title: Mitochondrial GTP insensitivity contributes to hypoglycemia in hyperinsulinemia hyperammonemia by inhibiting glucagon release.
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.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT richard.kibbey@yale.edu.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Kibbey
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.
authors.forename: Cheol Soo
authors.initials: CS
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.
authors.forename: Hui-Young
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL Department of Molecular Medicine and Surgery, The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Over
authors.initials: O
authors.lastname: Cabrera
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Pongratz
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Birkenfeld
authors.affiliation: Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, PA.
authors.forename: Changhong
authors.initials: C
authors.lastname: Li
authors.affiliation: Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL Department of Molecular Medicine and Surgery, The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.affiliation: Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, PA.
authors.forename: Charles
authors.initials: C
authors.lastname: Stanley
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D005934:Glucagon / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D015309:Glucose Clamp Technique; D005969:Glutamate Dehydrogenase / Q000235:genetics*; D006160:Guanosine Triphosphate / Q000378:metabolism*; D006801:Humans; D022124:Hyperammonemia / Q000235:genetics*; D006946:Hyperinsulinism / Q000235:genetics*; D007003:Hypoglycemia / Q000235:genetics*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D013577:Syndrome
chemical_list: D000596:Amino Acids; D007328:Insulin; D006160:Guanosine Triphosphate; D005934:Glucagon; D005969:Glutamate Dehydrogenase