INSR and diabetes mellitus: Third, in untreated diabetics, the skeletal muscle exhibited indices of impaired insulin and incretin signaling, which was supported by the downregulation of transcripts of insulin receptor and PI3K transcripts and decreased protein abundances of GLP-1 receptor and GLUT-4, and potentially increased hepatic lipid flux, with upregulation of both rate-limiting lipogenic (phosphorylated ACC) and lipolytic (phosphorylated HSL) enzymes.