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Diabetes. 2014 Dec;63(12):4218-29. doi: 10.2337/db14-0783. Epub 2014 Jul 14.

Mitochondrial GTP insensitivity contributes to hypoglycemia in hyperinsulinemia hyperammonemia by inhibiting glucagon release.

Author information

  • 1Department 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.
  • 2Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.
  • 3Diabetes 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.
  • 4Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, PA.
  • 5Department 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.

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.

© 2014 by the American Diabetes Association. 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.

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