Two genetic forms of hyperinsulinemic hypoglycemia caused by dysregulation of glutamate dehydrogenase

Abstract

Glutamate dehydrogenase (GDH) has recently been shown to be involved in two genetic disorders of hyperinsulinemic hypoglycemia in children. These include the hyperinsulinism/hyperammonemia syndrome caused by dominant activating mutations of GLUD1 which interfere with inhibitory regulation by GTP and hyperinsulinism due to recessive deficiency of short-chain 3-hydroxy-acyl-CoA dehydrogenase (SCHAD, encoded by HADH1). The clinical manifestations of the abnormalities in pancreatic ß-cell insulin regulation include fasting hypoglycemia, as well as protein-sensitive hypoglycemia. The latter is due to abnormally increased sensitivity of affected children to stimulation of insulin secretion by the amino acid, leucine. In patients with GDH activating mutations, mild hyperammonemia occurs in both the basal and protein-fed state, possibly due to increased renal ammoniagenesis. Some patients with GDH activating mutations appear to be at unusual risk of developmental delay and generalized epilepsy, perhaps reflecting consequences of increased GDH activity in the brain. Studies of these two disorders have been carried out in mouse models to define the mechanisms of insulin dysregulation. In SCHAD deficiency, the activation of GDH is due to loss of a direct inhibitory protein-protein interaction between SCHAD and GDH. These two novel human disorders demonstrate the important role of GDH in insulin regulation and illustrate unexpectedly important reasons for the unusually complex allosteric regulation of GDH.

Fig 1

Fasting vs. Protein-induced Hypoglycemia in a teen-age patient with the HI / HA Syndrome. Note the rapid onset of hypoglycemia after a protein meal compared to the more gradual development of hypoglycemia during fasting (modified from 9).

Figure 2

Role of GDH in the Hyperinsuliinism / Hyperammonemia Syndrome. In the ϐ-cell, GDH is activated by leucine to trigger insulin release in response to amino acids (protein meal). The increased oxidation of glutamate increases the ATP/ADP ratio leading to closure of the plasma membrane ATP-dependent potassium channel via the sulfonylurea receptor (SUR1), membrane depolarization, opening of voltage-gated calcium channels, increase in cytosolic calcium, and release of insulin from stored granules. In the liver, glutamate may be a source of ammonia, as well as a substrate for formation of N-acetylglutamate which is a required allosteric activator of the first step in urea synthesis. However, note that the direction of GDH in liver may be toward glutamate synthesis rather than oxidation. In the kidney, oxidation of glutamate via GDH provides ammonia in adaptation to acidemia. Uncontrolled GDH activity leads to excessive release of insulin in ϐ-cells and excessive ammonia production (primarily in kidney).

Figure 3

Effect of hyperglycemia on leucine AIR in HI/HA children (based on data in Ref 28).

Fig 4

Location and frequency of HI/HA mutations in GDH. Mutations indicated in circles as “sporadic”/”familial”; orange residues indicate exons 11&12 mutations, green residues indicagte exons 6&7 mutations. In the total of 84 cases, 66% were sporadic while 34% were familial.

Figure 5

GTP Sensitivity of HI / HA GDH (based on data from Ref 14 ).

Fig 6

H454Y transgenic islet responses to fuel-mediated insulin release. Transgenic islets are indicated as black diamonds, controls as open triangles. In panel B, closed circles show islets from an H454Y transgenic line with increased transgene expression; inset grey diamonds show suppression of insulin release by glutaminase inhibition with 40 μM DON (reproduced from with permission).

Figure 7

GDH flux in H454Y transgenic islets in the presence of 25 mM glucose, 10 mM leucine, and 10 mM [2–15N]-glutamine.

Fig 8

Studies of SCHAD−/− islets. A. Increased glutaminolysis. B. Increased responsiveness to amino acid mixture. C. Calcium response in SCHAD−/− islets requires glutamine + leucine + alanine. D. In contrast, islets with GDH activating mutation respond without alanine (reproduced from with permission).

Figure 9

SCHAD acts via a “moonlighting protein” effect to inhibit GDH enzymatic activity in pancreatic ϐ-cells.