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

项目总结/摘要 在美国，近十分之一的人口患有2型糖尿病（T2 DM）。慢性 在这种疾病中发现的高血糖症引起血管病，导致肾衰竭、失明、截肢， 中风和心脏病一些用于治疗T2 DM的药物具有不良副作用， 强调需要开发新的抗高血糖剂。最近发现的棕榈酸 羟基硬脂酸的酯（PAHSAs）已显示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。但 化学结构对生物活性的影响以及PAHSAs的起源仍然未知。的 该提案的具体目标是：1）开发PAHSAs的合成平台，并确定 PAHSA结构与抗糖尿病活性之间的关系，2）确定PAHSA的生物合成来源 PAHSA。揭示PAHSA抗糖尿病活性的结构元件可能会 提供了一种用于对抗糖尿病的新型治疗的引线结构。此外，阐明了 PAHSAs的生物合成可能会刺激未来的研究，这将有助于治疗这种疾病， 糖尿病患者增加其自身的内源性PAHSA合成。

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.