iPSC-derived β cells model diabetes due to glucokinase deficiency

J Clin Invest. 2013 Jul;123(7):3146-53. doi: 10.1172/JCI67638. Epub 2013 Jun 17.


Diabetes is a disorder characterized by loss of β cell mass and/or β cell function, leading to deficiency of insulin relative to metabolic need. To determine whether stem cell-derived β cells recapitulate molecular-physiological phenotypes of a diabetic subject, we generated induced pluripotent stem cells (iPSCs) from subjects with maturity-onset diabetes of the young type 2 (MODY2), which is characterized by heterozygous loss of function of the gene encoding glucokinase (GCK). These stem cells differentiated into β cells with efficiency comparable to that of controls and expressed markers of mature β cells, including urocortin-3 and zinc transporter 8, upon transplantation into mice. While insulin secretion in response to arginine or other secretagogues was identical to that in cells from healthy controls, GCK mutant β cells required higher glucose levels to stimulate insulin secretion. Importantly, this glucose-specific phenotype was fully reverted upon gene sequence correction by homologous recombination. Our results demonstrate that iPSC-derived β cells reflect β cell-autonomous phenotypes of MODY2 subjects, providing a platform for mechanistic analysis of specific genotypes on β cell function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Adult
  • Base Sequence
  • Case-Control Studies
  • Cation Transport Proteins / metabolism
  • Cell Differentiation
  • Cells, Cultured
  • Corticotropin-Releasing Hormone / metabolism
  • Diabetes Mellitus, Type 2 / enzymology*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / pathology
  • Female
  • Glucokinase / deficiency*
  • Glucokinase / genetics
  • Glucose / physiology
  • Humans
  • Induced Pluripotent Stem Cells / physiology*
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / enzymology*
  • Insulin-Secreting Cells / metabolism
  • Male
  • Middle Aged
  • Mutation, Missense
  • Sequence Analysis, DNA
  • Urocortins / metabolism
  • Zinc Transporter 8


  • Cation Transport Proteins
  • Insulin
  • SLC30A8 protein, human
  • UCN3 protein, human
  • Urocortins
  • Zinc Transporter 8
  • Corticotropin-Releasing Hormone
  • Glucokinase
  • Glucose

Supplementary concepts

  • Maturity-Onset Diabetes of the Young, Type 2