Promoting Glut4 Translocation in Diabetes with MGF E-domain Peptide
Abstract
The metabolic changes in diabetes are directly triggered by hyperglycemia and the rate limiting step in glucose uptake is the translocation of the insulin-sensitive glucose transporter protein-4 (GLUT4) in insulin sensitive tissues. The purpose of this was to test whether peptide analogs derived from the IGF-1 isoform expressed in muscle known as Mechano-growth factor can function as a bio-therapeutics to modulate of AS160 phosphorylation which is necessary to stimulate GLUT4 function. Using skeletal muscle cell based models, we aimed to define an optimal candidate peptide to test in animal based modes of diabetes. Skeletal muscle myotube cells undergoing membrane depolarization in the presence of 3 mM extracellular calcium are necessary to demonstrate peptide mediated actions. We have found by preventing phosphorylation within the 14-3-3 binding domain of the S/A18 peptide blocks Akt mediated inhibition of the Raf/ERK signaling branch following IGF-1 stimulation, whereas phosphorylation within the 14-3-3 binding domain of the S/E18 peptide may augment Akt signaling by shutting down Raf/ERK signaling. Consequently, we have defined that the MGF E-domain peptides act as modulators of branches of theIGF-1 signaling pathway through interactions with specific 14-3-3 binding proteins. Since Akt directly phosphorylates AS160 to stimulate GLUT4, we propose the S/E18 peptide may function as an optimal candidate for further testing.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2018
- Accession Number
- AD1056222
Entities
People
- Paul H. Goldspink
Organizations
- Medical College of Wisconsin