Effect of GLP-1 agonist Exenatide on cerebral, hepatic and peripheral glucose metabolism in postprandial state

GLP-1 receptors (GLP-1R) have been found in the brain and it has been hypothesized that GLP-1R agonists could improve brain glucose metabolism. The aims of the study were to evaluate the effects of Exenatide (EX) on cerebral as well as hepatic/peripheral glucose metabolism. We studied 15 male subjects with impaired glucose tolerance (n=12) or newly diagnosed with type 2 diabetes (n=3) (age=56±8 y, BMI=29±1 kg/m2, HbA1c=5.7±0.1%). Each subject underwent 2 oral glucose tests (OGTT 75 g) with double blind injection of EX (5 mcg) or placebo (PLC) 30min before OGTT; 6,6-2H-glucose was infused for 4h (2h before and 2h during OGTT) and U-13C-glucose was added to oral glucose to assess glucose absorption (RaO), production (EGP), total rate of glucose appearance (Ra) and disposal (Rd). Brain glucose uptake was measured by PET following injection of 18FDG (5mCi) at t=0 and acquiring brain images 1h into the OGTT. EX delayed gastric emptying (RaO AUC0-120min=660±167 vs 1885±148 μmol/min•kg); glucose (12607±760 vs 18353±1038 mg/dl) and insulin AUC0-120min (2704±562 vs 4872±650 mU/l) were lower in EX (all p<0.05). While glucose Rd AUC0-60min was comparable (127±9 vs 132±10 μmol/min•kg, EX vs PLC), cerebral glucose metabolic rate (CGMR) was increased with EX (0.18±0.01 vs 0.12±0.01 μmol/min•ml; p=0.02). Total CGMR was inversely correlated with RaO (r=-0.63; p<0.0005). The brain areas with the highest CGMR were: Thalamus 0.23±0.02 vs 0.14±0.01, Occipital 0.24±0.02 vs 0.16±0.02 and Frontal lobes 0.19±0.02 vs 0.12±0.01 μmol/min•ml (EX vs PLC, all p<0.004). However, in the Hypothalamus EX reduced the CGMR from 0.13±0.02 to 0.09±0.01 μmol/min•ml (p=0.003). Conclusion: EX modulates CGMR by increasing glucose uptake in multiple areas of the brain but reduces glucose uptake in the hypothalamus. These results provide a previously unrecognized mechanism via which EX-mediated changes in glucose metabolism can influence the regulation of glucose absorption and hepatic/peripheral glucose metabolism.