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

Abstract

Activating mutations in the GLUD1 gene, which encodes glutamate dehydrogenase (GDH), result in the hyperinsulinism-hyperammonemia syndrome. GDH is an allosterically regulated enzyme responsible for amino acid-mediated insulin secretion via the oxidative deamination of glutamate to 2-oxoglutarate, leading to ATP production and insulin release. This study characterizes a novel combination of mutations in GLUD1 found in a neonate who presented on the first day of life with severe hypoglycemia, hyperammonemia, and seizures. Mutation analysis revealed a novel frameshift mutation (c.37delC) inherited from the asymptomatic mother that results in a truncated protein and a de novo activating mutation (p.S445L) close to the GTP binding site that has previously been reported. GTP inhibition of GDH enzyme activity in 293T cells expressing the p.S445L or wild type GDH showed that the half-maximal inhibitory concentration (IC50) for GTP was approximately 800 times higher for p.S445L compared to wild type. GTP inhibition of GDH activity in lymphoblasts from the patient, from a heterozygote for the p.S445L mutation, and in wild type lymphoblasts showed that the IC50 for GTP of the patient was approximately 200 times that of wild type and 7 times that of heterozygote. However, while the patient had a loss of GTP inhibition of GDH that was more severe than that of heterozygotes, the patient’s clinical phenotype is similar to typical heterozygous mutations of GDH. This is the first time we have observed a functionally homozygous activating mutation of GDH in a human.

Alpha-ketoglutaric acid ameliorates hyperglycemia in diabetes by inhibiting hepatic gluconeogenesis via serpina1e signaling

“…One interesting glucose phenotype is that both acute and chronic AKG treatments increase blood insulin but not glucagon levels in DIO and db/db mice. These findings are consistent with previous reports that AKG stimulates insulin secretion through hypoxia-inducible factor-prolyl hydroxylases (PHDs) in clonal β-cells as well as rodent and human islets 21,43 . Glucose-induced secretion of insulin is wellknown to inhibit hepatic glucose production 44 , suggesting a possibility that AKG increases insulin secretion to indirectly inhibit hepatic gluconeogenesis.…”

Clinical and Molecular Spectrum of Glutamate Dehydrogenase Gene Defects in 26 Chinese Congenital Hyperinsulinemia Patients

“…These GLUD1 mutations are located in both the catalytic (exons 6 and 7) and allosteric (exons 10, 11, and 12) domains of GDH. Only one patient with disease caused by a combination of frameshift and missense mutations that are functionally homozygous has been reported [ 14 ]. A total of 92% (24/26) of patients in the present study carried a sporadic activating mutation in GLUD1 .…”

“…Functional analysis was performed by analyzing the expression of wild-type and mutated GDH in 293T cells. GDH enzyme kinetics were determined spectrophotometrically in cell homogenates as we described previously [ 12 – 14 ].…”

Role of upstream stimulatory factor 2 in glutamate dehydrogenase gene transcription

“…In favour of this hypothesis, overexpression of Gdh in mice increases insulin secretion (Carobbio et al 2004), whereas Gdh inhibition in pancreatic β-cells decrease impairs insulin secretion (Carobbio et al 2009). Furthermore, activating mutations in Gdh causes hyperinsulinemia and hyperammonemia in humans (Li et al 2014, Barrosse-Antle et al 2017. However, the effect of nutritional status on Gdh expression seems speciesspecific in fish.…”