Exenatide regulates cerebral glucose metabolism in brain areas associated with glucose homeostasis and reward system

Glucagon-like peptide 1 receptors (GLP-1Rs) have been found in the brain, but whether GLP-1R agonists (GLP-1RAs) influence brain glucose metabolism is currently unknown. The study aim was to evaluate the effects of a single injection of the GLP-1RA exenatide on cerebral and peripheral glucose metabolism in response to a glucose load. In 15 male subjects with HbA_1c of 5.7 ± 0.1%, fasting glucose of 114 ± 3 mg/dL, and 2-h glucose of 177 ± 11 mg/dL, exenatide (5 μg) or placebo was injected in double-blind, randomized fashion subcutaneously 30 min before an oral glucose tolerance test (OGTT). The cerebral glucose metabolic rate (CMR_glu) was measured by positron emission tomography after an injection of [¹⁸F]2-fluoro-2-deoxy-D-glucose before the OGTT, and the rate of glucose absorption (RaO) and disposal was assessed using stable isotope tracers. Exenatide reduced RaO_{0-60 min} (4.6 ± 1.4 vs. 13.1 ± 1.7 μmol/min · kg) and decreased the rise in mean glucose_{0-60 min} (107 ± 6 vs. 138 ± 8 mg/dL) and insulin_{0-60 min} (17.3 ± 3.1 vs. 24.7 ± 3.8 mU/L). Exenatide increased CMR_glu in areas of the brain related to glucose homeostasis, appetite, and food reward, despite lower plasma insulin concentrations, but reduced glucose uptake in the hypothalamus. Decreased RaO_{0-60 min} after exenatide was inversely correlated to CMR_glu. In conclusion, these results demonstrate, for the first time in man, a major effect of a GLP-1RA on regulation of brain glucose metabolism in the absorptive state.