A Single Dose of Phosphoinositide-3-kinase Inhibitor Alpelisib Induces Insulin Resistance in Healthy Adults: A Randomized Feasibility Study

IF 6.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes Pub Date : 2024-09-12 DOI:10.2337/db24-0402

Joshua R. Cook, Nur Bedeir, Zachary D. Sone, Julia Wattacheril, Henry N. Ginsberg, Blandine Laferrère

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Abstract

Our objective is to test a single dose of the phosphoinositide-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 randomized healthy adults to take a single oral dose of alpelisib 300 mg (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-hour, 75-g oral glucose tolerance test. Fasting plasma glucose trended higher with alpelisib (mean ± S.D.: 93 ± 11 mg/dL) versus placebo (84 ± 5 mg/dL), while mean fasting serum insulin increased nearly fivefold (23 ± 12 µU/mL vs. 5 ± 3 µU/mL, respectively) and Homeostasis Model Assessment of Insulin Resistance scored 5.4 ± 3.1 for alpelisib and 1.1 ± 0.6 for placebo. During OGTT, incremental area under the curve (AUC) for insulin was over fourfold greater with alpelisib (22 ± 15 mU/mL x min) than placebo (5 ± 2 mU/mL x 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. (ClinicalTrials.gov registration: NCT05733455)

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单剂量磷脂酰肌醇-3-激酶抑制剂 Alpelisib 可诱导健康成人的胰岛素抵抗：随机可行性研究

我们的目的是测试单剂量磷脂酰肌醇-3-激酶（PI3K）抑制剂 alpelisib 作为健康志愿者胰岛素抵抗急性建模工具的效果。这项单中心、双盲、1 期临床试验将健康成年人随机分组，睡前口服单剂量 alpelisib 300 毫克（5 人）或安慰剂（6 人），然后在一夜禁食后和 3 小时 75 克口服葡萄糖耐量试验期间测量血糖、胰岛素和 C 肽水平。使用阿沛利西布后，空腹血浆葡萄糖（平均值±S.D.：93±11 mg/dL）与安慰剂（84±5 mg/dL）相比呈上升趋势，而空腹血清胰岛素平均值增加了近五倍（分别为 23±12 µU/mL 与 5±3 µU/mL），阿沛利西布的胰岛素抵抗稳态模型评估得分为 5.4±3.1 分，安慰剂为 1.1±0.6 分。在OGTT期间，阿来替尼的胰岛素增量曲线下面积（AUC）（22 ± 15 mU/mL x min）是安慰剂（5 ± 2 mU/mL x min）的四倍多；阿来替尼的葡萄糖AUC呈上升趋势。单剂量阿来替尼耐受性良好，产生的代谢改变与急性诱导IR一致，因此可用于人体胰岛素作用机理研究。(临床试验网注册：NCT05733455）

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来源期刊

Diabetes 医学-内分泌学与代谢

CiteScore

12.50

自引率

2.60%

发文量

1968

审稿时长

1 months

期刊介绍： Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes. However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.