title: iPSC-derived β cells model diabetes due to glucokinase deficiency.
abstract: 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.
authors.affiliation: The New York Stem Cell Foundation Laboratory, New York, New York, USA.
authors.forename: Haiqing
authors.initials: H
authors.lastname: Hua
authors.forename: Linshan
authors.initials: L
authors.lastname: Shang
authors.forename: Hector
authors.initials: H
authors.lastname: Martinez
authors.forename: Matthew
authors.initials: M
authors.lastname: Freeby
authors.forename: Mary Pat
authors.initials: MP
authors.lastname: Gallagher
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
authors.forename: Liyong
authors.initials: L
authors.lastname: Deng
authors.forename: Ellen
authors.initials: E
authors.lastname: Greenberg
authors.forename: Charles
authors.initials: C
authors.lastname: Leduc
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.forename: Robin
authors.initials: R
authors.lastname: Goland
authors.forename: Rudolph L
authors.initials: RL
authors.lastname: Leibel
authors.forename: Dieter
authors.initials: D
authors.lastname: Egli
mesh_terms: D000328:Adult; D001483:Base Sequence; D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005260:Female; D005941:Glucokinase / Q000172:deficiency* / Q000235:genetics; D005947:Glucose / Q000502:physiology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA; D054832:Urocortins / Q000378:metabolism; D000075703:Zinc Transporter 8
chemical_list: D027682:Cation Transport Proteins; D007328:Insulin; C492522:SLC30A8 protein, human; C426704:UCN3 protein, human; D054832:Urocortins; D000075703:Zinc Transporter 8; D003346:Corticotropin-Releasing Hormone; D005941:Glucokinase; D005947:Glucose