Gray Steven G, De Meyts Pierre
Receptor Systems Laboratory, Hagedorn Research Institute, Gentofte, Denmark.
Diabetes Metab Res Rev. 2005 Sep-Oct;21(5):416-33. doi: 10.1002/dmrr.559.
Globally, diabetes (and, in particular, type 2 diabetes) represents a major challenge to world health. Currently in the United States, the costs of treating diabetes and its associated complications exceed 100 billion US dollars annually, and this figure is expected to soar in the near future. Despite decades of intense research efforts, the genetic basis of the events involved in the pathogenesis of diabetes is still poorly understood. Diabetes is a complex multigenic syndrome primarily due to beta-cell dysfunction associated with a variable degree of insulin resistance. Recent advances have led to exciting new developments with regard to our understanding of the mechanisms that regulate insulin transcription. These include data that implicate chromatin as a critical regulator of this event. The 'Histone Code' is a widely accepted hypothesis, whereby sequential modifications to the histones in chromatin lead to regulated transcription of genes. One of the modifications used in the histone code is acetylation. This is probably the best characterized modification of histones, which is carried out under the control of histone acetyltransferases (HATs) and histone deacetylases (HDACs). These enzymes also regulate the activity of a number of transcription factors through acetylation. Increasing evidence links possible dysregulation of these mechanisms in the pathogenesis of diabetes, with important therapeutic implications.
在全球范围内，糖尿病（尤其是2型糖尿病）是对世界健康的重大挑战。目前在美国，治疗糖尿病及其相关并发症的费用每年超过1000亿美元，而且这一数字预计在不久的将来还会飙升。尽管经过了数十年的深入研究，但糖尿病发病机制中所涉及事件的遗传基础仍知之甚少。糖尿病是一种复杂的多基因综合征，主要是由于与不同程度胰岛素抵抗相关的β细胞功能障碍所致。最近的进展使我们对调节胰岛素转录机制的理解有了令人兴奋的新进展。这些进展包括表明染色质是这一过程关键调节因子的数据。“组蛋白密码”是一个被广泛接受的假说，即染色质中组蛋白的顺序修饰导致基因的转录调控。组蛋白密码中使用的修饰之一是乙酰化。这可能是组蛋白最具特征的修饰，在组蛋白乙酰转移酶（HATs）和组蛋白去乙酰化酶（HDACs）的控制下进行。这些酶还通过乙酰化调节许多转录因子的活性。越来越多的证据表明这些机制在糖尿病发病机制中可能失调，具有重要的治疗意义。
