Stamou Maria I, Chiu Crystal J, Jadhav Shreya V, Lopes Vanessa Ferreira, Salnikov Kathryn B, Plummer Lacey, Lippincott Margaret F, Lee Hang, Seminara Stephanie B, Balasubramanian Ravikumar
Reproductive Endocrine Unit and Harvard Center for Reproductive Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
MGH Biostatistics Center and MGH Division of Clinical Research (DCR) Biostatistics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
J Endocr Soc. 2024 Jun 13;8(8):bvae118. doi: 10.1210/jendso/bvae118. eCollection 2024 Jul 1.
Activation of fibroblast growth factor receptor 1 (FGFR1) signaling improves the metabolic health of animals and humans, while inactivation leads to diabetes in mice. Direct human genetic evidence for the role of FGFR1 signaling in human metabolic health has not been fully established.
We hypothesized that individuals with naturally occurring variants ("experiments of nature") will display glucose dysregulation.
Participants with rare variants and noncarrier controls. Using a recall-by-genotype approach, we examined the β-cell function and insulin sensitivity of 9 individuals with rare deleterious variants compared to 27 noncarrier controls, during a frequently sampled intravenous glucose tolerance test at the Reproductive Endocrine Unit and the Harvard Center for Reproductive Medicine, Massachusetts General Hospital. -mutation carriers displayed higher β-cell function in the face of lower insulin sensitivity compared to controls.
These findings suggest that impaired FGFR1 signaling may contribute to an early insulin resistance phase of diabetes pathogenesis and support the candidacy of the FGFR1 signaling pathway as a therapeutic target for improving the human metabolic health.
成纤维细胞生长因子受体1（FGFR1）信号通路的激活可改善动物和人类的代谢健康，而该信号通路失活会导致小鼠患糖尿病。FGFR1信号通路在人类代谢健康中作用的直接遗传学证据尚未完全确立。
我们推测，具有自然发生变异的个体（“自然实验”）会出现葡萄糖调节异常。
有罕见变异的参与者和非携带者对照。在马萨诸塞州总医院生殖内分泌科和哈佛生殖医学中心进行的频繁采样静脉葡萄糖耐量试验中，采用基因分型召回方法，我们比较了9名携带罕见有害变异的个体与27名非携带者对照的β细胞功能和胰岛素敏感性。与对照相比，携带 - 突变的个体在胰岛素敏感性较低的情况下表现出更高的β细胞功能。
这些发现表明，FGFR1信号通路受损可能导致糖尿病发病机制的早期胰岛素抵抗阶段，并支持FGFR1信号通路作为改善人类代谢健康治疗靶点的候选资格。
