Department of Medicine, University of Melbourne (Austin Health), Heidelberg, VIC, Australia.
Diabetologia. 2015 Aug;58(8):1708-14. doi: 10.1007/s00125-015-3600-1. Epub 2015 Apr 24.
The advent of insulin treatment in 1923 meant fewer diabetes deaths from acute metabolic deterioration and sepsis and a progressive increase in the burden of disease caused by end-organ damage. These diabetic complications are the major cause of morbidity and premature mortality among diabetic subjects. Over the last 50 years it has become apparent that diabetic complications in disparate tissues may result from a combination of common pathological processes. Pathways activated by initial metabolic insults are promoted by co-factors such as renin-angiotensin-aldosterone system activation, hyperinsulinaemia, underlying genetic susceptibility, and traditional vascular risk factors, particularly hypertension and lipids. These common pathways include AGE formation, reactive oxygen species overproduction, protein kinase C activation, mitochondrial dysfunction and activation of proinflammatory and profibrotic signalling cascades. Once established, these interlinked pathways become self-perpetuating. Many drugs acting against individual downstream targets in these pathways have failed due to lack of efficacy or adverse effects. Gains in the future may be made by better control of existing risk factors, more sophisticated modulation of tissue glucose and insulin signalling, and interventions to improve mitochondrial function and reduce oxidative stress. Epigenetic and microRNA research may lead to methods to disrupt the mechanisms whereby pathological pathways are perpetuated. Expansion in capacity and expertise in biomarker measurement and analysis may allow better targeting of therapies to patients who are most likely to benefit. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965-2015).
胰岛素治疗的出现意味着急性代谢恶化和败血症导致的糖尿病死亡率降低，并且由终末器官损伤引起的疾病负担逐渐增加。这些糖尿病并发症是糖尿病患者发病率和过早死亡的主要原因。在过去的 50 年中，人们已经明显认识到不同组织中的糖尿病并发症可能是由共同的病理过程共同作用的结果。最初代谢损伤激活的途径，会被诸如肾素-血管紧张素-醛固酮系统激活、高胰岛素血症、潜在的遗传易感性以及传统的血管危险因素（特别是高血压和血脂）等协同因素所促进。这些共同的途径包括 AGE 形成、活性氧过度产生、蛋白激酶 C 激活、线粒体功能障碍以及促炎和促纤维化信号通路的激活。一旦建立，这些相互关联的途径就会自我维持。许多针对这些途径中单个下游靶点的药物由于疗效或不良反应而失败。通过更好地控制现有风险因素、更精细地调节组织葡萄糖和胰岛素信号以及干预以改善线粒体功能和减少氧化应激，未来可能会取得进展。表观遗传学和 microRNA 研究可能会导致破坏病理途径持续的机制的方法。生物标志物测量和分析能力的扩大和专业知识的提高，可能会使更多可能受益的患者得到更有针对性的治疗。这是一系列以“50 年展望”为标题的评论之一，旨在庆祝《糖尿病学》创刊 50 周年（1965-2015 年），就糖尿病的未来展望发表个人意见。
