The Genetic and Molecular Mechanisms of Congenital Hyperinsulinism

Abstract

Congenital hyperinsulinism (CHI) is a heterogenous and complex disorder in which the unregulated insulin secretion from pancreatic beta-cells leads to hyperinsulinaemic hypoglycaemia. The severity of hypoglycaemia varies depending on the underlying molecular mechanism and genetic defects. The genetic and molecular causes of CHI include defects in pivotal pathways regulating the secretion of insulin from the beta-cell. Broadly these genetic defects leading to unregulated insulin secretion can be grouped into four main categories. The first group consists of defects in the pancreatic K_ATP channel genes (ABCC8 and KCNJ11). The second and third categories of conditions are enzymatic defects (such as GDH, GCK, HADH) and defects in transcription factors (for example HNF1α, HNF4α) leading to changes in nutrient flux into metabolic pathways which converge on insulin secretion. Lastly, a large number of genetic syndromes are now linked to hyperinsulinaemic hypoglycaemia. As the molecular and genetic basis of CHI has expanded over the last few years, this review aims to provide an up-to-date knowledge on the genetic causes of CHI.

Keywords: genetics; hyperinsulinism; hypoglycaemia; molecular mechanisms; mutation.

Figure 1

Channel and transporter proteins involved in the process of insulin secretion from pancreatic β-cells. ADP, adenosine diphosphate; ATP, adenosine triphosphate; Ca²⁺, calcium ions; cAMP, cyclic adenosine monophosphate; G6P, glucose 6-phosphate; GLP1, glucagon like peptide 1; GLUT 2, glucose transporter 2; K⁺, potassium; Kir6.2, inward rectifier potassium channel 6.2; MCT1, monocarboxylate transporter 1; Pyr, pyruvate; SUR1, sulfonylurea receptor 1; TCA, tricarboxylic acid.

Figure 2

Metabolic pathways and transcription factors related to the development of CHI. ADP, adenosine diphosphate; ATP, adenosine triphosphate; αKG, alpha ketoglutarate; Ca²⁺, calcium ions; ER, endoplasmic reticulum; G1P, gluscose-1-phosphate; G6P, glucose 6-phosphate; GABA, γ-aminobutyric acid; GAD, glutamate decarboxylase enzyme; GDH, glutamate dehydrogenase; GLUT, glucose transporter; HADH, hydroxyacyl-CoA dehydrogenase; HNF1α, hepatocyte nuclear factor 1α; HNF4α, hepatocyte nuclear factor 4α; K⁺, potassium; NH3, ammonia; PGM1, phosphoglucomutase 1; PMM2, phosphomannomutase 2; Pyr, pyruvate; TCA, tricarboxylic acid; UCP2, mitochondrial uncoupling protein 2.

Figure 3

Schematic presentation of the histological subtypes of CHI. In the diffuse CHI, there is a global hyperchromatic β-cell enlargement and hyperplasia. In the focal subtype, β-cell hyperplasia is limited to a certain region of the pancreas with a superficial or deep localization. (A) Mode of inheritance and the genetic causes of CHI in the diffuse and focal subtype, respectively; (B) Schematic illustration of diffuse, atypical and focal subtypes; (C) Management approaches to different forms of CHI.