Congenital hyperinsulinism disorders: Genetic and clinical characteristics

Abstract

Congenital hyperinsulinism (HI) is the most frequent cause of persistent hypoglycemia in infants and children. Delays in diagnosis and initiation of appropriate treatment contribute to a high risk of neurocognitive impairment. HI represents a heterogeneous group of disorders characterized by dysregulated insulin secretion by the pancreatic beta cells, which in utero, may result in somatic overgrowth. There are at least nine known monogenic forms of HI as well as several syndromic forms. Molecular diagnosis allows for prediction of responsiveness to medical treatment and likelihood of surgically-curable focal hyperinsulinism. Timely genetic mutation analysis has thus become standard of care. However, despite significant advances in our understanding of the molecular basis of this disorder, the number of patients without an identified genetic diagnosis remains high, suggesting that there are likely additional genetic loci that have yet to be discovered.

Keywords: KATP channel; beta-cell; hypoglycemia; insulin; pancreas.

Figure 1.. Genetic causes of congenital HI.

Pancreatic β-cell insulin secretion is predominately controlled by oxidation of glucose and amino acids. Glucose is transported into the β-cell by an insulin-independent glucose transporter (GLUT), predominantly GLUT1, and is phosphorylated by glucokinase (GCK). Glucose metabolism leads to an elevated intracellular ATP/ADP ratio resulting in sequential closure of plasma membrane ATP-sensitive KATP channels (composed of SUR1 and Kir6.2 subunits), membrane depolarization, activation of voltage-gated calcium channels, elevation of cytosolic calcium, and release of insulin from storage granules into the circulation. Amino acids stimulate insulin secretion via a variety of mechanisms. Leucine stimulates insulin secretion by allosterically activating glutamate dehydrogenase (GDH), increasing the oxidation of glutamate to alpha-ketoglutarate which increases the ATP/ADP ratio and triggers the insulin secretion cascade. GDH is allosterically inhibited by GTP and SCHAD. Diazoxide activates KATP channels thereby inhibiting insulin secretion. Defects in the triggering pathway for insulin secretion cause monogenic HI. Genes associated with congenital HI are highlighted in bold and include: SUR1 (sulfonylurea receptor), Kir6.2 (inwardly rectifying potassium channel), GCK (glucokinase), HK1 (hexokinase 1), GDH (glutamate dehydrogenase), SCHAD (short-chain 3-OH acyl-CoA dehydrogenase), HNF4a (hepatocyte nuclear transcription factor 4alpha), and HNF1a (hepatocyte nuclear transcription factor 1alpha), MCT1 (monocarboxylate transporter 1), UCP2 (uncoupling protein 2).

Figure 2.. “Two-hit” mechanism of focal hyperinsulinism.

(A) The paternally inherited chromosome is depicted in blue and the maternally inherited chromosome in orange. The paternally inherited mutation in the ABCC8 or KCNJ11 gene (red) is present in all cells. The black circle highlights the imprinted 11p15 region normally containing maternally expressed tumor suppressor genes, H19 and CDKN1C, and paternally expressed growth promoting factor IGF2. (B) Somatic loss of the maternal 11p15 region is compensated by paternal uniparental disomy resulting in the focal pancreatic lesion.

Figure 3.. Genetic etiologies of HI stratified by diazoxide responsiveness.

Data from 814 children with hyperinsulinism treated at the Children’s Hospital of Philadelphia. Among those with diazoxide-unresponsive HI, K_ATP mutations were the most common etiology identified by genetic testing: focal K_ATP (50%), biallelic recessive K_ATP (31%), monoallelic dominant K_ATP (7%), GCK (3%), no mutation identified (9.5%). In contrast, the most common finding among those with diazoxide-responsive HI was no identified mutation (64.5%), followed by monoallelic dominant K_ATP (14.5%), GLUD1 (12%), HNF4A (3%), HNF1A (3%), UCP2 (2%), and HADH (0.6%).