SAR and Biosynthetic Origins of PAHSAs, a Novel Family of Anti-Diabetic Lipids

项目摘要/摘要 在美国，近十分之一的人口患有2型糖尿病(T2 DM)。慢性病患者 这种疾病中发现的高血糖会引起血管病变，导致肾功能衰竭、失明、截肢、 中风和心脏病发作。一些用于治疗T2 DM的药物有不良副作用， 强调需要开发新的抗高血糖药物。新近发现的棕榈酸 羟基硬脂酸酯(PAHSA)已被证明通过增加血糖水平来改善血糖水平 胰岛素释放和胰岛素敏感性通过其在游离脂肪酸受体-1和-4上的活性来实现。然而， 化学结构对生物活性的影响以及PAHSA的来源尚不清楚。这个 这项提议的具体目标是：1)为PAHSA开发一个合成平台并确定 PAHSA结构与抗糖尿病活性的关系及2)确定其生物合成的来源 多环芳烃。揭示PAHSA抗糖尿病活性的结构元素可能 为抗击糖尿病的新疗法提供先导结构。此外，还澄清了 PAHSA的生物合成可能会刺激未来的研究，允许通过帮助治疗这种疾病 糖尿病患者自身内源性PAHSA合成增加。

Project Summary/Abstract In the United States, nearly a tenth of the population has type 2 diabetes mellitus (T2DM). The chronic hyperglycemia found in this disease causes angiopathy, leading to kidney failure, blindness, amputation, stroke, and heart attack. Some of the medicines used to treat T2DM have an adverse side effect profile, underscoring the need to develop new anti-hyperglycemic agents. The recently discovered Palmitic Acid esters of HydroxyStearic Acids (PAHSAs) have been shown to improve blood glucose levels by increasing insulin release and insulin sensitivity through their activity on free fatty acid receptors-1 and -4. However, the effect that the chemical structure has on biological activity and the origins of PAHSAs remain unknown. The Specific Aims of this proposal are to: 1) develop a synthetic platform for PAHSAs and determine the relationship between PAHSA structure and anti-diabetic activity and 2) determine the biosynthetic origins of PAHSAs. Uncovering the structural elements responsible for the anti-diabetic activity of PAHSAs may provide a lead structure for a novel treatment in the fight against diabetes. Furthermore, elucidation of the biosynthesis of PAHSAs may spur future studies that would allow for treatment of this disease by helping patients with diabetes increase their own endogenous PAHSA synthesis.