Twigg Stephen M
Greg Brown Diabetes and Endocrinology Research Laboratory, Sydney Medical School (Central), Charles Perkins Centre and Bosch Institute, The University of Sydney, Level 3W, Charles Perkins Centre, Building D17, John Hopkins Drive, Sydney, NSW, 2006, Australia.
Department of Endocrinology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW, 2050, Australia.
J Cell Commun Signal. 2018 Mar;12(1):359-368. doi: 10.1007/s12079-018-0458-2. Epub 2018 Feb 6.
Across the years the CCNs have been increasingly implicated in the development of obesity, diabetes and its complications. Evidence for this is currently derived from their dysregulation in key metabolic pathological states in humans, animal and in vitro models, and also pre-clinical effects of their bioactivities. CCN2 is the best studied in this disease process and the other CCNs are yet to be better defined. Key steps where CCNs may play a pathogenic metabolic role include: (i) obesity and insulin resistance, where CCN2 inhibits fat cell differentiation in vitro and CCN3 may induce obesity and insulin resistance; (ii) elevated blood glucose levels to diabetes mellitus onset, where CCN2 may contribute to pancreatic beta cell and islet function; and (iii) in diabetes complications, such as nephropathy, retinopathy, liver disease (NAFLD/NASH), CVD and diabetes with heart failure. In contrast, CCN1, CCN2 and possibly CCN3, may have a reparative role in wound healing in diabetes, and CCN2 in islet cell development. In terms of CCN2 regulation by a diabetes metabolic environment and related mechanisms, the author's laboratory and others have progressively shown that advanced glycation-end products, protein kinase C isoforms, saturated fatty acids, reactive oxygen species and haemodynamic factors upregulate CCN2 in relevant cell and animal systems. Recent data has suggested that CCN2, CCN3 and CCN6 may affect energy homeostasis including in regulating glycolysis and mitochondrial function. This paper will address the current data implicating CCNs in diabetes and its complications, focusing on recent aspects with translational clinical relevance and future directions.
多年来，CCN家族越来越多地被认为与肥胖、糖尿病及其并发症的发生发展有关。目前，这方面的证据来源于它们在人类、动物和体外模型的关键代谢病理状态下的失调，以及它们生物活性的临床前效应。CCN2是在这个疾病过程中研究得最深入的，而其他CCN家族成员还有待进一步明确。CCN家族可能发挥致病代谢作用的关键步骤包括：（i）肥胖和胰岛素抵抗，其中CCN2在体外抑制脂肪细胞分化，而CCN3可能导致肥胖和胰岛素抵抗；（ii）血糖水平升高至糖尿病发病，其中CCN2可能影响胰腺β细胞和胰岛功能；以及（iii）在糖尿病并发症中，如肾病、视网膜病变、肝脏疾病（非酒精性脂肪性肝病/非酒精性脂肪性肝炎）、心血管疾病和糖尿病合并心力衰竭。相比之下，CCN1、CCN2以及可能的CCN3，可能在糖尿病伤口愈合中具有修复作用，而CCN2在胰岛细胞发育中具有修复作用。关于糖尿病代谢环境对CCN2的调节及其相关机制，作者所在的实验室和其他研究团队已逐步表明，晚期糖基化终产物、蛋白激酶C亚型、饱和脂肪酸、活性氧和血流动力学因素在相关细胞和动物系统中上调CCN2。最近的数据表明，CCN2、CCN3和CCN6可能影响能量稳态，包括调节糖酵解和线粒体功能。本文将阐述目前有关CCN家族与糖尿病及其并发症相关的数据，重点关注具有临床转化相关性的最新进展以及未来的研究方向。
