Fig. 4: Proposed signaling pathways from hyperglycemia to ROS production and cytokine release leading to diabetes complications

Hyperglycemia increases diacylglycerol (DAG) content by the activation of phospholipase C or D, which activates protein kinase C (PKC). PKC activates NADPH oxidase. NADPH oxidase complex consists of the cytosolic components p47phox, p67phox, p40phox, and a low-molecular-weight G-protein, Rac 1 or Rac 2, and the membrane-associated NOX2 and p22phox. Activation of the enzyme complex requires translocation of the cytosolic components to the plasma membrane, and their association to NOX2, produces reactive oxygen species (ROS). AGE-RAGE, FFA-TLR, and oxLDL-TLR activate downstream IKK (IkappaB kinases) pathways, and PKC. IKK phosphorylates IkappaB (inhibitor of kappa light chain gene enhancer in B cells), leading to translocation of the transcription factor NF-kappaB to the nucleus to control the expression of pro-inflammatory cytokines. ⊥ points of inhibition. 1 Inhibition of diacylglerol kinase; 2 Inhibition of PKC; 3 Inhibition of NADPH oxidase. AGE advanced glycation end products, DAG diacylglycerol, DAGK diacylicerol kinase, FFA free fatty acid, GPR G-protein-coupled receptors, IKK IkappaB kinases, IP3 inositol trisphosphate, LDL low density lipoprotein, NF-kappaB nuclear factor, oxLDL oxidized low density lipoprotein, PIP2 phosphatidylinositol-4,5-bisphosphate, PKC protein kinase C, PLC phospholipase, PLD phospholipase D, RAGE receptor for advanced glycation end products, ROS reactive oxygen species, TCA triacylglycerol, TLR Toll-like receptor.