Novel Glucose Responsive Insulin for Improved Treatment of Diabetes

摘要/摘要。 糖尿病正迅速成为全球健康危机。根据所使用的统计方法的类型， 据估计，全世界最常见的糖尿病类型，成人发病或II型糖尿病的发病率在以下范围内 2.85亿美元。在I型和II型糖尿病患者中，血糖控制是至关重要的，因为无法维持 血糖控制会导致几种继发性并发症，包括神经病变、肾病和视网膜病变， 这往往会导致截肢、透析和失明，并增加心血管并发症的风险。 对于大多数糖尿病患者来说，血糖控制需要持续警惕和监测血糖水平。 这个项目的首要目标是开发一种新型的葡萄糖反应性胰岛素(GRI)，它具有 胰岛素受体上的可逆的葡萄糖依赖反应。全面实现全球倡议的概念将 最接近健康胰腺的好处并保持正常血糖，减少/消除对 持续监测，最终减少/消除糖尿病并发症。这项提案的范围 是设计和测试一系列可以与葡萄糖变构结合并展示差异的类似物 胰岛素受体的反应。这将通过完成三个目标来实现。在目标1中，我们将使用 设计和生产一系列具有葡萄糖结合亲和力的GRI的新型计算平台 生理范围。在目标2中，我们将测定目标1中产生的类似物的葡萄糖结合亲和力。 最后，在目标3中，我们将测量胰岛素受体(IR)和胰岛素样生长因子(IGF-R1)亲和力。 GRI是在生理浓度的葡萄糖存在的情况下。完成这些目标将导致 在生理范围和可逆范围内与葡萄糖结合的几个GRI候选导联的鉴定 葡萄糖依赖的胰岛素受体结合和IGF-1R结合缺失。

SUMMARY/ABSTRACT. Diabetes is rapidly becoming a global health crisis. Depending on the type of statistical methodology used, the world-wide incidence of the most common type of diabetes, adult-onset or Type II, is estimated to be in the range of 285 million. In both Type I and Type II diabetics glycemic control is paramount as the inability to maintain glycemic control results in several secondary complications including neuropathy, nephropathy and retinopathy, that often lead to amputations, dialysis and blindness as well as increased risk of cardiovascular complications. For the majority of diabetics glycemic control requires constant vigilance and monitoring of blood glucose levels. The overarching goal of this project is the development of a novel glucose responsive insulin (GRI) with a reversible, glucose dependent response at the insulin receptor. The full realization of the GRI concept would most closely mimic the benefits of a healthy pancreas and maintain euglycemia, reduce/eliminate the need for constant monitoring, and ultimately, reduce/eliminate the complications of diabetes. The scope of this proposal is the design and testing of a series of analogs that can bind glucose allosterically and demonstrate differential response at the insulin receptor. This will be achieved through completion of three aims. In Aim 1 we will use a novel computational platform to design and produce a series of GRIs with glucose binding affinity in the physiological range. In Aim 2 we will determine the glucose binding affinity of the analogues produced in Aim 1. Finally, in Aim 3 we will measure the insulin receptor (IR) and insulin like growth factor (IGF-R1) affinity of the GRI’s in the presence of glucose at physiological concentrations. Completion of these Aims will result in the identification of several GRI lead candidates with glucose binding in the physiological range and reversible glucose dependent insulin receptor binding and absence of IGF-1R binding.