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

Abstract

Exercise-induced hyperinsulinism (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 beta -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 beta 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 beta 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.

Cluster analysis of rat pancreatic islet gene mRNA levels after culture in low-, intermediate- and high-glucose concentrations

“…When examining these figures, it should be born in mind that the overall islet mRNA profile reflects the mean of phenomena in different cell types. Thus, although most changes are likely to have occurred in beta cells (∼70-80% of islet mass), some may have occurred in non-beta cells, especially for genes normally disallowed in beta cells like the lactate/pyruvate transporter Mct1 (also known as Slc16a1) [1,38]. Please also note that changes in mRNA levels may result from altered transcription or mRNA stability and that the higher level of complexity due to alternative mRNA splicing was not addressed.…”

Tissue-specific disallowance of housekeeping genes: The other face of cell differentiation

“…One of the deeply repressed genes in islets of Langerhans is Mct1, encoding the monocarboxylate transporter MCT1, which mediates the transport of lactate and pyruvate across cell membranes and is present in all tissues except adult beta-cells (Otonkoski et al 2007;Quintens et al 2008). Inadvertent expression of MCT1 in beta-cells results in hypoglycemia after physical exercise due to inappropriate insulin release (Otonkoski et al 2003).…”

“…Despite this tissue-specific repression, lactate dehydrogenase A (Ldha), for example, appears in many published lists of housekeeping genes (Warrington et al 2000;Hsiao et al 2001;Eisenberg and Levanon 2003;Tu et al 2006). Inappropriate activation of a tissue-specifically repressed gene was previously demonstrated to be associated with human disease (Otonkoski et al 2007). Gain-of-function mutation of the Mct1 promoter leads to uptake of lactate and pyruvate by the beta-cells and disruption of correct glucose sensing.…”

“…Gain-of-function mutation of the Mct1 promoter leads to uptake of lactate and pyruvate by the beta-cells and disruption of correct glucose sensing. When large amounts of lactate and pyruvate are generated by muscles during physical exercise, insulin is secreted, resulting in hypoglycemia and potential brain dysfunction (Otonkoski et al 2003(Otonkoski et al , 2007.…”

The AMP-regulated kinase family: Enigmatic targets for diabetes therapy

“…Whether the predominance of AMPK 1 versus 2 isoforms in β-cells is also related to the unusual metabolic configuration of these cells (Sekine et al, 1994;Liang et al, 1996;Schuit et al, 1997;Zhao and Rutter, 1998;Zhao C. et al, 2001), in which anaerobic glycolysis is "disallowed" thanks to the absence of detectable lactate dehydrogenase and lactate/monocarboxylate (MCT-1) transport activity (Otonkoski et al, 2007) remains to be examined.…”