ESPE Yearbook of Paediatric Endocrinology

Diabetologia. 2021 Mar;64(3):630-640. doi: 10.1007/s00125-020-05346-7. PMID: 33404684.

The derivation of iPSCs and their subsequent conversion to islet like clusters from a patient with diffuse CHI due to a homozygous mutation in the ABCC8 provided these authors a unique opportunity to study the molecular basis of CHI and to develop potential novel treatment options by screening for new drug targets in-vitro. The engineered iPSCs and the islet like clusters and their implantation into NOD-SCID gamma mice recapitulates the phenotype of human CHI extremely well. The mice have typical biochemical features of hyperinsulinaemic hypoglycaemia and histologically the islet like clusters in the mice show increased beta-cell mass and proliferation as well as increased nuclear size.

Congenital hyperinsulinism (CHI) leads to unregulated insulin secretion and severe hypoglycaemia especially in the newborn period. The most common cause of medically unresponsive CHI is mutations in the genes ABCC8 and KCNJ11 encoding the 2 subunits (SUR1 and KIR6.2 respectively) of the pancreatic beta-cell K_ATP channel. Patients with CHI due to recessive or dominant ABCC8/KCNJ11 mutations typically have diffuse disease and require a near total pancreatectomy to alleviate the hypoglycaemia. However, the near total pancreatectomy in the long-term will lead to lifelong diabetes mellitus and pancreatic exocrine insufficiency. Rodent models of CHI do not recapitulate the typical clinical and biochemical features of CHI as observed in humans. Current treatment options are limited for patients with diffuse CHI who do not respond to conventional treatment options (like diazoxide). Thus, this novel model of iPSC derived CHI will be extremely valuable for studying new treatment options for diffuse forms of CHI.