The Journal of Pediatrics
Volume 149, Issue 1 , Pages 6-7, July 2006

Understanding protein-sensitive hypoglycemia

  • Joseph I. Wolfsdorf, MB, BCh

      Affiliations

    • Corresponding Author InformationReprint requests: Joseph I. Wolfsdorf, MB, BCh, Division of Endocrinology, Children’s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115.

Division of Endocrinology, Children’s Hospital Boston, Boston, MA

Article Outline

Abbreviations:  GDH, Glutamate dehydrogenase , SCHAD, Short-chain L-3-hydroxyacyl-CoA dehydrogenase

 

Considerable progress has been made elucidating the molecular genetics and pathophysiology of the heterogeneous disorders that cause congenital hyperinsulinism (formerly referred to as nesidioblastosis), and several distinct genetic defects in the mechanisms controlling insulin secretion have been identified.1, 2, 3 Autosomal recessive loss of function mutations of the β-cell ATP-sensitive potassium (KATP) channel are the most common cause of congenital hyperinsulinism. The KATP channel consists of the sulphonylurea receptor (SUR1) and the potassium ion pore (Kir6.2), which are encoded by two adjacent genes on chromosome 11p, ABCC8 and KCNJ11, respectively.4, 5 Mutations in either of these genes result in loss of function of the KATP channel and uncoupling of insulin secretion from glucose metabolism. Infants with mutations of both alleles of either of these two genes encoding the KATP channel have diffuse dysregulation of insulin secretion throughout the pancreas.6, 7 Recessive mutations in the genes encoding the KATP channel may also cause focal hyperinsulinism characterized by discrete areas of β-cell adenomatosis because of loss of heterozygosity for the maternal 11p region and expression of a paternally derived KATP channel mutation.8, 9

See related article, p 47

Two reports of autosomal dominant hyperinsulinism, both with generally milder clinical phenotypes than the autosomal recessive form, have also been described involving the ABCC8 gene.10, 11 Another form is caused by an activating mutation in GCK, the gene encoding β-cell glucokinase, resulting in increased affinity of the enzyme for glucose.12, 13

A third form of autosomal dominant hyperinsulinism is associated with persistent mild asymptomatic hyperammonemia (blood ammonia levels 100–200 μmol/L or approximately 3-5 times normal), and is caused by gain of function mutations in GLUD1, the gene encoding mitochondrial glutamate dehydrogenase (GDH).14, 15 The phenotype is characterized by both fasting hypoglycemia and postprandial hypoglycemia following meals that contain protein.16 Leucine induces insulin secretion by allosterically activating GDH to stimulate oxidation of glutamate to α-ketoglutarate and ammonia. Mutations cause impaired GDH sensitivity to its allosteric inhibitor GTP, resulting in a gain of enzyme function and increased sensitivity to leucine.16 Children with GDH hyperinsulinism have an exaggerated acute insulin response to intravenous leucine17 and are leucine sensitive. In contrast, normal children and those with diffuse KATP channel hyperinsulinism have little or no insulin response to leucine.17, 18

In the current issue of The Journal, Fourtner et al19 have shown that in patients with KATP hyperinsulinism, ingestion of a 1 to 1.5 g per kg protein load, either as a meal or an amino acid hydrolysate, induced a decrease in blood glucose ranging from 17 to 69 mg/dL, similar to the response previously observed in children with GDH hyperinsulinism.20 It was previously thought that leucine-sensitive hypoglycemia and protein-induced hypoglycemia were synonymous, but Fourtner et al have shown that they are not the same.19 Whereas the protein sensitivity of GDH hyperinsulinism improves with diazoxide, which acts on the KATP channel, protein-induced hypoglycemia in KATP hyperinsulinism is not caused by leucine stimulation of excessive insulin release17 and is unresponsive to diazoxide. Rather, it is thought that other amino acids, particularly glutamine, may stimulate insulin secretion via mechanisms independent of both the GDH and KATP channel pathways. As illustrated by Case 1 in the article by Fourtner et al,19 protein-induced hypoglycemia can be as severe in patients with KATP channel hyperinsulinism as it is in GDH hyperinsulinism. A high-protein diet can aggravate hyperinsulinemic hypoglycemia and should be avoided.

Although glucose and amino acids are the prime regulators of insulin secretion, fatty acids can increase insulin secretion in vivo and can amplify glucose-induced insulin secretion in vitro. Mutations in the gene (HADHSC) encoding short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) are associated with autosomally recessive inherited hyperinsulinemic hypoglycemia. The clinical presentation is heterogeneous with either severe neonatal hypoglycemia or mild late-onset hypoglycemia.21, 22, 23, 24 SCHAD is an intramitochondrial enzyme that catalyses the penultimate reaction in the β-oxidation of fatty acids, the NAD+-dependent dehydrogenation of 3-hydroxyacyl-CoA to the corresponding 3-ketoacyl-CoA. The disease is characterized by raised plasma levels of 3-hydroxybutyryl-carnitine and 3-hydroxyglutaric aciduria. The precise mechanism where-by this intramitochondrial metabolic defect causes hyperinsulinism is not yet understood.

Despite extraordinary advances in our understanding of the pathophysiology of hyperinsulinism, only 30% to 50% of patients have a definable genetic abnormality.7, 25, 26 It is likely that other abnormalities will be revealed as the search continues for new defects in the insulin secretory apparatus, including defects in the intracellular control of calcium signaling of exocytosis.25

Congenital hyperinsulinism consists of numerous discrete genetic and etiologic entities that have considerable phenotypic overlap. Appropriate management of infants with this disorder requires precisely identifying and understanding the specific cause in the individual patient. Fifty years after Cochrane et al described protein-sensitive hypoglycemia in three infants with “spontaneous idiopathic hypoglycemia,”27 and owing in no small part to the contributions of investigators at Children’s Hospital of Philadelphia over the past 30 years, identifying the specific cause of congenital hyperinsulinism has become increasingly possible with tests now available to the clinician.

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PII: S0022-3476(06)00384-2

doi:10.1016/j.jpeds.2006.04.062

Refers to article:

  • Protein-sensitive hypoglycemia without leucine sensitivity in hyperinsulinism caused by KATP channel mutations

    Shannon H. Fourtner, Charles A. Stanley, Andrea Kelly
    The Journal of Pediatrics July 2006 (Vol. 149, Issue 1, Pages 47-52)

The Journal of Pediatrics
Volume 149, Issue 1 , Pages 6-7, July 2006

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