Prevention of type 1 diabetes using early glycation products

项目摘要 1型糖尿病（T1 D）是一种毁灭性和昂贵的器官特异性自身免疫性疾病，曾经主要困扰 青少年，在美国成年人中的发病率增加，女性死亡风险增加40%。长期 该项目的目标是为T1 D管理制定一项预防和补充战略， 无创、持久、低成本。糖基化前两步产生的早期糖基化产物（EGPs） 美拉德反应/糖化是用还原糖部分修饰的蛋白质，并且它们在我们的细胞中普遍存在。 日常饮食我们成功地从乳清蛋白分离物（WPI）中生产了早期糖化产物（EGPs）， 葡萄糖使用冷冻干燥方法，并且它们被证明是基于功能性抗炎的。 巨噬细胞产生的细胞因子/趋化因子的分析。此外，在T1 D模型中，非肥胖糖尿病患者 (NOD)在小鼠中，我们发现EGPs通过下调CD 8+细胞来保护小鼠免受高血糖症的影响 在胸腺和脾脏中，脾脏M1巨噬细胞减少。这些观察结果提供了临床前 支持EGP在胰岛炎和T1 D患者中的潜在营养应用（例如，医疗 食物）。对于EGPs的大规模生产，由于其能量，喷雾干燥法更适合 效率和增强的产品和工艺灵活性。然而，喷雾干燥的参数和 喷雾干燥产品的抗高血糖作用仍然未知。第一阶段拟议的研究 将集中在（目标1）测试是否使用喷雾干燥方法产生的EGPs发挥类似的 保护T1 D和（目标2）测试EGPs的吸收对宿主抗性没有不利影响 机制等HGG Research LLC是一家通过优化喷雾参数来产生EGPs的公司 干燥，用于生产。目前在格鲁吉亚大学的学术合作伙伴的研究将 评价EGP摄取后T1 D预防和毒性。其次，这将是一个合乎逻辑的延伸， 使用其他模型确定EGP对T1 D预防的影响（例如，生物繁殖糖尿病易感大鼠） 以及底层机制（例如，微生物组），并研究EGP组分在此过程中具有活性。 适应症逆转自身免疫可能对T1 D受试者有益。研究的设计， 测试其他自身免疫性疾病，如克罗恩病，类风湿性关节炎和狼疮性肾炎将是 下一个阶段，这个STTR项目。我们认为，这项研究具有创新性和重大意义。 重要性;并代表了医疗保健和研究的前沿。

PROJECT SUMMARY Type 1 diabetes (T1D), a devastating and expensive organ-specific autoimmune disease once afflicting mainly juveniles, is increasing in incidence among US adults with 40% excess risk of death in women. The long-term objective of this project is to develop a preventive and complementary strategy for T1D management that is non-invasive, long-lasting, and low-cost. Early glycation products (EGPs) generated in the first two steps of Maillard reaction/glycation are proteins modified with reducing sugar moieties, and they are ubiquitous in our daily diet. We successfully produced early glycation products (EGPs) from whey protein isolate (WPI) and glucose using the freeze-drying method, and they were shown to be anti-inflammatory based on functional analysis of cytokines/chemokines produced by macrophages. Further, in a T1D model, the non-obese diabetic (NOD) mouse, we showed that EGPs protected the mice from hyperglycemia with down-regulated CD8+ cells in both thymus and spleen and decreased splenic M1 macrophages. These observations provide preclinical support for the potential nutraceutical application of EGPs for patients with insulitis and T1D (e.g., medical food). For the large-scale production of EGPs, the spray-drying method is more appropriate due to  its energy  efficiencies  and enhanced product and process flexibility. However, the parameters for spray drying and the anti-hyperglycemia effects of the spray dried products remained unknown. The proposed research in phase I will focus on (Aim 1) testing whether the EGPs produced using the spray drying method exert a similar protection in T1D and (Aim 2) on testing that the uptake of EGPs has no adverse effects in host resistance mechanisms. HGG Research LLC is a company that will generate EGPs by optimizing the parameters of spray drying for their production. Research by the academic partner, currently at the University of Georgia, will evaluate the T1D prevention and toxicity following EGP uptake. Next, it would be a logical extension to determine the effects of EGPs on T1D prevention using other models (e.g., Biobreeding diabetes-prone rat) and the underlying mechanisms (e.g., microbiome), and investigate which EGP component(s) are active in this indication. Reversing autoimmunity could be beneficial well beyond subjects with T1D. The design of studies to test other autoimmune diseases such as Crohn's, rheumatoid arthritis and lupus erythematous would be the next stage following this STTR project. We believe that the proposed research is innovative and of great significance; and represents a frontier in health care and research.