. ; 30:1, s. 38-51
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Abstract
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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 R 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 0 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 0 cells. Our findings identify a pathogenic mechanism leading to 0 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)
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- ref (subject category)
- art (subject category)
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- By the author/editor
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Hermann, Florian ...
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Kjaergaard, 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 Ronn
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show more...
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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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Uppsala University