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Mitochondrial GTP Insensitivity Contributes to Hypoglycemia in Hyperinsulinemia Hyperammonemia by Inhibiting Glucagon Release
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 understa...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237996/ https://www.ncbi.nlm.nih.gov/pubmed/25024374 http://dx.doi.org/10.2337/db14-0783 |
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author | Kibbey, Richard G. Choi, Cheol Soo Lee, Hui-Young Cabrera, Over Pongratz, Rebecca L. Zhao, Xiaojian Birkenfeld, Andreas L. Li, Changhong Berggren, Per-Olof Stanley, Charles Shulman, Gerald I. |
author_facet | Kibbey, Richard G. Choi, Cheol Soo Lee, Hui-Young Cabrera, Over Pongratz, Rebecca L. Zhao, Xiaojian Birkenfeld, Andreas L. Li, Changhong Berggren, Per-Olof Stanley, Charles Shulman, Gerald I. |
author_sort | Kibbey, Richard G. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4237996 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-42379962015-12-01 Mitochondrial GTP Insensitivity Contributes to Hypoglycemia in Hyperinsulinemia Hyperammonemia by Inhibiting Glucagon Release Kibbey, Richard G. Choi, Cheol Soo Lee, Hui-Young Cabrera, Over Pongratz, Rebecca L. Zhao, Xiaojian Birkenfeld, Andreas L. Li, Changhong Berggren, Per-Olof Stanley, Charles Shulman, Gerald I. Diabetes Islet Studies 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. American Diabetes Association 2014-12 2014-11-13 /pmc/articles/PMC4237996/ /pubmed/25024374 http://dx.doi.org/10.2337/db14-0783 Text en © 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. |
spellingShingle | Islet Studies Kibbey, Richard G. Choi, Cheol Soo Lee, Hui-Young Cabrera, Over Pongratz, Rebecca L. Zhao, Xiaojian Birkenfeld, Andreas L. Li, Changhong Berggren, Per-Olof Stanley, Charles Shulman, Gerald I. Mitochondrial GTP Insensitivity Contributes to Hypoglycemia in Hyperinsulinemia Hyperammonemia by Inhibiting Glucagon Release |
title | Mitochondrial GTP Insensitivity Contributes to Hypoglycemia in Hyperinsulinemia Hyperammonemia by Inhibiting Glucagon Release |
title_full | Mitochondrial GTP Insensitivity Contributes to Hypoglycemia in Hyperinsulinemia Hyperammonemia by Inhibiting Glucagon Release |
title_fullStr | Mitochondrial GTP Insensitivity Contributes to Hypoglycemia in Hyperinsulinemia Hyperammonemia by Inhibiting Glucagon Release |
title_full_unstemmed | Mitochondrial GTP Insensitivity Contributes to Hypoglycemia in Hyperinsulinemia Hyperammonemia by Inhibiting Glucagon Release |
title_short | Mitochondrial GTP Insensitivity Contributes to Hypoglycemia in Hyperinsulinemia Hyperammonemia by Inhibiting Glucagon Release |
title_sort | mitochondrial gtp insensitivity contributes to hypoglycemia in hyperinsulinemia hyperammonemia by inhibiting glucagon release |
topic | Islet Studies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237996/ https://www.ncbi.nlm.nih.gov/pubmed/25024374 http://dx.doi.org/10.2337/db14-0783 |
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