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

Hermann, Florian M. ; Kjærgaard, Maya Friis ; Tian, Chenglei ; Tiemann, Ulf ; Jackson, Abigail ; Olsen, Lars Rønn ; Kraft, Maria LU ; Carlsson, Per Ola ; Elfving, Iina M. and Kettunen, Jarno L.T. , et al. (2023) In Cell Stem Cell 30(1). p.8-51
Abstract

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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
calcium signaling, congenital hyperinsulinemia, disease modeling, HNF1A, HNF4A, K channel, membrane potential, MODY3, pancreatic β cell, patient-specific hiPSCs
in
Cell Stem Cell
volume
30
issue
1
pages
8 - 51
publisher
Cell Press
external identifiers
  • scopus:85145229760
  • pmid:36563694
ISSN
1934-5909
DOI
10.1016/j.stem.2022.12.001
language
English
LU publication?
yes
id
73cd2060-9df2-4d0f-b857-e02f245d3235
date added to LUP
2023-02-21 09:46:51
date last changed
2024-06-14 19:50:16
@article{73cd2060-9df2-4d0f-b857-e02f245d3235,
  abstract     = {{<p>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<sup>+/R272C</sup> 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 K<sub>ATP</sub> 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.</p>}},
  author       = {{Hermann, Florian M. and Kjærgaard, Maya Friis and Tian, Chenglei and Tiemann, Ulf and Jackson, Abigail and Olsen, Lars Rønn and Kraft, Maria and Carlsson, Per Ola and Elfving, Iina M. and Kettunen, Jarno L.T. and Tuomi, Tiinamaija and Novak, Ivana and Semb, Henrik}},
  issn         = {{1934-5909}},
  keywords     = {{calcium signaling; congenital hyperinsulinemia; disease modeling; HNF1A; HNF4A; K channel; membrane potential; MODY3; pancreatic β cell; patient-specific hiPSCs}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{1}},
  pages        = {{8--51}},
  publisher    = {{Cell Press}},
  series       = {{Cell Stem Cell}},
  title        = {{An insulin hypersecretion phenotype precedes pancreatic β cell failure in MODY3 patient-specific cells}},
  url          = {{http://dx.doi.org/10.1016/j.stem.2022.12.001}},
  doi          = {{10.1016/j.stem.2022.12.001}},
  volume       = {{30}},
  year         = {{2023}},
}