iPSC-derived β cells model diabetes due to glucokinase deficiency.
J Clin Invest, 2013/07;123(7):3146-53.
Hua H[1], Shang L, Martinez H, Freeby M, Gallagher MP, Ludwig T, Deng L, Greenberg E, Leduc C, Chung WK, Goland R, Leibel RL, Egli D
Affiliations
PMID: 23778137
Impact factor: 19.456
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.
MeSH terms
Adult; Base Sequence; Case-Control Studies; Cation Transport Proteins; Cell Differentiation; Cells, Cultured; Corticotropin-Releasing Hormone; Diabetes Mellitus, Type 2; Female; Glucokinase; Glucose; Humans; Induced Pluripotent Stem Cells; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Mutation, Missense; Sequence Analysis, DNA; Urocortins; Zinc Transporter 8
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