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“Hyperinsulinism-Hyperammonemia Syndrome”, Victor McKusick, Mendelian Inheritance in Man, 1966. (GDH) icd10=E72.8

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Genomic coordinate (human 10:87,050,202 GDH) & (mouse 14:34,032,684 Gdh).

Cytoband (human 10q23.2 GDH) & (mouse 14qB Gdh).

Here I present: “Hyperinsulinism-Hyperammonemia Syndrome“, Victor McKusick, Mendelian Inheritance in Man’, 1966. (GDH) icd10=E72.8

INTRODUCTION.
 
In pancreatic beta cells,
glutamate dehydrogenase (GDH) plays a pivotal role in regulating the secretion of insulin’, acting as a key energy sensor and link between amino acid metabolism and the glucose-stimulated insulin’ release pathway.
  • Glucose as the Primary Trigger: The primary trigger for insulin’ secretion is high glucose levels. Glucose metabolism in the beta cell increases the ATP/ADP ratio, which closes ATP-dependent potassium channels, leading to membrane depolarization and an influx of calcium ions. This rise in intracellular Ca2+Ca raised to the 2 plus power Ca2+ is the direct trigger for insulin’ exocytosis.
  • GDH in the Amplifying Pathway: GDH is essential for the full amplitude and sustained phase of glucose-stimulated insulin’ secretion (GSIS). GDH contributes to the pool of intracellular glutamate, which acts as a signaling molecule that amplifies the Ca2+Ca raised to the 2 plus power
    Ca2+-induced insulin’ release. In GDH-deficient cells, the GSIS response is significantly reduced, but it can be restored by adding a membrane-permeable glutamate precursor.
  • Amino Acid Stimulation: Certain amino acids, particularly leucine and glutamine, stimulate insulin’ release by allosterically activating GDH. This activation enhances the oxidative deamination of glutamate to α-ketoglutarate, which enters the TCA cycle, increases ATP production, and contributes to the closure of channels, thus triggering insulin’ secretion.
  • Energy Sensor Role: GDH activity is tightly regulated by the cellular energy state. High energy signals (high GTP and ATP levels) inhibit GDH activity, preventing inappropriate insulin’ secretion when energy stores are sufficient. Low energy signals (high ADP levels) and leucine activate GDH, allowing amino acid metabolism to support energy production and basal insulin’ release during fasting gene encoding GDH cause the hyperinsulinism-hyperammonemia syndrome.
These mutations impair the enzyme’s sensitivity to its normal inhibitor, GTP, leading to chronically elevated GDH activity.
  • The result is persistent hypersecretion of insulin’, particularly after protein-rich meals (leucine-sensitive hypoglycemia), and mildly elevated blood ammonia levels.

Familial hyperinsulinism, hyperammonemia of infancy is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin’ secretion by low glucose levels. Unless early and aggressive intervention is undertaken, brain damage may occur.

There evidence that familial hyper­­insulinism, hyperammonemia is caused by mutation in the glutamate dehydrogenase (GDH) gene encoded on genomic coordinate 10:87,050,202 and cytoband 10q2­3.2 in humans.

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