Functional and Metabolomic Consequences of KATP Channel Inactivation in Human Islets
| Autor: | Diva D. De León, Tricia R. Bhatti, N. Scott Adzick, Charles A. Stanley, Jonathan Schug, Ali Naji, Nicolai M. Doliba, Itzhak Nissim, Kara E. Boodhansingh, Mark J. Dunne, Chengyang Liu, Franz M. Matschinsky, Indraneel Banerjee, Changhong Li, Bing Han, Karen E. Cosgrove, Amanda M. Ackermann, Klaus H. Kaestner |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Glutamine Endocrinology Diabetes and Metabolism Gene Expression Sulfonylurea Receptors Serine 0302 clinical medicine KATP Channels Insulin-Secreting Cells Insulin Secretion Insulin Glycolysis gamma-Aminobutyric Acid Alanine Carbon Isotopes Flow Cytometry Immunohistochemistry Female endocrine system Basal rate medicine.medical_specialty Glycine 030209 endocrinology & metabolism Carbohydrate metabolism Biology Hypoglycemia Islets of Langerhans 03 medical and health sciences Oxygen Consumption Pancreatectomy Microscopy Electron Transmission Internal medicine Journal Article Internal Medicine medicine Humans Metabolomics RNA Messenger Potassium Channels Inwardly Rectifying Calcium metabolism Sequence Analysis RNA Infant Newborn Infant medicine.disease Glucose 030104 developmental biology Endocrinology Islet Studies Case-Control Studies Mutation Congenital hyperinsulinism Calcium Congenital Hyperinsulinism |
| Zdroj: | Diabetes Li, C, Ackermann, A M, Boodhansingh, K E, Bhatti, T R, Liu, C, Schug, J, Doliba, N, Han, B, Cosgrove, K E, Banerjee, I, Matschinsky, F M, Nissim, I, Kaestner, K H, Naji, A, Adzick, N S, Dunne, M J, Stanley, C A & De León, D D 2017, ' Functional and Metabolomic Consequences of KATP Channel Inactivation in Human Islets ', Diabetes, vol. 66, no. 7, pp. 1901-1913 . https://doi.org/10.2337/db17-0029 |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | Loss-of-function mutations of β-cell KATP channels cause the most severe form of congenital hyperinsulinism (KATPHI). KATPHI is characterized by fasting and protein-induced hypoglycemia that is unresponsive to medical therapy. For a better understanding of the pathophysiology of KATPHI, we examined cytosolic calcium ([Ca2+]i), insulin secretion, oxygen consumption, and [U-13C]glucose metabolism in islets isolated from the pancreases of children with KATPHI who required pancreatectomy. Basal [Ca2+]i and insulin secretion were higher in KATPHI islets compared with controls. Unlike controls, insulin secretion in KATPHI islets increased in response to amino acids but not to glucose. KATPHI islets have an increased basal rate of oxygen consumption and mitochondrial mass. [U-13C]glucose metabolism showed a twofold increase in alanine levels and sixfold increase in 13C enrichment of alanine in KATPHI islets, suggesting increased rates of glycolysis. KATPHI islets also exhibited increased serine/glycine and glutamine biosynthesis. In contrast, KATPHI islets had low γ-aminobutyric acid (GABA) levels and lacked 13C incorporation into GABA in response to glucose stimulation. The expression of key genes involved in these metabolic pathways was significantly different in KATPHI β-cells compared with control, providing a mechanism for the observed changes. These findings demonstrate that the pathophysiology of KATPHI is complex, and they provide a framework for the identification of new potential therapeutic targets for this devastating condition. |
| Databáze: | OpenAIRE |
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