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 (KATP) 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 KATP channel-independent pathway for amplification of glucose-stimulated insulin secretion also exists that may depend upon glutamine.2
KATP channel–dependent pathways of insulin secretion. Glucose enters the β-cell through the GLUT-1 and GLUT-2 transporters and is phosphorylated by GK. Further metabolism of glucose generates ATP leading to an increase in the β-cell ATP to ADP ratio. This increase closes the ATP-sensitive potassium (KATP) channel, and β-cell membrane depolarization ensues. VDCC open allowing calcium entry into the β-cell, and ultimately insulin release. Amino acids stimulate insulin secretion through GDH which deaminates glutamate to α-ketoglutarate. GDH is allosterically activated by leucine and ADP and is inhibited by GTP. As with glucose, further metabolism of α-ketoglutarate generates ATP and triggers the KATP channel–dependent pathway of insulin secretion. Diazoxide inhibits insulin secretion by maintaining the KATP channel open via SUR1. Octreotide inhibits insulin secretion downstream of the VDCC. GLUT-2, glucose transporter-2; GK, glucokinase; KATP channel is composed of SUR1, sulfonylurea receptor-1 and Kir6.2, inwardly rectifying potassium pore; VDCC, voltage-dependent calcium channel; GDH, glutamate dehydrogenase.
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 KATP 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 ...