Pretz Dominik, Heyward Philip M, Krebs Jeremy, Gruchot Joel, Barter Charles, Silcock Pat, Downes Nerida, Rizwan Mohammed Zubair, Boucsein Alisa, Bender Julia, Burgess Elaine J, Boer Geke Aline, Keerthisinghe Pramuk, Perry Nigel B, Tups Alexander
Centre for Neuroendocrinology, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand.
Department of Physiology, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand.
Life Metab. 2023 Jun 18;2(4):load026. doi: 10.1093/lifemeta/load026. eCollection 2023 Aug.
Butein, a rare chalcone found in the toxic plant , has been shown to regulate glucose homeostasis via inhibition of the nuclear factor kappa-B kinase subunit beta (IKKβ)/nuclear factor kappa B (NF-κB) pathway in the brain. Here, we investigated whether the nonpoisonous plant could be a source of butein as a potential treatment for type 2 diabetes (T2D). In mice fed a high-fat diet (HFD) to induce glucose intolerance, an oral petal extract improved glucose tolerance at doses of 3.3 mg/kg body weight and 10 mg/kg body weight. Surprisingly, this effect was not mediated by butein alone but by butein combined with the closely related flavonoids, sulfuretin and/or isoliquiritigenin. Mechanistically, the extract improved systemic insulin tolerance. Inhibition of phosphatidylinositol 3-kinase to block insulin signaling in the brain abrogated the glucoregulatory effect of the orally administered extract. The extract reinstated central insulin signaling and normalized astrogliosis in the hypothalamus of HFD-fed mice. Using NF-κB reporter zebrafish to determine IKKβ/NF-κB activity, a potent anti-inflammatory action of the extract was found. A randomized controlled crossover clinical trial on participants with prediabetes or T2D confirmed the safety and efficacy of the extract in humans. In conclusion, we identified an extract from the flower petals of as a novel treatment option for T2D, potentially targeting the central regulation of glucose homeostasis as a root cause of the disease.
紫铆因是一种存在于有毒植物中的罕见查耳酮,已被证明可通过抑制大脑中的核因子κB激酶亚基β(IKKβ)/核因子κB(NF-κB)信号通路来调节葡萄糖稳态。在此,我们研究了这种无毒植物是否能成为紫铆因的来源,作为2型糖尿病(T2D)的潜在治疗方法。在喂食高脂饮食(HFD)以诱导葡萄糖不耐受的小鼠中,口服该植物花瓣提取物在3.3毫克/千克体重和10毫克/千克体重的剂量下可改善葡萄糖耐量。令人惊讶的是,这种作用并非仅由紫铆因介导,而是由紫铆因与密切相关的类黄酮、硫磺菊素和/或异甘草素共同介导。从机制上讲,该提取物改善了全身胰岛素耐受性。抑制磷脂酰肌醇3激酶以阻断大脑中的胰岛素信号,消除了口服提取物的葡萄糖调节作用。该提取物恢复了HFD喂养小鼠下丘脑的中枢胰岛素信号并使星形胶质细胞增生正常化。使用NF-κB报告基因斑马鱼来确定IKKβ/NF-κB活性,发现该提取物具有强大的抗炎作用。一项针对糖尿病前期或T2D参与者的随机对照交叉临床试验证实了该提取物在人体中的安全性和有效性。总之,我们鉴定出一种来自该植物花瓣的提取物,作为T2D的一种新型治疗选择,可能靶向葡萄糖稳态的中枢调节,而这是该疾病的根本原因。