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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

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; Carlsson, Per Ola; Elfving, Iina M.; Kettunen, Jarno L.T.; Tuomi, Tiinamaija; Novak, Ivana; Semb, Henrik.

In: Cell Stem Cell, Vol. 30, No. 1, 2023, p. 38-51.e8.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Hermann, FM, Kjærgaard, MF, Tian, C, Tiemann, U, Jackson, A, Olsen, LR, Kraft, M, Carlsson, PO, Elfving, IM, Kettunen, JLT, Tuomi, T, Novak, I & Semb, H 2023, 'An insulin hypersecretion phenotype precedes pancreatic β cell failure in MODY3 patient-specific cells', Cell Stem Cell, vol. 30, no. 1, pp. 38-51.e8. https://doi.org/10.1016/j.stem.2022.12.001

APA

Hermann, F. M., Kjærgaard, M. F., Tian, C., Tiemann, U., Jackson, A., Olsen, L. R., Kraft, M., Carlsson, P. O., Elfving, I. M., Kettunen, J. L. T., Tuomi, T., Novak, I., & Semb, H. (2023). An insulin hypersecretion phenotype precedes pancreatic β cell failure in MODY3 patient-specific cells. Cell Stem Cell, 30(1), 38-51.e8. https://doi.org/10.1016/j.stem.2022.12.001

Vancouver

Hermann FM, Kjærgaard MF, Tian C, Tiemann U, Jackson A, Olsen LR et al. An insulin hypersecretion phenotype precedes pancreatic β cell failure in MODY3 patient-specific cells. Cell Stem Cell. 2023;30(1):38-51.e8. https://doi.org/10.1016/j.stem.2022.12.001

Author

Hermann, Florian M. ; Kjærgaard, Maya Friis ; Tian, Chenglei ; Tiemann, Ulf ; Jackson, Abigail ; Olsen, Lars Rønn ; Kraft, Maria ; Carlsson, Per Ola ; Elfving, Iina M. ; Kettunen, Jarno L.T. ; Tuomi, Tiinamaija ; Novak, Ivana ; Semb, Henrik. / An insulin hypersecretion phenotype precedes pancreatic β cell failure in MODY3 patient-specific cells. In: Cell Stem Cell. 2023 ; Vol. 30, No. 1. pp. 38-51.e8.

Bibtex

@article{4b29f15e340a4b07a240814aa6f1ba23,

title = "An insulin hypersecretion phenotype precedes pancreatic β cell failure in MODY3 patient-specific cells",

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.",

keywords = "calcium signaling, congenital hyperinsulinemia, disease modeling, HNF1A, HNF4A, K channel, membrane potential, MODY3, pancreatic β cell, patient-specific hiPSCs",

author = "Hermann, {Florian M.} and Kj{\ae}rgaard, {Maya Friis} and Chenglei Tian and Ulf Tiemann and Abigail Jackson and Olsen, {Lars R{\o}nn} and Maria Kraft and Carlsson, {Per Ola} and Elfving, {Iina M.} and Kettunen, {Jarno L.T.} and Tiinamaija Tuomi and Ivana Novak and Henrik Semb",

note = "Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2023",

doi = "10.1016/j.stem.2022.12.001",

language = "English",

volume = "30",

pages = "38--51.e8",

journal = "Cell Stem Cell",

issn = "1934-5909",

publisher = "Cell Press",

number = "1",

}

RIS

TY - JOUR

T1 - An insulin hypersecretion phenotype precedes pancreatic β cell failure in MODY3 patient-specific cells

AU - Hermann, Florian M.

AU - Kjærgaard, Maya Friis

AU - Tian, Chenglei

AU - Tiemann, Ulf

AU - Jackson, Abigail

AU - Olsen, Lars Rønn

AU - Kraft, Maria

AU - Carlsson, Per Ola

AU - Elfving, Iina M.

AU - Kettunen, Jarno L.T.

AU - Tuomi, Tiinamaija

AU - Novak, Ivana

AU - Semb, Henrik

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - calcium signaling

KW - congenital hyperinsulinemia

KW - disease modeling

KW - HNF1A

KW - HNF4A

KW - K channel

KW - membrane potential

KW - MODY3

KW - pancreatic β cell

KW - patient-specific hiPSCs

U2 - 10.1016/j.stem.2022.12.001

DO - 10.1016/j.stem.2022.12.001

M3 - Journal article

C2 - 36563694

AN - SCOPUS:85145229760

VL - 30

SP - 38-51.e8

JO - Cell Stem Cell

JF - Cell Stem Cell

SN - 1934-5909

IS - 1

ER -

ID: 332195647

Department of Biology