Molecular mechanisms underlying congenital hyperinsulinemia of infancy and its relevance to management – A review

Abstract

Congenital hyperinsulinemia of infancy (CHI), characterized by inappropriate insulin secretion despite low blood glucose, is by far the most common cause of persistent hypoglycemia in infancy. The presentation is typically in the first few days of life and could be life-threatening. A critical sample drawn at the time of hypoglycemia is crucial for biochemical characterization and is the beginning of a cascade of investigations that further elucidate our course of action. The majority of the cases relate to defects in KATP channels that regulate insulin secretion from pancreatic beta-cells. These are mostly attributable to mutations in ABCC8 and KCNJ11, both located on the short arm of chromosome 11, that code subunits of the KATP channel (sulfonylurea receptor [SUR] and Kir6.2, respectively). However, the underlying molecular defect may be identified in only about half of them. Much before the molecular diagnosis is established, therapy needs to be initiated. Diazoxide is the initial choice as it acts on the KATP channels at SUR1 and opens them, preventing insulin release. The involvement of the pancreas may be diffuse or focal. The diffuse form arises from dominant or recessive mutations affecting the KATP channel. The recessive ones are more common and cause the more severe forms of CHI. Where diazoxide proves ineffective, other interventions, such as octreotide, may be tried. If hypoglycemia remains unresolved despite all medical therapy, a near-total pancreatectomy would be required. On the other hand, focal involvement of a specific group of beta-cells results from paternally inherited germinal mutation together with post-zygotic loss of normal maternal allele. Elective partial pancreatectomy in these focal cases would completely ameliorate hypoglycemia. Hence, based on the genotype, one can plan further diagnostic modalities such as fluorine 18L-3,4 dihydroxyphenylalanine positron emission tomography scan to define whether the involvement is diffuse or focal and consider the management accordingly.