DEVELOPMENT OF CONCENTRATED, STABLE ULTRA FAST-ACTING INSULIN FORMULATION

对于糖尿病患者来说，保持最佳的血糖水平能有效延缓甚至延缓 预防长期并发症。大力发展速效食品和 持久的类似物，与天然胰岛素相比，提供更好的血糖控制。不幸的是，大多数 人们无法始终如一地达到他们的目标血糖范围，并积极努力达到这一目标 Goal可导致频繁的、可能危及生命的低血糖发作。一个关键的挑战在于 在目前可用的速效胰岛素疗法起效慢、持续时间长的情况下， 限制了胰岛素治疗的有效性。开发新的速效胰岛素的努力一直有限 通过参与胰岛素二聚化和受体结合的相同残基，这 提出了一个难题，即增加可获得性速度的突变也否定了信号。 因此，在过去的十年中，没有新的速效胰岛素被批准。要克服这一点 根本性障碍，我们正在采取的方法是受到最近对 猎鱼锥形蜗牛，使用一种特殊的毒液胰岛素变体来快速诱导低血糖 惊吓到它们的猎物。我们的初步数据显示，这种有毒的胰岛素是单体，与人结合 胰岛素受体，激活胰岛素信号通路，降低小鼠的血糖水平。这些 数据为进一步了解令人着迷的有毒物质武器库提供了坚实的基础 胰岛素。成功的结果将提供一个平台，在这个平台上，强大的新一代治疗学可以 将被开发用于治疗糖尿病。

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.