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

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.

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Endokrinologi och diabetes hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Endocrinology and Diabetes hsv//eng
calcium signaling
congenital hyperinsulinemia
disease modeling
HNF1A
HNF4A
K channel
membrane potential
MODY3
pancreatic β cell
patient-specific hiPSCs

Kjærgaard, Maya FriisUniversity of Copenhagen (author)
Tian, ChengleiHelmholtz Zentrum München,University of Copenhagen (author)
Tiemann, UlfUniversity of Copenhagen (author)
Jackson, AbigailUniversity of Copenhagen (author)
Olsen, Lars RønnTechnical University of Denmark (author)
Kraft, MariaLund University,Lunds universitet,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine,Faculty of Medicine(Swepub:lu)molm-men (author)
Carlsson, Per OlaUppsala University (author)
Elfving, Iina M.Folkhälsan Research Center (author)
Kettunen, Jarno L.T.University of Helsinki,Helsinki University Central Hospital,Folkhälsan Research Center (author)
Tuomi, TiinamaijaHelsinki University Central Hospital,Folkhälsan Research Center,University of Helsinki (author)
Novak, IvanaUniversity of Copenhagen (author)
Semb, HenrikUniversity of Copenhagen,Helmholtz Zentrum München(Swepub:lu)endo-hse (author)
University of CopenhagenHelmholtz Zentrum München (creator_code:org_t)

By the author/editor: Hermann, Florian ...; Kjærgaard, Maya ...; Tian, Chenglei; Tiemann, Ulf; Jackson, Abigail; Olsen, Lars Rønn; show more...; Kraft, Maria; Carlsson, Per Ol ...; Elfving, Iina M.; Kettunen, Jarno ...; Tuomi, Tiinamaij ...; Novak, Ivana; Semb, Henrik; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Endocrinology an ...

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