1728-P: Oral Consumption of a PI3K P110a Inhibitor Perturbs Glucose Homeostasis without Affecting the Physical or Cognitive Function of Adult Mice

Advances in medicine have contributed to an ageing population, and various age-associated pathologies contribute to loss of independence and quality of life. Calorie restriction and genetic inhibition of insulin signalling pathway intermediates such as phosphatidylinositol-3-kinase (PI3K), have shown promise in improving lifespan but are difficult to implement clinically. Therefore, we sought to test whether pharmacological inhibition of PI3K using an orally ingested p110α-selective inhibitor, BYL-719, promotes changes in glucose homeostasis and physical function in adult (8-month old) male and female mice. Three days of exposure to a standard chow diet containing 0.30 g/kg BYL-719 elevated blood glucose in response to a meal challenge, however, following four weeks of BYL-719 diet consumption blood glucose response to a meal was normalised in females, but not males. Despite this, both male and female mice fed the BYL-719 diet were glucose intolerance and had impaired insulin sensitivity compared to mice fed a control diet. There was no difference between groups in measures of physical performance (treadmill, rotarod or hang time performance) or stress/anxiety behaviour assessed through open field test. However, female mice fed the BYL-719 diet showed greater exploratory behaviour in an object recognition test. Collectively, these data indicate that short-term pharmacological inhibition of PI3K p110α alters glucose homeostasis, but has only mild effect with respect to the physiological stimulus of a meal, and without deterioration of physical or cognitive function in adult mice. This indicates BYL-719 is safely tolerated in adult mice, and longer-term study is warranted to test the efficacy of BYL-719 in prolonging lifelong health in an aged population.