Mitochondrial GTP Insensitivity Contributes to Hypoglycemia in Hyperinsulinemia Hyperammonemia by Inhibiting Glucagon Release

Abstract

Mitochondrial GTP (mtGTP)-insensitive mutations in glutamate dehydrogenase (GDHH454Y) result in fasting and amino acid–induced hypoglycemia in hyperinsulinemia hyperammonemia (HI/HA). Surprisingly, hypoglycemia may occur in this disorder despite appropriately suppressed insulin. To better understand the islet-specific contribution, transgenic mice expressing the human activating mutation in β-cells (H454Y mice) were characterized in vivo. As in the humans with HI/HA, H454Y mice had fasting hypoglycemia, but plasma insulin concentrations were similar to the controls. Paradoxically, both glucose- and glutamine-stimulated insulin secretion were severely impaired in H454Y mice. Instead, lack of a glucagon response during hypoglycemic clamps identified impaired counterregulation. Moreover, both insulin and glucagon secretion were impaired in perifused islets. Acute pharmacologic inhibition of GDH restored both insulin and glucagon secretion and normalized glucose tolerance in vivo. These studies support the presence of an mtGTP-dependent signal generated via β-cell GDH that inhibits α-cells. As such, in children with activating GDH mutations of HI/HA, this insulin-independent glucagon suppression may contribute importantly to symptomatic hypoglycemia. The identification of a human mutation causing congenital hypoglucagonemic hypoglycemia highlights a central role of the mtGTP–GDH–glucagon axis in glucose homeostasis.

A severe case of hyperinsulinism due to hemizygous activating mutation of glutamate dehydrogenase

“…7,12,13 In addition, recent studies in a transgenic mouse model with expression of p.H454Y GDH mutation in beta-cells suggest that inhibition of glucagon release may play a role in the mechanism of hypoglycemia associated with GDH activating mutation. 14 It is interesting that, despite evidence of more severe hypoglycemia, our patient's plasma ammonia concentrations were not higher than in patients with p.S445L heterozygous mutants or other GDH activating mutants in general. Recent work suggests that the elevated ammonia in HI/HA is caused by increased production of ammonia from GDH overactivity in the kidney, rather than impaired hepatic ureagenesis.…”

“…Hypoglycemia in the context of appropriately suppressed insulin levels has been seen previously in HI/HA patients and in other forms of congenital HI . In addition, recent studies in a transgenic mouse model with expression of p.H454Y GDH mutation in beta‐cells suggest that inhibition of glucagon release may play a role in the mechanism of hypoglycemia associated with GDH activating mutation …”

Integrated, Step-Wise, Mass-Isotopomeric Flux Analysis of the TCA Cycle

“…Glutamate anaplerosis requires a net loss of nitrogen either to ammonia or urea. Consequently, metabolic exchange is the most likely since at 9 mM glucose concentrations aspartate levels are reduced (Supplemental Table S5), transaminases do not generate free ammonia, and GDH is completely inhibited by mitochondrial GTP (Kibbey et al, 2014; Tanizawa et al, 2002). Since there was relatively little dilution in the distal reactions of the TCA cycle (Φ GS , Φ SM and Φ MO ; Figures 2F, 3C and Supplemental Figure S2) then glutamate is fully in exchange with αKG at a rate that is very fast relative to the TCA cycle rate.…”

Argininosuccinate synthetase regulates hepatic AMPK linking protein catabolism and ureagenesis to hepatic lipid metabolism

“…GDH activity is highly controlled by allosteric regulation; mitochondrial GTP (mtGTP) inhibits GDH, whereas L-leucine activates GDH (22,23). mtGTP is an important mitochondrial energy sensor in both hepatocytes and pancreatic islet cells, reflecting the balance between tricarboxylic acid cycle and gluconeogenic fluxes implicated in glucose production, insulin secretion, and glucagon secretion (2,(24)(25)(26). In contrast, as an essential amino acid, L-leucine reflects high nutrient protein levels and can activate GDH even when mitochondrial energy is high.…”