Curtis T M, Scholfield C N
Department of Ophthalmology, The Queen's University of Belfast, The Royal Victoria Hospital, Institute of Clinical Science, Belfast, BT12 6BA, Northern Ireland.
Diabetes Metab Res Rev. 2004 Jan-Feb;20(1):28-43. doi: 10.1002/dmrr.431.
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.
糖尿病视网膜病变是糖尿病最常见的并发症之一，也是发达国家劳动年龄人口中新发失明的主要原因。虽然这种疾病的确切发病机制仍不明确，但高血糖显然是其病因中的关键因素。蛋白激酶C（PKC）激活是高血糖的后果之一，并且被认为在糖尿病并发症的发生发展中起重要作用。本综述对目前认为糖尿病中PKC刺激仅通过富含棕榈酸酯和油酸酯的二酰基甘油过量产生介导的教条提出质疑。血糖浓度与游离脂肪酸水平的变化密切相关，除氧化应激外，这些因素可能解释了糖尿病中PKC的异常激活。关于糖尿病中PKC为何未能下调知之甚少，应致力于获取此类信息。大量证据表明PKCβ亚型与糖尿病视网膜病变的发病机制有关，但其他亚型可能也有相关性。除了PKC外，显然新型二酰基甘油激活的非激酶受体也可能在糖尿病并发症的发生发展中起作用。已经开发出治疗药物来抑制特定的PKC亚型，目前PKCβ拮抗剂正在进行临床试验，以测试其在抑制糖尿病并发症方面的毒性和疗效。考虑了这些药物对糖尿病患者治疗可能产生的影响。
