Exenatide Regulates Cerebral Glucose Metabolism in Brain Areas Associated With Glucose Homeostasis and Reward System

Abstract

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 HbA1c 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 (CMRglu) was measured by positron emission tomography after an injection of [(18)F]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 RaO0-60 min (4.6 ± 1.4 vs. 13.1 ± 1.7 μmol/min ⋅ kg) and decreased the rise in mean glucose0-60 min (107 ± 6 vs. 138 ± 8 mg/dL) and insulin0-60 min (17.3 ± 3.1 vs. 24.7 ± 3.8 mU/L). Exenatide increased CMRglu 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 RaO0-60 min after exenatide was inversely correlated to CMRglu. 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.

Trial registration: ClinicalTrials.gov NCT01588418.

Figure 1

Protocol of the study: each subject underwent two studies, one with EX and one with PLC (in double-blind order). In each session, tracer infusion and a 75-g OGTT were performed.

Figure 2

Image of ¹⁸F-FDG brain glucose uptake during PLC (A, C, and D) and EX (B, E, and F) in one study subject. G: Mean cerebral glucose uptake after oral glucose load (OGTT) was increased after EX compared with PLC in total gray matter, cortex, and areas involved in glucose homeostasis and food reward, but not in the hypothalamus, where glucose uptake was reduced. *P < 0.05.

Figure 3

Correlation between RaO (A) or systemic glucose Ra (B) and CMR_glu in brain regions associated with glucose homeostasis (left panels) or food reward (right panels). Data were log-transformed before analysis. C: Mean insulin and glucose concentrations (left panels) and mean glucose fluxes (i.e., RaO, EGP, and Rd) (right panels) during the first hour of the OGTT. *P < 0.05.