Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106-4935, USA.
Protein Cell. 2010 Jun;1(6):537-51. doi: 10.1007/s13238-010-0069-z.
Insulin is a hormone that is essential for regulating energy storage and glucose metabolism in the body. Insulin in liver, muscle, and fat tissues stimulates the cell to take up glucose from blood and store it as glycogen in liver and muscle. Failure of insulin control causes diabetes mellitus (DM). Insulin is the unique medicine to treat some forms of DM. The population of diabetics has dramatically increased over the past two decades, due to high absorption of carbohydrates (or fats and proteins), lack of physical exercise, and development of new diagnostic techniques. At present, the two largest developing countries (India and China) and the largest developed country (United States) represent the top three countries in terms of diabetic population. Insulin is a small protein, but contains almost all structural features typical of proteins: α-helix, β-sheet, β-turn, high order assembly, allosteric T®R-transition, and conformational changes in amyloidal fibrillation. More than ten years' efforts on studying insulin disulfide intermediates by NMR have enabled us to decipher the whole picture of insulin folding coupled to disulfide pairing, especially at the initial stage that forms the nascent peptide. Two structural switches are also known to regulate insulin binding to receptors and progress has been made to identify the residues involved in binding. However, resolving the complex structure of insulin and its receptor remains a challenge in insulin research. Nevertheless, the accumulated knowledge of insulin structure has allowed us to specifically design a new ultra-stable and active single-chain insulin analog (SCI-57), and provides a novel way to design super-stable, fast-acting and cheaper insulin formulations for DM patients. Continuing this long journey of insulin study will benefit basic research in proteins and in pharmaceutical therapy.
胰岛素是一种激素，对于调节体内能量储存和葡萄糖代谢至关重要。肝脏、肌肉和脂肪组织中的胰岛素刺激细胞从血液中摄取葡萄糖，并将其储存为肝和肌肉中的糖原。胰岛素控制的失败会导致糖尿病（DM）。胰岛素是治疗某些类型 DM 的独特药物。在过去的二十年中，由于碳水化合物（或脂肪和蛋白质）的高吸收、缺乏体育锻炼以及新的诊断技术的发展，糖尿病患者人数急剧增加。目前，两个最大的发展中国家（印度和中国）和最大的发达国家（美国）在糖尿病患者人数方面排名前三。胰岛素是一种小蛋白质，但包含几乎所有蛋白质的典型结构特征：α-螺旋、β-折叠、β-转角、高级组装、变构 T®R-跃迁和淀粉样纤维状的构象变化。十多年来，通过 NMR 研究胰岛素二硫键中间体的努力使我们能够破译与二硫键配对偶联的胰岛素折叠的全貌，特别是在形成新生肽的初始阶段。还知道有两个结构开关可以调节胰岛素与受体的结合，并且在识别参与结合的残基方面已经取得了进展。然而，解决胰岛素及其受体的复杂结构仍然是胰岛素研究中的一个挑战。尽管如此，胰岛素结构的积累知识使我们能够专门设计一种新的超稳定和活性的单链胰岛素类似物（SCI-57），并为 DM 患者提供了一种设计超稳定、快速作用和更便宜胰岛素制剂的新方法。继续进行胰岛素研究的漫长旅程将有益于蛋白质基础研究和药物治疗。
