DEVELOPMENT OF CONCENTRATED, STABLE ULTRA FAST-ACTING INSULIN FORMULATION

对于糖尿病患者来说，保持最佳血糖水平可以有效延缓甚至 预防长期并发症。在开发速效和 与天然胰岛素相比，长效类似物可提供更好的血糖控制。不幸的是大多数 人们不能持续地达到他们的目标血糖范围， 目标可能导致频繁和潜在的危及生命的低血糖发作。一个关键的挑战在于 目前可用的速效胰岛素治疗剂起效慢且持续时间长， 限制了胰岛素治疗的有效性。开发新的速效胰岛素的努力受到限制 由于胰岛素二聚化和受体结合中涉及相同的残基， 提出了一个难题，即增加可用性速度的突变也会否定信号传导。 因此，在过去十年中没有新的速效胰岛素被批准。为了克服这个 根本性的阻塞，我们正在采取一种方法，这种方法的灵感来自最近的研究， 一种捕鱼用的锥形蜗牛，它使用一种特殊的毒液胰岛素变异体来迅速引起低血糖 在他们的猎物震惊。我们的初步数据显示，这种有毒的胰岛素是单体的， 胰岛素受体，激活胰岛素信号通路，并降低小鼠的血糖水平。这些 数据提供了一个强大的基础，以了解进一步的见解，从迷人的阿森纳有毒 胰岛素成功的结果将提供一个平台，在这个平台上，一种强大的新的治疗方法可以 用于治疗糖尿病。

For people with diabetes, maintaining optimal blood glucose levels is effective in delaying or even preventing long-term complications. Tremendous efforts have been made in developing fast-acting and long-lasting analogues to provide better glycemic control compared to native insulin. Unfortunately, most people are unable to consistently meet their target glycemic range, and aggressive efforts to reach this goal can cause frequent and potentially life-threatening episodes of hypoglycemia. A key challenge lies in the slow onset and long duration of the currently available fast-acting insulin therapeutics, which restricts the effectiveness of insulin therapy. Efforts to develop new fast-acting insulins have been limited by the involvement of the same residues in both insulin dimerization and receptor binding, which presents the conundrum that mutations that increase speed of availability also negate signaling. Consequently, no new fast-acting insulins have been approved in the past decade. To overcome this fundamental blockage, we are taking an approach that is inspired by recent insights from the study of fish-hunting cone snails that use a specialized venom insulin variant to rapidly induce hypoglycemic shock in their prey. Our preliminary data show that this venomous insulin is monomeric, binds to human insulin receptor, activates the insulin-signaling pathway, and reduces blood sugar levels in mice. These data provide a strong foundation to learn further insights from the fascinating arsenal of venomous insulins. Successful outcome will provide a platform upon which a powerful new class of therapeutics can be developed for the treatment of diabetes.