Novel Glucose Responsive Insulin for Improved Treatment of Diabetes

概要/摘要。 糖尿病正在迅速成为一个全球性的健康危机。根据所使用的统计方法的类型， 成人型或II型糖尿病最常见类型的全球发病率估计在 2.85亿。在I型和II型糖尿病患者中，血糖控制是最重要的，因为不能维持血糖水平。 血糖控制导致几种继发性并发症，包括神经病、肾病和视网膜病， 这通常会导致截肢、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，血糖控制需要持续的警惕和血糖水平的监测。 该项目的总体目标是开发一种新型葡萄糖响应性胰岛素（GRI）， 胰岛素受体的可逆葡萄糖依赖性反应。全面实现全球报告倡议的概念将 最接近地模仿健康胰腺的益处，并维持健康，减少/消除对 持续监测，并最终减少/消除糖尿病并发症。本提案的范围 是设计和测试一系列类似物，可以结合葡萄糖变构和表现出差异 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 一种新的计算平台，用于设计和生产一系列具有葡萄糖结合亲和力的GRI， 生理范围。在目标2中，我们将确定目标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）的亲和力， 在生理浓度的葡萄糖存在下的GRI。这些目标的实现将导致 鉴定了几种GRI先导候选物，其葡萄糖结合在生理范围内并且可逆 葡萄糖依赖性胰岛素受体结合和缺乏IGF-1 R结合。

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.