Genetics and Pathophysiology of Hyperinsulinism in Infancy

Abstract

Hyperinsulinism in infancy (HI) is a condition of neonates and early childhood. For many years the pathophysiology of this potentially lethal disorder was unknown. Advances in the genetics, histopathology and molecular physiology of this disease have now provided insights into the causes of β-cell dysfunction and revealed levels of diversity far in excess of our previous knowledge. These include defects in ion channel subunit genes and mutations in several enzymes associated with β-cell metabolism and anaplerosis. In most cases, β-cell pathophysiology leads to an alteration in the function of ATP-sensitive K⁺ channels. This can manifest as ‘channelopathies’ of K_ATP channels through gene defects in ABCC8 and KCNJ11 (Ch.11p15); or as a result of ‘metabolopathies’ through defects in the genes encoding glucokinase (GCK, Ch.7p15–p13), glutamate dehydrogenase (GLUD1, Ch.10q23.3) and short-chain L-3-hydroxyacyl-CoA dehydrogenase (HADHSC, Ch.4q22–q26). This review focuses upon the relationship between the causes of HI and therapeutic options.

KATP channelopathies in the pancreas

“…HI is characterized by excessive insulin secretion despite dangerously low blood glucose levels, and in the absence of treatment, severe mental retardation and epilepsy can occur [32]. Morphologically, both diffuse and focal forms of HI are reported: in the diffuse form, all the β-cells in the pancreas are affected, whereas, in the focal form, the affected cell population presents as a localized adenoma [23].…”

“…Loss-of-function (inactivating) mutations in K ATP , both Kir6.2 (KCNJ11) and SUR1 (ABCC8), are the most common cause of HI, accounting for~70% of all HI cases with more than 200 mutations reported to date [23,35,37,43]. In most cases, the K ATP mutations are recessively inherited although there are increasing reports of dominantly inherited inactivating mutations that are generally associated with milder, drug-responsive forms of HI [60,95].…”

Hyperinsulinaemic Hypoglycaemia in Infancy and Childhood - Resolving the Enigma

“…HI can occur due to defects in KATP channels as a result of mutations in the genes ABCC8 and KCNJ11 ('channelopathies') or as a result of increased metabolic signals ('metabolopathies') generated in the ß-cell through defects in the genes encoding glucokinase (GCK), glutamate dehydrogenase (GLUD1) and short-chain L-3-hydroxy acyl-CoA dehydrogenase (SCHAD) 27 . The commonest genetic cause of persistent HI is an abnormality of the KATP channels 28 .…”

Emergencias endocrinas en pediatría: diagnóstico y manejo

“…El diagnóstico de esta condición es un diagnóstico de descarte. En la Tabla 1 se muestran las distintas causas de hipoglicemia en pediatría según la edad [3][4][5][6] .…”

“…Si ésto se confirma, se puede utilizar diazoxide 5 a 20 mg/kg/día, dividido en 2 a 3 dosis. Este medicamento abre el canal de potasio ATP dependiente y aumenta la secreción de epinefrina, aumentando la gluconeogénesis e inhibiendo la secreción de insulina 3,5 .…”