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

• Published in: Diabetologia 2014-08, Vol.57 (8), p.1684-1692
• Main Authors: Hamilton, D. Lee, Findlay, John A., Montagut, Gemma, Meakin, Paul J., Bestow, Dawn, Jalicy, Susan M., Ashford, Michael L. J.
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - metabolism; Animals; Aspartic Acid Endopeptidases - genetics; Aspartic Acid Endopeptidases - metabolism; Biological and medical sciences; Cell Line; Ceramides - pharmacology; Diabetes; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzymes; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fundamental and applied biological sciences. Psychology; Glucose; Glucose - metabolism; Human Physiology; Insulin resistance; Internal Medicine; Kinases; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - metabolism; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Musculoskeletal system; Oxidation; Palmitic Acid - pharmacology; Proteins; Rats; Striated muscle. Tendons; Vertebrates: osteoarticular system, musculoskeletal system
• ISSN: 0012-186X; 1432-0428; 1432-0428
• DOI: 10.1007/s00125-014-3269-x

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 C 2 C 12 myotubes decreased glucose uptake, glucose oxidation and oxygen consumption rate. APP overexpression increased and α-secretase inhibition decreased glucose uptake in C 2 C 12 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.