Congenital hyperinsulinism: From bench to bedside

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Congenital Hyperinsulinism in Infancy （HI） is a potentially-lethal condition of neonates and duringearly childhood. For many years the pathophysiology of this disorder was unknown. Recent advances in genetics,histopathology and molecule physiology have now revealed the causes of HI in a large cohort of patients. From defectsin ion channel subunit genes to lesions in the control of pancreatic B-cell metabolism and anaplerosis, the causes ofHI are both varied and numerous. However, in all cases they appear to share a common target protein - the ATPsensitiveK-channel. The function of these channels is not only critical to the control of healthy normal insulin-secretingcell function, but “activating” defects in these channels lead to permanent neonatal diabetes and type 2 diabetes. HIcan therefore arise through “channelopathies” of K-ATP channels: HI-KATP through gene defects in ABCC8 andKCNJ11 （Ch11.p15）; or as a result of “metabolopathies” through defects in the genes encoding glucokinase HI-GK（GCK, Ch.7p15-p13）, glutamate dehydrogenase HI-GDH （GLUD1, Ch.10q23.3） and Short-chain L-3-hydroxyacyl-CoAdehydrogenase HI-SCHAD（ HADHSC, Ch.4q22-q26）. Advances in the integration of genetic medicine and cell biologyhave provided key insights into the causes of HI, and this has been of key importance to the defi nition of pathogenesis.However, medical therapy for HI remains largely unchanged due to the availability of limited agents that are selectiveand specifi c for the termination of insulin release from β-cells. CHI can be a devastating disease, and in this reviewfocuses upon the relationship between the basis of HI and current / future therapies, including stem cells.

Congenital hyperinsulinism: From bench to bedside

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