iPSC-derived β cells model diabetes due to glucokinase deficiency

• Published in: The Journal of clinical investigation Vol. 123; no. 7; pp. 3146 - 3153
• Main Authors: Hua, Haiqing, Shang, Linshan, Martinez, Hector, Freeby, Matthew, Gallagher, Mary Pat, Ludwig, Thomas, Deng, Liyong, Greenberg, Ellen, LeDuc, Charles, Chung, Wendy K., Goland, Robin, Leibel, Rudolph L., Egli, Dieter
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.07.2013
• Subjects: Adult; Base Sequence; Case-Control Studies; Cation Transport Proteins - metabolism; Cell Differentiation; Cells, Cultured; Corticotropin-Releasing Hormone - metabolism; Diabetes; Diabetes Mellitus, Type 2 - enzymology; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - pathology; Female; Glucokinase; Glucokinase - deficiency; Glucokinase - genetics; Glucose - physiology; Health aspects; 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; Stem cells; Technical Advance; Transplantation; Urocortins - metabolism; Zinc Transporter 8; United States
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI67638

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.