ArticleDiabetes2014
Mitochondrial GTP insensitivity contributes to hypoglycemia in hyperinsulinemia hyperammonemia by inhibiting glucagon release.
Article in Diabetes, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 21 citations in OpenAlex.
- Glutamate dehydrogenase hyperinsulinism: mechanisms, diagnosis, and treatment.Orphanet journal of rare diseases · 2023Review
- Article
- Metabolic cycles and signals for insulin secretion.Cell metabolism · 2022Review
- Multi-Tissue Acceleration of the Mitochondrial Phosphoenolpyruvate Cycle Improves Whole-Body Metabolic Health.Cell metabolism · 2020Article
- Localization of Human Glutamate Dehydrogenases Provides Insights into Their Metabolic Role and Their Involvement in Disease Processes.Neurochemical research · 2019Review
- The Genetic and Molecular Mechanisms of Congenital Hyperinsulinism.Frontiers in endocrinology · 2019Review
- Congenital Hyperinsulinism: Diagnosis and Treatment Update.Journal of clinical research in pediatric endocrinology · 2017Review
- A severe case of hyperinsulinism due to hemizygous activating mutation of glutamate dehydrogenase.Pediatric diabetes · 2017Article
- Argininosuccinate synthetase regulates hepatic AMPK linking protein catabolism and ureagenesis to hepatic lipid metabolism.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- The Hypoglycemic Phenotype Is Islet Cell-Autonomous in Short-Chain Hydroxyacyl-CoA Dehydrogenase-Deficient Mice.Diabetes · 2016Article
- Perspective on the Genetics and Diagnosis of Congenital Hyperinsulinism Disorders.The Journal of clinical endocrinology and metabolism · 2016Review
- Integrated, Step-Wise, Mass-Isotopomeric Flux Analysis of the TCA Cycle.Cell metabolism · 2015Article
- Mitochondrial regulation of β-cell function: maintaining the momentum for insulin release.Molecular aspects of medicine · 2015Review
- Article
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
Mitochondrial GTP (mtGTP)-insensitive mutations in glutamate dehydrogenase (GDH(H454Y)) 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.