Chapter 4: Hyperinsulinism

CONGENITAL HYPERINSULINISM

Etiology/Pathophysiology

Congenital hyperinsulinism (HI) refers to a group of disorders characterized by dysregulated insulin secretion from pancreatic β-cells that leads to recurrent hypoketotic hypoglycemia, in both the fasting and the postprandial states. With the identification of specific genetic defects responsible for congenital hyperinsulinism, a more complete description of the clinical manifestations of these disorders has become possible. In addition, the roles of these various pathways in normal insulin secretion are becoming better understood. As shown in Figure 4-1, glucose is the primary stimulant for insulin secretion. After glucose enters the β-cell through the GLUT-2 and GLUT-1 transporters, it is phosphorylated by glucokinase, the rate-limiting “glucosensor” of the β-cell. Subsequent metabolism of glucose generates adenosine triphosphate (ATP), leading to an increase in the ATP-to-ADP ratio of the β-cell. This increase closes the ATP-sensitive potassium (K_ATP) channel, which is composed of the sulfonylurea receptor regulatory subunit (SUR1) and the inwardly–rectifying potassium pore (KIR6.2). β-Cell membrane depolarization ensues. Voltage-dependent calcium channels (VDCCs) open and calcium enters the β-cell, leading to insulin release.¹ A K_ATP channel-independent pathway for amplification of glucose-stimulated insulin secretion also exists that may depend upon glutamine.²

Amino acids stimulate insulin secretion through glutamate dehydrogenase (GDH) (Figure 4-1), a mitochondrial enzyme responsible for the oxidative deamination of glutamate to α-ketoglutarate.^3,4,5,6,7 GDH is allosterically activated by leucine and inhibited by GTP and ATP. As with glucose, further metabolism of α-ketoglutarate generates ATP and triggers the K_ATP channel-dependent pathway of insulin secretion. The mechanisms by which fatty acids stimulate insulin secretion are not well understood.

In congenital hyperinsulinism, defects in each of the above pathways lead to dysregulated insulin secretion.^8–22 Inappropriate insulin secretion leads to recurrent hypoketotic hypoglycemia: insulin suppresses not only gluconeogenesis and glycogenolysis to cause hypoglycemia ...