title: 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.
authors.affiliation: University of Texas Health Science Center, San Antonio, TX.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Daniele
authors.affiliation: Institute of Clinical Physiology, Pisa, Italy.
authors.forename: Patricia
authors.initials: P
authors.lastname: Iozzo
authors.affiliation: University of Texas Health Science Center, San Antonio, TX.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Molina-Carrion
authors.affiliation: University of Texas Health Science Center, San Antonio, TX.
authors.forename: Jack
authors.initials: J
authors.lastname: Lancaster
authors.affiliation: Institute of Clinical Physiology, Pisa, Italy.
authors.forename: Demetrio
authors.initials: D
authors.lastname: Ciociaro
authors.affiliation: University of Texas Health Science Center, San Antonio, TX.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Cersosimo
authors.affiliation: University of Texas Health Science Center, San Antonio, TX.
authors.forename: Devjit
authors.initials: D
authors.lastname: Tripathy
authors.affiliation: University of Texas Health Science Center, San Antonio, TX.
authors.forename: Curtis
authors.initials: C
authors.lastname: Triplitt
authors.affiliation: University of Texas Health Science Center, San Antonio, TX.
authors.forename: Peter
authors.initials: P
authors.lastname: Fox
authors.affiliation: University of Texas Health Science Center, San Antonio, TX.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Musi
authors.affiliation: University of Texas Health Science Center, San Antonio, TX.
authors.forename: Ralph
authors.initials: R
authors.lastname: DeFronzo
authors.affiliation: University of Texas Health Science Center, San Antonio, TX Institute of Clinical Physiology, Pisa, Italy amalia@ifc.cnr.it.
authors.forename: Amalia
authors.initials: A
authors.lastname: Gastaldelli
mesh_terms: D001786:Blood Glucose; D054022:Cerebrum / Q000187:drug effects / Q000378:metabolism*; D018592:Cross-Over Studies; D003920:Diabetes Mellitus / Q000175:diagnosis; D004311:Double-Blind Method; D000077270:Exenatide; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000494:pharmacology*; D011236:Prediabetic State; D014688:Venoms / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D000077270:Exenatide; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; C517652:hemoglobin A1c protein, human