Altered amyloid precursor protein processing regulates glucose uptake and oxidation in cultured rodent myotubes

D. Lee Hamilton, John A. Findlay, Gemma Montagut , Paul J. Meakin, Dawn Bestow, Susan M. Jalicy, Michael L. J. Ashford (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    10 Citations (Scopus)
    157 Downloads (Pure)

    Abstract

    Aims/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 C 2C12 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.

    Original languageEnglish
    Pages (from-to)1684-1692
    Number of pages9
    JournalDiabetologia
    Volume57
    Issue number8
    Early online date22 May 2014
    DOIs
    Publication statusPublished - Aug 2014

    Keywords

    • Amyloid
    • BACE1
    • Glucose uptake
    • Glut4
    • Insulin
    • PI3K
    • Skeletal muscle
    • Type 2 diabetes

    Fingerprint Dive into the research topics of 'Altered amyloid precursor protein processing regulates glucose uptake and oxidation in cultured rodent myotubes'. Together they form a unique fingerprint.

    Cite this