2型糖尿病（T2D）是全球范围内日益严重的公共卫生问题，除非进行手术干预，否则通常无法实现T2D的持续缓解，但最近的报道以及我们前期工作表明，成纤维细胞生长因子家族旁分泌成员FGF1和FGF4能通过中枢单次给药发挥长达1个月以上的持续降糖作用，且不引起低血糖，为治疗甚至逆转T2D带来全新希望。但FGF1/FGF4维持血糖稳态的生理调控规律和药理作用机制均不清楚，构成重要科学问题。本课题拟通过研究下丘脑内源性FGF1或FGF4表达水平与代谢异常的内在关系揭示FGF1/FGF4生理调控规律；进一步利用下丘脑不同亚区（细胞）特异性基因干预技术、电生理神经信号记录并结合多组学技术探明FGF1/FGF4作用靶标和分子机制；最后基于FGF蛋白结构设计鼻腔靶向中枢递送系统实现无创给药，进而从生理、药理和药物设计三个纬度探索持久缓解2型糖尿病的可行性和分子机制，为发展代谢健康新策略提供重要理论支撑。

Type 2 diabetes (T2D) is an increasingly severe public health problem across all nations. Currently, performing bariatric surgery is the only way to achieve sustained remission of T2D. Previous studies and our preliminary data suggest that the paracrine subfamily members of fibroblast growth factors (FGFs) including FGF1 and FGF4 may persistently reduce hyperglycemia without causing hypoglycemia when administered directly into the central nervous system. This new finding provides promising therapeutics for the treatment of T2D. However, the physiological regulation and pharmacological mechanism of FGF1/FGF4 to maintain glucose homeostasis is unclear - an important scientific question remained to be solved. This study aims to reveal the physiological regulation by studying the internal relationship between endogenous hypothalamic FGF1 or FGF4 level and metabolic abnormalitiesa, and to explore therapeutic target and molecular mechanism of FGF1/FGF4 by using gene intervention on specific subsets of hypothalamus, neural electrophysiological recording and multi-omics techniques. Finally, we will design a nasal targeting central delivery system based on FGF structure to achieve non-invasive drug delivery. In summary, this study will explore the molecular mechanism and feasibility of sustained remission of type 2 diabetes from three latitudes of physiology, pharmacology and drug design, which will provide promising theoretical basis to develop new strategies for anti-hyperglycemia metabolic health.