iPSC-derived β cells model diabetes due to glucokinase deficiency

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