title: Aegeline from Aegle marmelos stimulates glucose transport via Akt and Rac1 signaling, and contributes to a cytoskeletal rearrangement through PI3K/Rac1.
abstract: Aegeline is an alkaloidal-amide, isolated from the leaves of Aegle marmelos and have shown antihyperglycemic as well as antidyslipidemic activities in the validated animal models of type 2 diabetes mellitus. Here we delineate, aegeline enhanced GLUT4 translocation mediated 2-deoxy-glucose uptake in both time and concentration-dependent manner. 2-deoxy-glucose uptake was completely stymied by the transport inhibitors (wortmannin and genistein) in C2C12 myotubes. Pharmacological inhibition of Akt (also known as protein kinase B) and Ras-related C3 botulinum toxin substrate 1 (Rac1) suggest that both Akt and Rac1 operate aegeline-stimulated glucose transport via distinct parallel pathways. Moreover, aegeline activates p21 protein-activated kinase 1 (PAK1) and cofilin (an actin polymerization regulator). Rac1 inhibitor (Rac1 inhib II) and PAK1 inhibitor (IPA-3) completely blocked aegeline-induced phosphorylation of cofilin and p21 protein-activated kinase 1 (PAK1). In summary, these findings suggest that aegeline stimulates the glucose transport through Akt and Rac1 dependent distinct parallel pathways and have cytoskeletal roles via stimulation of the PI3-kinase-Rac1-PAK1-cofilin pathway in the skeletal muscle cells. Therefore, multiple targets of aegeline in the improvement of insulin sensitivity of the skeletal muscle cells may be suggested.
authors.affiliation: Division of Biochemistry, CSIR- Central Drug Research Institute, Lucknow 226021, India.
authors.forename: Sudeep
authors.initials: S
authors.lastname: Gautam
authors.affiliation: Division of Biochemistry, CSIR- Central Drug Research Institute, Lucknow 226021, India.
authors.forename: Nayab
authors.initials: N
authors.lastname: Ishrat
authors.affiliation: Medicinal and Process Chemistry, CSIR- Central Drug Research Institute, Lucknow 226021, India.
authors.forename: Rohit
authors.initials: R
authors.lastname: Singh
authors.affiliation: Medicinal and Process Chemistry, CSIR- Central Drug Research Institute, Lucknow 226021, India.
authors.forename: Tadigoppula
authors.initials: T
authors.lastname: Narender
authors.affiliation: Division of Biochemistry, CSIR- Central Drug Research Institute, Lucknow 226021, India. Electronic address: drarv55cdri@rediffmail.com.
authors.forename: Arvind K
authors.initials: AK
authors.lastname: Srivastava
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000199:Actins / Q000737:chemistry; D045471:Aegle / Q000737:chemistry*; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019833:Genistein / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D054462:p21-Activated Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D000577:Amides; D051275:Glucose Transporter Type 4; C560978:aegeline; D019833:Genistein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein; D005947:Glucose
keywords: Aegeline; Aegle marmelos; C2C12 myotubes; Cofilin; Glucose uptake; Insulin resistance