972-P: Liraglutide Attenuates Lipid-Induced Microvascular Insulin Resistance in Humans

Abstract

Insulin recruits skeletal and cardiac muscle microvasculature to increase insulin and nutrient delivery, but this action is lost in insulin resistant states. Glucagon-like peptide 1 (GLP-1) improves microvascular perfusion in humans with obesity and the GLP-1 receptor agonist liraglutide attenuates muscle microvascular insulin resistance (IR) in rodents. To examine whether GLP-1 receptor agonism improves insulin’s microvascular actions in humans with acute IR, 18 healthy human subjects randomly received a systemic infusion of either saline or lipid emulsion (20%, 45 mL x 1 h and then 30 mL x 4 h) for 5 h or lipid emulsion for 5 h + liraglutide pre-treatment (0.6, 1.2, then 1.8 mg daily SC each x 2 days) with euglycemic insulin clamp (1 mU/kg/min) superimposed for the last 120 min. Skeletal and cardiac muscle microvascular blood volume (MBV), flow-mediated dilation (FMD), pulse wave velocity (PWV), and augmentation index (AI) were determined before and after insulin clamp. Compared with saline admission, insulin failed to increase MBV following lipid infusion in both skeletal (28.4 ± 14.1% vs. -1.3 ± 9.6% respectively, p=0.011) and cardiac (28.4 ± 14.1% vs. -1.3 ± 8.9%, p=0.027) muscle, consistent with acute IR induced by lipid infusion in both microvascular beds. Liraglutide pre-treatment improved insulin-mediated increases in MBV in the presence of lipid infusion in skeletal (8.9 ± 13.5%, p=0.117 vs. saline) and cardiac (12.6 ± 12.1%, p=0.101 vs. saline) muscle. There was no significant change in PWV, AI, or FMD amongst admissions. Glucose infusion rates were not significantly different amongst admissions (saline 6.02 ± 0.52, lipid 5.58 ± 0.62, vs. liraglutide + lipid 5.46 ± 0.46 mg/kg/min). In conclusion, liraglutide pretreatment effectively ameliorates lipid-induced skeletal and cardiac muscle microvascular IR in healthy humans. These data provide a mechanistic insight into the metabolic and cardiovascular benefits of GLP-1 receptor agonism seen in humans with obesity and type 2 diabetes. Disclosure K. Love: None. L. Jahn: None. L. Hartline: None. Z. Liu: None. Funding American Diabetes Association (1-17-ICST-059 to Z.L.); National Institutes of Health (1R01DK102359-01A1)