Diabetes and Endocrinology Research Center, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY.
Center for Liver Disease and Transplantation, Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY.
Diabetes. 2024 Dec 1;73(12):2003-2008. doi: 10.2337/db24-0402.
Our objective was to test a single dose of the phosphatidylinositol 3-kinase (PI3K) inhibitor alpelisib as a tool for acute modeling of insulin resistance in healthy volunteers. This single-center double-blind phase 1 clinical trial randomly assigned healthy adults to a single oral dose of 300 mg alpelisib (n = 5) or placebo (n = 6) at bedtime, followed by measurement of glucose, insulin, and C-peptide levels after an overnight fast and during a 3-h 75-g oral glucose tolerance test (OGTT). Fasting plasma glucose trended higher with alpelisib (mean ± SD 93 ± 11 mg/dL) versus placebo (84 ± 5 mg/dL); mean fasting serum insulin increased nearly fivefold (23 ± 12 vs. 5 ± 3 μU/mL, respectively), and HOMA of insulin resistance (IR) scores were 5.4 ± 3.1 for alpelisib and 1.1 ± 0.6 for placebo. During OGTT, incremental area under the curve (AUC) for insulin was more than fourfold greater with alpelisib (22 ± 15 mU/mL × min) than with placebo (5 ± 2 mU/mL × min); glucose AUC trended higher with alpelisib. Single-dose alpelisib was well tolerated and produced metabolic alterations consistent with acute induction of IR, validating its use for mechanistic study of insulin action in humans.
我们的目的是测试单剂量的磷脂酰肌醇 3-激酶（PI3K）抑制剂阿培利司作为健康志愿者胰岛素抵抗急性模型的工具。这项单中心、双盲、I 期临床试验将健康成年人随机分为单口服 300mg 阿培利司（n=5）或安慰剂（n=6）组，睡前给药，然后在禁食过夜后和 3 小时 75g 口服葡萄糖耐量试验（OGTT）期间测量血糖、胰岛素和 C 肽水平。阿培利司组空腹血糖趋势较高（平均 ± SD 93 ± 11mg/dL），安慰剂组（84 ± 5mg/dL）；平均空腹血清胰岛素增加近五倍（分别为 23 ± 12μU/mL 和 5 ± 3μU/mL），胰岛素抵抗（IR）评分分别为阿培利司组 5.4 ± 3.1 和安慰剂组 1.1 ± 0.6。在 OGTT 期间，阿培利司组的胰岛素增量曲线下面积（AUC）增加超过四倍（22 ± 15mU/mL×min），安慰剂组（5 ± 2mU/mL×min）；阿培利司组的葡萄糖 AUC 趋势较高。单剂量阿培利司耐受性良好，代谢改变与 IR 的急性诱导一致，验证了其在人类胰岛素作用机制研究中的应用。
