An insulin hypersecretion phenotype precedes pancreatic β cell failure in MODY3 patient-specific cells
(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.
(Less)
- author
- organization
- publishing date
- 2023-01-05
- 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
-
- pmid:36563694
- scopus:85145229760
- 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
- 2024-09-20 02:11:54
@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}}, }