Glucagon‐like peptide‐1 receptor is a regulator of glucose clearance in oxidative tissues independent of insulin

Abstract

Activation of the glucagon‐like peptide‐1 receptor (GLP‐1R) stimulates insulin secretion. GLP‐1R also plays a role in the control of glucose homeostasis via mechanisms that are independent of this incretin action. Exercise was used to unmask glucoregulatory properties of GLP‐1R related to increased insulin‐independent glucose flux. Wild type (WT) and GLP‐1R knockout (KO) mice (n=7–8) were catheterized in the carotid artery (sampling) and jugular vein (infusion). 7 days later, 5h fasted mice underwent treadmill exercise (30 min @ 16.6 m/min) or remained sedentary. Fasting glucose (mg/dL) was higher in KO than WT (233±6 vs 198±9) and rose with exercise in KO but not WT (263±16 vs 201±11). Tissue glucose clearance (Kg μl/gtissue/min) was determined using 2[3H]deoxyglucose. Sedentary heart Kg was higher in KO than WT (84±17 vs 48±11) and did not increase further with exercise (ΔKg 6±14 vs 76±19). Sedentary diaphragm Kg was equal in WT and KO and increased with exercise in KO but not WT (ΔKg 29±10 vs 2±5). Insulin levels were equal in both groups. Oxygen consumption (VO2, ml/kg/min) was equal in WT and KO at rest but was higher in KO during moderate (75% VO2max 103±3 vs 121±4) and maximal (VO2max 132±4 vs 141±2) exercise. In summary, deletion of GLP‐1R leads to a) elevated sedentary cardiac glucose uptake to levels observed in exercised WT mice and b) increased diaphragm glucose uptake and higher VO2 during exercise. Thus exercise studies reveal the insulin‐independent glucoregulatory properties of GLP‐1R. Supported by DK50277.