Diabetes Research Unit, Cardiff University, University Hospital Llandough, Penarth, United Kingdom.
Diabetes Technol Ther. 2011 Jun;13 Suppl 1:S5-14. doi: 10.1089/dia.2011.0068.
The discovery of insulin and its clinical application early in the last century dramatically improved the prospects of people with diabetes. However, the limitations of those initial, unmodified insulin preparations were quickly recognized; most notably, their relatively "short action" meant that multiple daily subcutaneous injections were required. This stimulated a concerted effort to modify the properties of insulin in order to extend the duration of its blood glucose-lowering effect, minimize dosing frequency, and decrease the burden of treatment. The first successful attempts to prolong insulin's action were achieved by modifying its formulation with additives such as protamine and zinc, culminating in the production of "intermediate-acting" neutral protamine Hagedorn (NPH) insulin in the 1940s and the lente family of insulins in the 1950s. However, NPH and lente insulins were still associated with several limitations, including considerable variability of effect and a pronounced peak in their time-action profile. In the 1980s, the focus of research moved toward the modification of insulin itself with the aim of producing a "long-acting" insulin that would better satisfy basal insulin requirements over the entire day. Once-daily insulin glargine was the first "long-acting" insulin analog in clinical practice, followed by once- or twice-daily insulin detemir and, more recently, insulin degludec, which is now being evaluated for administration at less frequent intervals. These analogs demonstrate several benefits over "intermediate-acting" insulins, including a lower risk of both overall hypoglycemia and nocturnal hypoglycemia and reduced day-to-day glucose variability, making it more feasible to achieve better fasting and overall glycemic control. Long-acting insulin analogs (insulin glargine and insulin detemir) are now firmly established as key tools in the battle against diabetes, and ongoing clinical research of insulin-based therapy should focus on treatment strategies to maximize their benefits. To date, the clinical experience with insulin degludec is limited but demonstrates it has comparable efficacy to insulin glargine.
上个世纪初胰岛素的发现及其临床应用极大地改善了糖尿病患者的前景。然而，这些最初未经修饰的胰岛素制剂的局限性很快就被认识到；最明显的是，它们相对“短效”意味着需要每天多次皮下注射。这刺激了人们共同努力修饰胰岛素的特性，以延长其降低血糖的作用持续时间，最小化给药频率，并减少治疗负担。最初通过用添加剂（如鱼精蛋白和锌）修饰胰岛素制剂来延长其作用的成功尝试，最终在 20 世纪 40 年代生产出了“中效”中性鱼精蛋白 Hagedorn（NPH）胰岛素，以及 20 世纪 50 年代的长效胰岛素家族。然而，NPH 和长效胰岛素仍存在一些局限性，包括作用效果的相当大的可变性和其时间-作用曲线的明显峰值。20 世纪 80 年代，研究的重点转向胰岛素本身的修饰，旨在产生一种“长效”胰岛素，以更好地满足全天基础胰岛素的需求。甘精胰岛素是临床实践中第一种“长效”胰岛素类似物，随后是每日或每日两次的地特胰岛素，最近是德谷胰岛素，目前正在评估更频繁的给药间隔。与“中效”胰岛素相比，这些类似物具有几个优势，包括总体低血糖和夜间低血糖的风险较低，以及日常血糖变异性降低，从而更有可能实现更好的空腹和整体血糖控制。长效胰岛素类似物（甘精胰岛素和地特胰岛素）现已成为对抗糖尿病的重要工具，基于胰岛素的治疗的持续临床研究应侧重于最大限度发挥其益处的治疗策略。迄今为止，德谷胰岛素的临床经验有限，但表明其疗效与甘精胰岛素相当。
