Glucagon-Like Peptide-1 Receptor Knockout Mice Are Protected from High-Fat Diet-Induced Insulin Resistance

Glucagon-like peptide-1 augments nutrient-stimulated insulin secretion. Chow-fed mice lacking the glucagon-like peptide-1 receptor (Glp1r) exhibit enhanced insulin-stimulated muscle glucose uptake but impaired suppression of endogenous glucose appearance (endoRa). This proposes a novel role for theGlp1r to regulate the balance of glucose disposal inmuscle and liver bymodulating insulin action. Whether this is maintained in an insulin-resistant state is unknown. The present studies tested the hypothesis that disruption of Glp1r expression overcomes high-fat (HF) diet-induced muscle insulin resistanceandexacerbatesHFdiet-inducedhepatic insulinresistance.Micewithafunctionaldisruption of the Glp1r (Glp1r/) were compared with wild-type littermates (Glp1r/) after12 wk on a regular chow diet or a HF diet. Arterial and venous catheters were implanted for sampling and infusions. Hyperinsulinemic-euglycemic clamps were performed on weight-matched male mice. [3-3H]glucose was used to determine glucose turnover, and 2[14C]deoxyglucose was used to measure the glucose metabolic index, an indicator ofglucoseuptake.Glp1r/miceexhibited increasedglucosedisappear-ance andmuscle glucosemetabolic index on either diet. Thiswas associatedwith enhanced activation of muscle Akt and AMP-activated protein kinase and reducedmuscle triglycerides in HF-fed Glp1r/ mice.Chow-fedGlp1r/miceexhibited impaired suppressionofendoRaandhepatic insulin signaling