Sustained remission of type 2 diabetes in rodents by centrally administered fibroblast growth factor 4
Sustained remission of type 2 diabetes in rodents by centrally administered fibroblast growth factor 4
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DOI：
10.1016/j.cmet.2023.04.018
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发表时间：
2023-06-06
期刊：
影响因子：
29
通讯作者：
Huang，Zhifeng
中科院分区：
文献类型：
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作者：
Sun，Hongbin;Lin，Wei;Huang，Zhifeng
2型糖尿病（T2D）是全球主要的健康和经济负担。尽管有多种药物可用于短期管理，但T2D的持续缓解目前尚无法实现。脑室内注射成纤维细胞生长因子1（icvFGF1）可诱导T2D啮齿动物持续缓解，推动了深入的研究工作，以了解其作用机制。其他FGF是否具有类似的治疗益处目前尚不清楚。在这里，我们发现icvFGF4还通过激活下丘脑内侧基底节内葡萄糖敏感神经元中表达的FGF受体1（FGFR1），在maledb/db小鼠和饮食诱导的肥胖小鼠中产生持续的抗糖尿病作用。具体来说，FGF 4兴奋葡萄糖兴奋（GE）神经元，同时抑制葡萄糖抑制（GI）神经元。此外，icvFGF4恢复GI神经元的百分比indb/db小鼠。重要的是，鼻内递送FGF 4减轻了indb/db小鼠的高血糖症，为非侵入性治疗铺平了道路。我们得出结论，icvFGF4具有显著的治疗潜力，实现持续缓解的T2D。
Type 2 diabetes (T2D) is a major health and economic burden worldwide. Despite the availability of multiple drugs for short-term management, sustained remission of T2D is currently not achievable pharmacologically. Intracerebroventricular administration of fibroblast growth factor 1 (icvFGF1) induces sustained remission in T2D rodents, propelling intense research efforts to understand its mechanism of action. Whether other FGFs possess similar therapeutic benefits is currently unknown. Here, we show that icvFGF4 also elicits a sustained antidiabetic effect in both maledb/dbmice and diet-induced obese mice by activating FGF receptor 1 (FGFR1) expressed in glucose-sensing neurons within the mediobasal hypothalamus. Specifically, FGF4 excites glucose-excited (GE) neurons while inhibiting glucose-inhibited (GI) neurons. Moreover, icvFGF4 restores the percentage of GI neurons indb/dbmice. Importantly, intranasal delivery of FGF4 alleviates hyperglycemia indb/dbmice, paving the way for non-invasive therapy. We conclude that icvFGF4 holds significant therapeutic potential for achieving sustained remission of T2D.