Congenital hyperinsulinism: from bench to bedside .... and back?

M.J. Dunne, R.M. Shepherd and K.E. Cosgrove, Faculty of Life Sciences, University of Manchester, Core Technology Facility, 46 Grafton Street, Manchester, M13 9NT, UK.

Congenital Hyperinsulinism in Infancy (HI) is a potentially-lethal condition of neonates and early childhood. Recent advances in genetics, histopathology and the molecular physiology of insulin release have now revealed the causes of HI in a large cohort of patients. From defects in the genes that encode ion channel subunits, β-cell metabolism and anaplerosis, the causes of HI are both varied and numerous. However, the consequences of these mutations appear to converge in their action upon a common target protein – the ATP-sensitive K-channel. The function of these channels is not only critical to the control of healthy normal insulin-secreting cell function, but “activating” defects in these channels lead to permanent neonatal diabetes and type 2 diabetes. HI can arise through 'channelopathies' by way of defects in the sulfonylurea receptor (encoded by ABCC8, Ch11.p15)¹ or the inwardly-rectifying potassium channel subunit Kir6.2 (encoded by KCNJ11, Ch11.p15).² It can also arise as a result of 'metabolopathies' through defects in the genes encoding glucokinase HI-GK (GCK, Ch.7p15-p13),³ glutamate dehydrogenase HI-GDH (GLUD1, Ch.10q23.3)⁴ and Short-chain L-3-hydroxyacyl-CoA dehydrogenase HI-SCHAD (HADHSC, Ch.4q22-q26).⁵ Despite advances, medical therapy for HI remains largely unchanged due to the availability of limited agents that are selective and specific for the termination of insulin release from ß-cells. Congenital Hyperinsulinism can be a devastating disease, and interest focuses upon the relationship between the causes of HI and current / future therapies, including stem cells.

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