3032-LB: ß2-Adrenergic Receptor Modulators Improve Insulin Sensitivity in Obese and PI3K-Mutant Mice

Introduction and Objective: Skeletal muscle is a pivotal regulator of whole-body metabolism, as it accounts for a substantial proportion of postprandial insulin-stimulated glucose disposal and is a major contributor to total energy expenditure. In this context, activation of β2adrenergic receptors (β2AR) in human skeletal muscle is well known to exert beneficial anabolic and metabolic effects, including promoting muscle hypertrophy and stimulating glucose uptake. Classical β2AR agonists such as clenbuterol are reported to improve glucose homeostasis and insulin sensitivity in mice with diet-induced obesity (DIO) but are limited by safety concerns with chronic use in humans. We recently developed novel β2AR modulators with unique GRK2-biased signaling aiming to improve their safety and suitability for chronic use. Here, we evaluated the effects of the novel modulator ATR-258 on insulin sensitivity in DIO mice as well as effects of clenbuterol on Pik3r1WT/Y657** mice heterozygous for a PIK3R1 mutation affecting the PI3K insulin signaling pathway, analogous to mutations causing SHORT syndrome with severe insulin resistance in humans. Methods: Male DIO mice (n = 9/group) received ATR-258 (0. 3 or 1 mg/kg, oral gavage). Fasting glucose, fasting insulin, HOMA-IR, and insulin tolerance tests (ITT) were assessed after up to 24 days of treatment. Male Pik3r1WT/Y657** mice (n = 5-6/group) were treated with clenbuterol in drinking water. ITT was performed after 11 days. Results: In DIO mice, ATR-258 at 1 mg/kg improved insulin sensitivity in ITT (p 0. 05). Both 0. 3 and 1 mg/kg doses reduced fasting glucose by 13% (p 0. 01) and fasting insulin by 39% and 49% (p = 0. 09 and p 0. 05), lowering HOMA-IR by 45% and 56% (p 0. 01 and p 0. 001). In Pik3r1WT/Y657** mice, clenbuterol improved insulin sensitivity in ITT (p0. 05). Conclusion: β2AR modulators improve insulin sensitivity in two mechanistically distinct murine models of insulin resistance and represent promising insulin sensitizing candidates for further development. Disclosure A. Kalinovich: Employee; Current; Atrogi AB. M. Bokhari: Employee; Current; Atrogi. J. de Jong: Employee; Ended; Atrogi. N. Dehvari: Employee; Current; Atrogi AB. C. Halleskog: Employee; Current; Atrogi AB. C. Kallenberg: Employee; Ended; Atrogi. I. Luijten: None. R. K. Semple: Consultant; Current; Chiesi USA, Inc. Speaker's Bureau; Current; Chiesi USA, Inc. Consultant; Current; Hybolic, RA Ventures. T. Bengtsson: Other - Founder; Current; Atrogi AB, Sigrid Therapeutics AB. Consultant; Current; Insulife AS. Other - Founder; Current; TBRC research and Development AB. Funding Swedish Research Council (2019-01508 and 2024-02446), the Eurostar project SYNSTAR (E114421), and Diabetes Wellness Sverige.