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

Citation

Hamilton DL, Findlay JA, Montagut G, Meakin PJ, Bestow D, Jalicy SM & Ashford MLJ (2014) Altered amyloid precursor protein processing regulates glucose uptake and oxidation in cultured rodent myotubes. Diabetologia, 57 (8), pp. 1684-1692. https://doi.org/10.1007/s00125-014-3269-x

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 C2C12myotubes decreased glucose uptake, glucose oxidation and oxygen consumption rate. APP overexpression increased and α-secretase inhibition decreased glucose uptake in C2C12myotubes. 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.

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

Journal
Diabetologia: Volume 57, Issue 8