Mitochondrial GTP insensitivity contributes to hypoglycemia in Hyperinsulinemia Hyperammonemia (HI/HA) by inhibiting glucagon release

  1. Gerald I. Shulman1,2,3
  1. Departments of 1Internal Medicine,
  2. 2Cellular & Molecular Physiology, and
  3. 3Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, 06520, USA
  4. 4Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
  5. 5The Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery Karolinska Institutet, SE-171 76 Stockholm, Sweden;
  6. 6Division of Endocrinology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
  1. Corresponding author: Richard G. Kibbey, E-mail richard.kibbey{at}


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 beta-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 counter regulation. 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 a mtGTP-dependent signal generated via beta-cell GDH that inhibits alpha-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.

  • Received May 16, 2014.
  • Accepted July 3, 2014.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See for details.

No Related Web Pages