Maturity-onset diabetes of the young (MODY) is one of the hereditary forms of diabetes mellitus caused by mutations in an autosomal dominant gene disrupting insulin production. Patients with MODY1 typically develops diabetes (persistent hyperglycemia) before the age of 25 years, but this may not appear until later decades. The degree of insulin deficiency is slowly progressive. Many patients with MODY1 are treated with sulfonylureas for years before insulin is required.
MODY 1 is caused by a loss-of-function mutation in the HNF4α gene. HNF4α is part of a transcription network, including HNF1α (responsible for MODY3) and perhaps HNF1β (MODY5 – see Early Developmental Perturbations in a Human Stem Cell Model of MODY5/HNF1B Pancreatic Hypoplasia), which plays a role in the early development of the pancreas, liver, and intestines. In the pancreas these genes influence the expression of insulin, the principal glucose transporter (GLUT2), and several proteins involved in glucose and mitochondrial metabolism.
We used a combination of global proteomics and cellular biology techniques to investigate the differentiation capacity of insulin-producing cells using a seven-step differentiation protocol (as established by Rezania et al.) of induced pluripotent stem cells, generated from either healthy subjects or MODY1 patients.
Our data show that a human HNF4A mutation is neither blocking the expression of the insulin genes nor the development of insulin-producing cells in vitro. Our analyses also suggest key developmental signalling pathways representing potential targets for improving the efficiency of the current differentiation protocols.
Future studies are required on improving later differentiation stages up to mature insulin-producing β-like cells, which should also reveal the impact of HNF4A-directed transcriptional perturbations on β-cell survival and function.
The paper can be read here.
Probing the missing mature β-cell proteomic landscape in differentiating patient iPSC-derived cells Heidrun Vethe, Yngvild Bjørlykke, Luiza M. Ghila, Joao A. Paulo, Hanne Scholz, Steven P. Gygi, Simona Chera & Helge Ræder
Scientific Reports.2017 Jul 6;7(1):4780. doi: 10.1038/s41598-017-04979-w.