The role of lipids and protein kinase Cs in the pathogenesis of diabetic retinopathy.
Diabetic retinopathy is one of the most common complications of diabetes and is a major cause of new blindness in the working-age population of developed countries. While the exact pathogenic basis of this condition remains ill defined, it is clear that hyperglycaemia is a critical factor in its aetiology. Protein kinase C (PKC) activation is one of the sequelae of hyperglycaemia and it is thought to play an important role in the development of diabetic complications. This review questions the currently held dogma that PKC stimulation in diabetes is solely mediated through the overproduction of palmitate and oleate enriched diacylglycerols. Blood glucose concentrations are closely tracked by changes in the levels of free fatty acids and these, in addition to oxidative stress, may account for the aberrant activation of PKCs in diabetes. Little is known about why PKCs fail to downregulate in diabetes and efforts should be directed towards acquiring such information. Considerable evidence implicates the PKCbeta isoform in the pathogenesis of diabetic retinopathy, but other isoforms may also be of relevance. In addition to PKCs, it is evident that novel diacyglycerol-activated non-kinase receptors could also play a role in the development of diabetic complications. Therapeutic agents have been developed to inhibit specific PKC isoforms and PKCbeta antagonists are currently undergoing clinical trials to test their toxicity and efficacy in suppressing diabetic complications. The likely impact of these drugs in the treatment of diabetic patients is considered.
Curtis
T M
TM
Department of Ophthalmology, The Queen's University of Belfast, The Royal Victoria Hospital, Institute of Clinical Science, Belfast, BT12 6BA, Northern Ireland. t.curtis@qub.ac.uk
Scholfield
C N
CN
D000818:Animals; D003930:Diabetic Retinopathy / Q000503:physiopathology*; D004075:Diglycerides / Q000502:physiology; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology; D008055:Lipids / Q000502:physiology*; D018384:Oxidative Stress; D011493:Protein Kinase C / Q000502:physiology*; D012171:Retinal Vessels / Q000502:physiology / Q000503:physiopathology
D004075:Diglycerides; D008055:Lipids; D011493:Protein Kinase C