hamilton-alteredamyloid-2014.pdf (852.79 kB)
Altered amyloid precursor protein processing regulates glucose uptake and oxidation in cultured rodent myotubes
journal contribution
posted on 2014-08-01, 00:00 authored by Lee HamiltonLee Hamilton, John A Findlay, Gemma Montagut, Paul J Meakin, Dawn Bestow, Susan M Jalicy, Michael L J AshfordAIMS/HYPOTHESIS: Impaired glucose uptake in skeletal muscle is an important contributor to glucose intolerance in type 2 diabetes. The aspartate protease, beta-site APP-cleaving enzyme 1 (BACE1), a critical regulator of amyloid precursor protein (APP) processing, modulates in vivo glucose disposal and insulin sensitivity in mice. Insulin-independent pathways to stimulate glucose uptake and GLUT4 translocation may offer alternative therapeutic avenues for the treatment of diabetes. We therefore addressed whether BACE1 activity, via APP processing, in skeletal muscle modifies glucose uptake and oxidation independently of insulin. METHODS: Skeletal muscle cell lines were used to investigate the effects of BACE1 and α-secretase inhibition and BACE1 and APP overexpression on glucose uptake, GLUT4 cell surface translocation, glucose oxidation and cellular respiration. RESULTS: In the absence of insulin, reduction of BACE1 activity increased glucose uptake and oxidation, GLUT4myc cell surface translocation, and basal rate of oxygen consumption. In contrast, overexpressing BACE1 in C2C12 myotubes decreased glucose uptake, glucose oxidation and oxygen consumption rate. APP overexpression increased and α-secretase inhibition decreased glucose uptake in C2C12 myotubes. The increase in glucose uptake elicited by BACE1 inhibition is dependent on phosphoinositide 3-kinase (PI3K) and mimicked by soluble APPα (sAPPα). CONCLUSIONS/INTERPRETATION: Inhibition of muscle BACE1 activity increases insulin-independent, PI3K-dependent glucose uptake and cell surface translocation of GLUT4. As APP overexpression raises basal glucose uptake, and direct application of sAPPα increases PI3K-protein kinase B signalling and glucose uptake in myotubes, we suggest that α-secretase-dependent shedding of sAPPα regulates insulin-independent glucose uptake in skeletal muscle.
History
Journal
DiabetologiaVolume
57Issue
8Pagination
1684 - 1692Publisher
SpringerLocation
Berlin, GermanyPublisher DOI
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eISSN
1432-0428Language
engPublication classification
C1 Refereed article in a scholarly journalCopyright notice
2014, The AuthorsUsage metrics
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Amyloid Precursor Protein SecretasesAmyloid beta-Protein PrecursorAnimalsAspartic Acid EndopeptidasesCell LineCeramidesGlucoseMuscle Fibers, SkeletalMuscle, SkeletalPalmitic AcidRatsScience & TechnologyLife Sciences & BiomedicineEndocrinology & MetabolismAmyloidBACE1Glucose uptakeGlut4InsulinPI3KSkeletal muscleType 2 diabetesHUMAN SKELETAL-MUSCLEINDUCED INSULIN-RESISTANCEGLUT4 TRANSLOCATIONDIABETES-MELLITUSPRIMARY DEFECTIN-VIVOTRANSPORTBETAOBESITYNIDDM
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