Physical Exercise–Induced Hypoglycemia Caused by Failed Silencing of Monocarboxylate Transporter 1 in Pancreatic β Cells

• Published in: American journal of human genetics Vol. 81; no. 3; pp. 467 - 474
• Main Authors: Otonkoski, Timo, Jiao, Hong, Kaminen-Ahola, Nina, Tapia-Paez, Isabel, Ullah, Mohammed S., Parton, Laura E., Schuit, Frans, Quintens, Roel, Sipilä, Ilkka, Mayatepek, Ertan, Meissner, Thomas, Halestrap, Andrew P., Rutter, Guy A., Kere, Juha
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.09.2007; University of Chicago Press; The American Society of Human Genetics
• Subjects: Animals; Base Sequence; Biological and medical sciences; Electrophoretic Mobility Shift Assay; Exercise; Female; Fundamental and applied biological sciences. Psychology; Gene Silencing; General aspects. Genetic counseling; Genetics of eukaryotes. Biological and molecular evolution; Humans; Hypoglycemia - genetics; Insulin-Secreting Cells - metabolism; Male; Medical genetics; Medical sciences; Medicin och hälsovetenskap; Mice; Molecular and cellular biology; Molecular Sequence Data; Monocarboxylic Acid Transporters - genetics; Mutation; Pedigree; Promoter Regions, Genetic; Symporters - genetics; Physical exercise; Human; Metabolic diseases; Genetics; β Cell; Hypoglycemia; Pancreas; Failure
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/520960

Exercise- induced hyper insulinism (EIHI) is a dominantly inherited hypoglycemic disorder characterized by inappropriate insulin secretion during anaerobic exercise or on pyruvate load. We aimed to identify the molecular basis of this novel disorder of β-cell regulation. EIHI mapped to chromosome 1 (LOD score 3.6) in a genome scan performed for two families with 10 EIHI-affected patients. Mutational analysis of the promoter of the SLC16A1 gene, which encodes monocarboxylate transporter 1 (MCT1), located under the linkage peak, revealed changes in all 13 identified patients with EIHI. Patient fibroblasts displayed abnormally high SLC16A1 transcript levels, although monocarboxylate transport activities were not changed in these cells, reflecting additional posttranscriptional control of MCT1 levels in extrapancreatic tissues. By contrast, when examined in β cells, either of two SLC16A1 mutations identified in separate pedigrees resulted in increased protein binding to the corresponding promoter elements and marked (3- or 10-fold) transcriptional stimulation of SLC16A1 promoter-reporter constructs. These studies show that promoter-activating mutations in EIHI induce SLC16A1 expression in β cells, where this gene is not usually transcribed, permitting pyruvate uptake and pyruvate-stimulated insulin release despite ensuing hypoglycemia. These findings describe a novel disease mechanism based on the failure of cell-specific transcriptional silencing of a gene that is highly expressed in other tissues.