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Congenital hyperinsulinism
Published in Demetrius Pertsemlidis, William B. Inabnet III, Michel Gagner, Endocrine Surgery, 2017
Christopher A. Behr, Stephen E. Dolgin
While mutations in the genes affecting the KATP channel are implicated in 80%–90% of the identifiable causes of CH, the other 10%–20% of cases are caused by mutations in one of six different genes affecting other processes. The GLUD1 (encoding glutamate dehydrogenase enzyme), CGK (encoding glucokinase), HADH (encoding short-chain L-3-hydroxyacyl-CoA dehydrogenase), SLC16A1 (encoding a monocarboxylate transporter), and UCP2 (encoding UCP2 protein) genes all affect the ATP/ADP ratio within the beta cells, which determines the status of the KATP channel [4, 23–26]. Likewise, a transcription factor defect in the HNF4A (hepatocyte nuclear factor 4 alpha) gene has been shown to cause neonatal hyperinsulinemia [27]. All of these mutations result in the diffuse, usually mild, form of CH, and all are diazoxide responsive (except GCK, which has variable diazoxide responsiveness) (Figure 39.2).
High-fat and combined high-fat–high-fructose diets impair episodic-like memory and decrease glutamate and glutamine in the hippocampus of adult mice
Published in Nutritional Neuroscience, 2022
Humberto Martínez-Orozco, Luis A. Reyes-Castro, Consuelo Lomas-Soria, Cuauhtémoc Sandoval-Salazar, Joel Ramírez-Emiliano, Sofía Díaz-Cintra, Silvia Solís-Ortiz
Samples of hippocampus were collected immediately after mice were euthanized to analyze the gene expression of Pyruvate carboxylase gene (PCX), Solute Carrier Family 2 Member 1 gene (SLC2A1), Glutamate-Ammona Ligase gene (GLUL), Glutamate Decarboxylase 2 gene (GAD2), Glutamate Decarboxylase 1 gene (GAD1) and Glutamate Dehydrogenase 1 gene (GLUD1). These genes are involved in glucose transport and metabolism-related proteins for GABA, glutamine, and glutamate metabolism-related proteins. Gene expression was studied by extracting the total RNA from hippocampus using 1mL of TRIzol reagent (Invitrogen™) and the number of independent replicates was n=6 per group. The amount and quality of RNA were estimated spectrophotometrically at 260/280 nm and a constant amount of RNA (1-3 µg) was reverse transcribed using a reverse transcription assay (Roche Diagnostics). Identical qPCR conditions were used for all genes, which were normalized against the housekeeping gene Rrpl32 as internal control. The list of primer sequences used in qPCR are presented in Table 1. Amplifications were performed on a Light Cycler 2.0 real-time qPCR instrument (Roche) using the Roche master mix in combination with hydrolysis probes (Universal Probe Library; Roche) following a standard protocol. Briefly, activation of Taq DNA polymerase and DNA denaturation was performed at 95°C for 10 min, followed by 45 amplification cycles consisting of 10 s at 95°C, 30 s at 60°C and 1 s at 72°C. Data obtained from qPCR were analyzed using the ΔΔCT method [22].
An expert overview of emerging therapies for acute myeloid leukemia: novel small molecules targeting apoptosis, p53, transcriptional regulation and metabolism
Published in Expert Opinion on Investigational Drugs, 2020
Kapil Saxena, Marina Konopleva
Glutamine metabolism is involved in hematopoietic cell survival primarily via an indirect role in ATP production [116]. Glutamine is converted to glutamate via the enzyme glutaminase (GLS) [116]. The mitochondrial enzyme glutamate dehydrogenase 1 (GLUD1, encoded by the gene GLUD1) subsequently converts glutamate to alpha-ketoglutarate, a substrate in the citric acid (TCA) cycle [116]. There are two major isoenzymes of GLS: GLS1 (encoded by the gene GLS) and GLS2 (encoded by the gene GLS2) [117]. The Cancer Genome Atlas shows that GLS and GLUD1 are overexpressed in AML cells [116]. Furthermore, the GLS1 isoforms kidney-type glutaminase (KGA) and glutaminase C (GAC) are present at the protein level in both AML cell lines and primary samples [116,118]. AML cells have an increased number of mitochondria and a higher oxygen consumption rate (OCR) compared to normal hematopoietic cells, not unexpected given their high replicative capacity [116]. Removal of glutamine from the cell culture medium of AML cells leads to a reduction in oxidative phosphorylation (OxPhos), which leads to decreased ATP production and resultant apoptosis [116,118]. Furthermore, GLS1 knockdown leads to increased apoptosis of AML cell lines but not of nontransformed CD34+ hematopoietic cells [118]. Thus, as with other cancer cell types, AML cells seem to require high levels of glutamine for sufficient energy production and survival.