IPSC-derived ? cells model diabetes due to glucokinase deficiency.

ABSTRACT: Diabetes is a disorder characterized by loss of ? cell mass and/or ? cell function, leading to deficiency of insulin relative to metabolic need. To determine whether stem cell-derived ? 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 ? cells with efficiency comparable to that of controls and expressed markers of mature ? 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 ? 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 ? cells reflect ? cell-autonomous phenotypes of MODY2 subjects, providing a platform for mechanistic analysis of specific genotypes on ? cell function.

SUBMITTER: Hua H 

PROVIDER: S-EPMC3696557 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature