An insulin hypersecretion phenotype precedes pancreatic β cell failure in MODY3 patient-specific cells
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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.
Original language | English |
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Journal | Cell Stem Cell |
Volume | 30 |
Issue number | 1 |
Pages (from-to) | 38-51.e8 |
Number of pages | 23 |
ISSN | 1934-5909 |
DOIs | |
Publication status | Published - 2023 |
Bibliographical note
Publisher Copyright:
© 2022 The Author(s)
- calcium signaling, congenital hyperinsulinemia, disease modeling, HNF1A, HNF4A, K channel, membrane potential, MODY3, pancreatic β cell, patient-specific hiPSCs
Research areas
ID: 332195647