Role of AKT-glycogen synthase kinase axis in monocyte activation in human beings with and without type 2 diabetes.

Publication Type:

Journal Article


Journal of cellular and molecular medicine, Volume 14, Issue 6B, p.1396-407 (2010)


Cell Linedigestive disease, digestive deseases Cell Movementdigestive disease, digestive deseases Diabetes Mellitus, Type 2digestive disease, digestive deseases Endothelial Cellsdigestive disease, digestive deseases Enzyme Activationdigestive disease, digestive deseases Femaledigestive disease, digestive deseases Gene Knockout Techniquesdigestive disease, digestive deseases Glycogen Synthase Kinase 3digestive disease, digestive deseases Humansdigestive disease, digestive deseases Maledigestive disease, digestive deseases Middle Ageddigestive disease, digestive deseases Models, Biologicaldigestive disease, digestive deseases Monocytesdigestive disease, digestive deseases Platelet Activating Factordigestive disease, digestive deseases Protein Kinase Inhibitorsdigestive disease, digestive deseases Proto-Oncogene Proteins c-aktdigestive disease, digestive deseases Signal Transduction


Monocyte activation by chemokines is a vital trigger for initiation of atherosclerotic process. Circulating levels of platelet activating factor (PAF), a recognized chemokine, is known to be increased in type 2 diabetes that is linked to accelerated atherosclerosis. To explore the molecular basis we examined the signalling pathways involved in PAF induced monocyte activation. PAF increased migration in monocytes obtained from THP-1 cells, nondiabetic and diabetic subjects. This effect was blocked by AKT inhibition. It did so by phosphorylation of glycogen synthase kinase (GSK)-3betaS(9), which was completely blocked by AKT inhibition. Additionally, PAF induced GSK-3beta phosphorylation was linked to Rac-1 activation and Rho-A inactivation leading to migration. Paradoxically, inhibition of GSK-3beta phosphorylation also augmented monocyte migration in THP-1, ND and diabetic monocytes through phosphorylation of AKT and activation of Rho-A that was independent of GSK. This was validated when (i) overexpression of dominant negative mutants of Rho-A reversed GSK inhibitor induced monocyte migration and (ii) AKT inhibition blocked GSK inhibitor induced Rho-A activity. Constitutively active ARAP3 (Rho-GAP) appears to have a regulatory role in monocyte activity during GSK inhibition. Finally, inhibition of monocyte GSK-3beta activity (by inhibitors and genetic manipulation) led to enhanced migration in diabetes compared to persons without diabetes. We conclude that diabetic monocytes show increased migratory capacity in response to GSK-3beta inhibition. GSK inhibitors developed to treat the metabolic complications of diabetes should therefore be used with caution.