Introduction & Objective: Understanding the pathophysiology of insulin resistance (IR) is essential to treating type 2 diabetes, but mechanistic studies of IR in human subjects are often complicated by ancestry and phenotypic heterogeneity, variable chronicity, and difficulty in causal inference. We therefore seek to establish a safe, reliable, acute method for modeling IR in a translational setting. Our objective is to test a single dose of the phosphoinositide-3-kinase (PI3K) inhibitor alpelisib, versus placebo, for tolerability and effect on glucose and insulin metabolism.
Methods: This single-center, double-blind phase I clinical trial randomized healthy adults, ages 18-65 y with body mass index 18.0-26.9 kg/m2 and HbA1C ≤ 5.6%, to take a single oral dose of alpelisib 300 mg (n = 5) or placebo (n = 6) at bedtime. The next morning, participants had blood drawn for fasting insulin and glucose levels (co-primary endpoints) followed by a 3-hour, 75-g oral glucose tolerance test (OGTT). Data are analyzed based on intention to treat using an independent two-sample t test.
Results: Fasting plasma glucose trended higher with alpelisib (mean ± SEM = 93 ± 6 mg/dL) versus placebo (84 ± 2 mg/dL) (p = 0.07). Mean fasting serum insulin increased nearly fivefold: 23 ± 6 μIU/mL for alpelisib versus 5 ± 1 μIU/mL for placebo (p < 0.01), resulting in Homeostasis Model Assessment of Insulin Resistance scores of 5.4 ± 1.4 vs. 1.1 ± 0.2 and Matsuda Index scores of 8.6 ± 2.2 vs. 3.0 ± 1.6, respectively. During OGTT, area under the curve (AUC) for insulin was greater with alpelisib (26.0 ± 7.5 mIU/mL × min) than placebo (5.8 ± 1.0 mIU/mL × min) (p < 0.02); glucose AUC trended higher with alpelisib. Single-dose alpelisib was well tolerated without serious adverse events.
Conclusion: A single dose of alpelisib produced metabolic derangements consistent with acute induction of IR, validating its use as a safe and effective tool for studying insulin action in humans.
J.R. Cook: None. N. Bedeir: None. Z.D. Sone: None. J. Wattacheril: Research Support; Intercept Pharmaceuticals, Inc. Advisory Panel; GlaxoSmithKline plc. Consultant; Alphasights. Research Support; AMRA, Galectin Therapeutics. H.N. Ginsberg: None. B. Laferrère: Consultant; Up-To-Date.
