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

Florian M. Hermann, Maya Friis Kjærgaard, Chenglei Tian, Ulf Tiemann, Abigail Jackson, Lars Rønn Olsen, Maria Kraft, Per Ola Carlsson, Iina M. Elfving, Jarno L.T. Kettunen, Tiinamaija Tuomi, Ivana Novak, Henrik Semb*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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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 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 languageEnglish
JournalCell Stem Cell
Volume30
Issue number1
Pages (from-to)38-51.e1-e8
ISSN1934-5909
DOIs
Publication statusPublished - 2023

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