Browsing by Author "Saarimäki-Vire, Jonna"

Modeling congenital hyperinsulinism with patient stem cell derived β cells Congenital hyperinsulinism (CHI), caused by mutations in the KATP -channel encoding genes (KATPHI), is a potentially life-threatening disorder of the beta cells. We aimed to create a model of KATPHI based on patient iPSC derived beta-like cells (BLCs) to allow future studies for improved management of KATPHI. Cells were derived from a patient with a homozygous ABCC8V187D -mutation, leading to loss of KATP -channel membrane expression due to loss of the SUR1 subunit, causing diazoxide unresponsive diffuse CHI. The mutation was corrected with CRISPR/Cas9 to enable controlled studies with isogenic cells. Quantification of the in vitro differentiated endocrine populations showed increased differentiation to beta- and delta cells in the SUR1-mutants. The proliferation of insulin positive cells was also increased in the SUR1-mutants. The SUR1-mutant BLCs secreted more insulin and did not respond to KATP -channel acting drugs in vitro. Mice carrying implants of SUR1-mutant islet-like clusters developed hyperinsulinemic hypoglycemia and their grafts failed to shut down insulin secretion during hypoglycemia. In conclusion, we have created a model of KATPHI in vitro and in humanized mice allowing study of pathophysiology and management of KATPHI.