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

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Abstrakti

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.
Alkuperäiskielienglanti
LehtiCell Stem Cell
Vuosikerta30
Numero1
Sivut38-51.e8
Sivumäärä22
ISSN1934-5909
DOI - pysyväislinkit
TilaJulkaistu - 5 tammik. 2023
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

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