1889-P: Light Exercise and Liraglutide Synergistically Improve Muscle Insulin Action in Diet-Induced Obesity

Insulin recruits muscle microvasculature which contributes to insulin’s metabolic action but is blunted in humans with obesity. Both exercise and glucagon-like peptide 1 (GLP-1) are potent enhancers of muscle microvascular perfusion and their actions are preserved in the insulin resistant states. To examine whether light exercise and GLP-1 receptor agonism modulate insulin’s microvascular and metabolic actions during the development of obesity, adult male rats were fed a high-fat diet (HFD) for 2 weeks with either free access to running wheel (light exercise), liraglutide (200 mcg/kg subcutaneously twice daily), or light exercise + liraglutide. Rats were then fasted overnight and received a euglycemic insulin clamp (3 mU/kg/min) for 120 min. Insulin-mediated muscle microvascular recruitment was measured using contrast-enhanced ultrasound. Rats on HFD alone (control) displayed marked microvascular insulin resistance. Light exercise increased basal plasma nitric oxide levels and fully rescued insulin’s microvascular action. Liraglutide similarly increased basal plasma NO contents but did not reverse microvascular insulin resistance. Both light exercise and liraglutide improved insulin-stimulated whole body glucose disposal in the first 30 min but did not significantly increase the steady-state glucose infusion rates. Combined light exercise and liraglutide treatment not only fully restored microvascular insulin responses but also significantly enhanced insulin-stimulated whole body glucose disposal (>50%, p<0.01). We conclude that light exercise and liraglutide differentially modulate microvascular insulin responses but synergistically enhance metabolic insulin actions during the development of obesity. Our findings provide a novel insight into the exercise and liraglutide interplay and support the early use of exercise and GLP-1 receptor agonism to correct microvascular and metabolic insulin resistance during the development of obesity. Disclosure J. Liu: None. K.W. Aylor: None. Z. Liu: None. Funding American Diabetes Association (1-17-ICTS-059 to Z.L.); National Institutes of Health (R01HL094722, R01DK102359)