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Review
. 2018 Aug;30(4):568-575.
doi: 10.1097/MOP.0000000000000645.

Genetic characteristics of patients with congenital hyperinsulinism

Mary Ellen Vajravelu  1   2 , Diva D De León  1   2
Affiliations
Review

Genetic characteristics of patients with congenital hyperinsulinism

Mary Ellen Vajravelu et al. Curr Opin Pediatr. 2018 Aug.

Abstract

Purpose of review: Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in infants and children. Early and appropriate recognition and treatment of hypoglycemia is vital to minimize neurocognitive impairment.

Recent findings: There are at least 11 known monogenic forms of hyperinsulinism and several associated syndromes. Molecular diagnosis allows for prediction of the effectiveness of diazoxide and the likelihood of focal hyperinsulinism. Inactivating mutations in the genes encoding the ATP-sensitive potassium channel (KATP hyperinsulinism) account for 60% of all identifiable mutations, including 85% of diazoxide-unresponsive cases. Syndromes or disorders associated with hyperinsulinism include Beckwith-Wiedemann syndrome, Kabuki syndrome, Turner syndrome, and congenital disorders of glycosylation. Although focal hyperinsulinism can be cured by resection of the lesion, therapeutic options for nonfocal hyperinsulinism remain limited and include diazoxide, octreotide, long-acting somatostatin analogs, and near-total pancreatectomy. Although sirolimus has been reported to improve glycemic control in infants with diazoxide-unresponsive hyperinsulinism, the extent of improvement has been limited, and significant adverse events have been reported.

Summary: Identification of the cause of congenital hyperinsulinism helps guide management decisions. Use of therapies with limited benefit and significant potential risks should be avoided.

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Conflict of interest statement

Conflicts of interest

The authors have no conflict of interest.

Figures

Figure 1
Figure 1. Beta-cell depicting the impact of known monogenic causes of HI on insulin secretion
Glucose-stimulated insulin secretion is triggered by an increased in ATP/ADP ratio resulting from glucose metabolism. Glucokinase (GCK) is the β-cell glucose sensor setting the threshold for insulin secretion. The increased in ATP/ADP ratio results in closing of the ATP-sensitive KATP channels (SUR1/Kir6.2), with subsequent plasma membrane depolarization, activation of voltage-gated calcium channels, cytosolic calcium increase, and insulin release from stored intracellular granules. Eleven known β-cell genes are responsible for monogenic HI: ABCC8 (encoding sulfonylurea receptor 1, SUR1), KCNJ11 (encoding inwardly rectifying potassium channel 6.2, Kir6.2), GCK (encoding glucokinase), SLC16A1 (encoding monocarboxylate transporter 1, MCT1), FOXA2 (forkhead box A2), HADH (encoding short-chain 3-hydroxyacyl-CoA dehydrogenase, SCHAD), GLUD1 (encoding glutamate dehydrogenase, GDH), PGM1 (encoding phosphoglucomutase 1), HNF1A (hepatocyte nuclear factor 1A), HNF4A (hepatocyte nuclear factor 4A), and UCP2 (uncoupling protein 2). Other abbreviations: αKG, α-ketoglutarate; Ac-CoA, acetyl-CoA; G6P, glucose 6-phosphate; G-1,6-P, glucose 1,6-bisphosphate; INS, insulin.
Figure 2
Figure 2. Recommended approach to diagnosis and management of congenital hyperinsulinism
Hypoketotic hypoglycemia, with positive glycemic response to glucagon. Data from (5).
See this image and copyright information in PMC

References

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