Endocrine and Metabolic Consultants, Rockville, MD; and.
Biomedical Informatics Consultants LLC, Potomac, MD.
Am J Ther. 2020 Jan/Feb;27(1):e42-e51. doi: 10.1097/MJT.0000000000001089.
Biosynthetic human insulins and analogs have replaced animal insulins and permitted structural modifications to alter the rate of absorption, duration of action, improve reproducibility of effects, and modulate relative efficacy in various target tissues. Several forms of rapidly acting insulins nearly achieve rapid pharmacokinetics and pharmacodynamics similar to first-phase insulin release. There is need for even faster-acting analogs to mimic normal physiology and improve control of postprandial glycemic excursions. Two biosynthetic insulin analogs have sufficiently long duration of action for use as once-daily basal insulins; controversy persists regarding their respective risks of hypoglycemia and relative glycemic variability.
Basal-bolus therapy and insulin pump therapy, including closed-loop automated insulin delivery, require rapid-acting insulin analogs. The longer acting insulins can provide stable, reproducible basal insulin with reduced rates of hypoglycemia, particularly nocturnal hypoglycemia, greater efficacy in reducing mean glucose and glucose variability while increasing time in glucose target range. Inhalable human insulin provides very rapid action. Premixture of rapid-acting analogs with protamine has been useful for some patients with type 2 diabetes. An insulin analog with preferential efficacy at the liver has been developed and tested clinically but not marketed. Current research is aimed at developing even faster-acting insulin analogs. Long-acting basal insulins coformulated with GLP-1 receptor agonists or with a rapidly acting insulin analog have valuable clinical applications. Excipients, chaperones, local heating of the infusion site, and hyaluronidase have also been used to accelerate the absorption of insulin analogs.
Biosynthetic human insulins have radically revolutionized management of both type 1 and type 2 diabetes worldwide. The ability to manipulate the structure and formulation of insulin provides for more physiologic pharmacokinetics and pharmacodynamics, enabling improved glycemic control, reduced risk of hypoglycemia, and reduced rates of long-term complications.
合成人胰岛素和类似物已经取代了动物胰岛素，并允许进行结构修饰，以改变吸收速度、作用持续时间、提高效果的重现性，并调节在各种靶组织中的相对效力。几种速效胰岛素制剂几乎可以实现与第一时相胰岛素分泌相似的快速药代动力学和药效动力学。因此，需要更快作用的类似物来模拟正常生理，并改善餐后血糖波动的控制。两种合成胰岛素类似物的作用持续时间足够长，可以作为每日一次的基础胰岛素使用；关于它们各自的低血糖风险和相对血糖变异性，仍存在争议。
基础-餐时胰岛素治疗和胰岛素泵治疗，包括闭环自动化胰岛素输注，都需要速效胰岛素类似物。作用时间较长的胰岛素可以提供稳定、可重现的基础胰岛素，降低低血糖的发生率，特别是夜间低血糖的发生率，在提高血糖达标时间的同时，提高平均血糖和血糖变异性的疗效。吸入型人胰岛素可迅速起效。将速效类似物与鱼精蛋白混合使用已被证明对一些 2 型糖尿病患者有效。一种在肝脏中具有优先疗效的胰岛素类似物已被开发和临床测试，但尚未上市。目前的研究旨在开发更快速作用的胰岛素类似物。长效基础胰岛素与 GLP-1 受体激动剂或速效胰岛素类似物联合应用具有重要的临床应用价值。赋形剂、分子伴侣、输注部位局部加热和透明质酸酶也被用于加速胰岛素类似物的吸收。
合成人胰岛素彻底改变了全球 1 型和 2 型糖尿病的管理方式。操纵胰岛素的结构和配方的能力提供了更符合生理的药代动力学和药效动力学，从而改善血糖控制、降低低血糖风险和降低长期并发症的发生率。
