title: Mapping glucose-mediated gut-to-brain signalling pathways in humans.
abstract: OBJECTIVE
  Previous fMRI studies have demonstrated that glucose decreases the hypothalamic BOLD response in humans. However, the mechanisms underlying the CNS response to glucose have not been defined. We recently demonstrated that the slowing of gastric emptying by glucose is dependent on activation of the gut peptide cholecystokinin (CCK1) receptor. Using physiological functional magnetic resonance imaging this study aimed to determine the whole brain response to glucose, and whether CCK plays a central role.
  
  
  METHODS
  Changes in blood oxygenation level-dependent (BOLD) signal were monitored using fMRI in 12 healthy subjects following intragastric infusion (250ml) of: 1M glucose+predosing with dexloxiglumide (CCK1 receptor antagonist), 1M glucose+placebo, or 0.9% saline (control)+placebo, in a single-blind, randomised fashion. Gallbladder volume, blood glucose, insulin, and GLP-1 and CCK concentrations were determined. Hunger, fullness and nausea scores were also recorded.
  
  
  RESULTS
  Intragastric glucose elevated plasma glucose, insulin, and GLP-1, and reduced gall bladder volume (an in vivo assay for CCK secretion). Glucose decreased BOLD signal, relative to saline, in the brainstem and hypothalamus as well as the cerebellum, right occipital cortex, putamen and thalamus. The timing of the BOLD signal decrease was negatively correlated with the rise in blood glucose and insulin levels. The glucose+dex arm highlighted a CCK1-receptor dependent increase in BOLD signal only in the motor cortex.
  
  
  CONCLUSIONS
  Glucose induces site-specific differences in BOLD response in the human brain; the brainstem and hypothalamus show a CCK1 receptor-independent reduction which is likely to be mediated by a circulatory effect of glucose and insulin, whereas the motor cortex shows an early dexloxiglumide-reversible increase in signal, suggesting a CCK1 receptor-dependent neural pathway.
authors.affiliation: University of Manchester, Manchester Academic Health Sciences Centre (MAHSC), Gastrointestinal Centre, Institute of Inflammation and Repair, Faculty of Medical and Human Sciences, University of Manchester, Clinical Sciences Building, Salford Royal Hospital, Stott Lane, Salford, UK, M6 8HD, UK.
authors.forename: Tanya J
authors.initials: TJ
authors.lastname: Little
authors.affiliation: University of Manchester, Manchester Academic Health Sciences Centre (MAHSC), Gastrointestinal Centre, Institute of Inflammation and Repair, Faculty of Medical and Human Sciences, University of Manchester, Clinical Sciences Building, Salford Royal Hospital, Stott Lane, Salford, UK, M6 8HD, UK; University of Manchester, Manchester Academic Health Sciences Centre (MAHSC), Neuroscience and Psychiatry Unit, Institute of Brain, Behaviour and Mental Health, The University of Manchester, G907 Stopford Building, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Shane
authors.initials: S
authors.lastname: McKie
authors.affiliation: University of Manchester, Manchester Academic Health Sciences Centre (MAHSC), Gastrointestinal Centre, Institute of Inflammation and Repair, Faculty of Medical and Human Sciences, University of Manchester, Clinical Sciences Building, Salford Royal Hospital, Stott Lane, Salford, UK, M6 8HD, UK.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Jones
authors.affiliation: Rottapharm SpA, Via Valosa di Sopra, 20900 Monza, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: D'Amato
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Manchester M13 9PT, UK.
authors.forename: Craig
authors.initials: C
authors.lastname: Smith
authors.affiliation: University of Manchester, Manchester Academic Health Sciences Centre (MAHSC), Gastrointestinal Centre, Institute of Inflammation and Repair, Faculty of Medical and Human Sciences, University of Manchester, Clinical Sciences Building, Salford Royal Hospital, Stott Lane, Salford, UK, M6 8HD, UK.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Kiss
authors.affiliation: University of Manchester, Manchester Academic Health Sciences Centre (MAHSC), Gastrointestinal Centre, Institute of Inflammation and Repair, Faculty of Medical and Human Sciences, University of Manchester, Clinical Sciences Building, Salford Royal Hospital, Stott Lane, Salford, UK, M6 8HD, UK.
authors.forename: David G
authors.initials: DG
authors.lastname: Thompson
authors.affiliation: University of Manchester, Manchester Academic Health Sciences Centre (MAHSC), Gastrointestinal Centre, Institute of Inflammation and Repair, Faculty of Medical and Human Sciences, University of Manchester, Clinical Sciences Building, Salford Royal Hospital, Stott Lane, Salford, UK, M6 8HD, UK. Electronic address: john.mclaughlin@manchester.ac.uk.
authors.forename: John T
authors.initials: JT
authors.lastname: McLaughlin
mesh_terms: D000328:Adult; D001921:Brain / Q000502:physiology*; D001931:Brain Mapping / Q000379:methods*; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D010101:Oxygen Consumption / Q000502:physiology*; D011949:Receptors, Cholecystokinin / Q000378:metabolism*; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D011949:Receptors, Cholecystokinin; D005947:Glucose
keywords: Cholecystokinin (CCK); Dexloxiglumide; Glucose; nutrient; physMRI