title: Endogenous GLP-1 mediates postprandial reductions in activation in central reward and satiety areas in patients with type 2 diabetes.
abstract: OBJECTIVE
  The central nervous system (CNS) is a major player in the regulation of food intake. The gut hormone glucagon-like peptide-1 (GLP-1) has been proposed to have an important role in this regulation by relaying information about nutritional status to the CNS. We hypothesised that endogenous GLP-1 has effects on CNS reward and satiety circuits.
  
  
  METHODS
  This was a randomised, crossover, placebo-controlled intervention study, performed in a university medical centre in the Netherlands. We included patients with type 2 diabetes and healthy lean control subjects. Individuals were eligible if they were 40-65 years. Inclusion criteria for the healthy lean individuals included a BMI <25 kg/m(2) and normoglycaemia. Inclusion criteria for the patients with type 2 diabetes included BMI >26 kg/m(2), HbA1c levels between 42 and 69 mmol/mol (6.0-8.5%) and treatment for diabetes with only oral glucose-lowering agents. We assessed CNS activation, defined as blood oxygen level dependent (BOLD) signal, in response to food pictures in obese patients with type 2 diabetes (n = 20) and healthy lean individuals (n = 20) using functional magnetic resonance imaging (fMRI). fMRI was performed in the fasted state and after meal intake on two occasions, once during infusion of the GLP-1 receptor antagonist exendin 9-39, which was administered to block actions of endogenous GLP-1, and on the other occasion during saline (placebo) infusion. Participants were blinded for the type of infusion. The order of infusion was determined by block randomisation. The primary outcome was the difference in BOLD signal, i.e. in CNS activation, in predefined regions in the CNS in response to viewing food pictures.
  
  
  RESULTS
  All patients were included in the analyses. Patients with type 2 diabetes showed increased CNS activation in CNS areas involved in the regulation of feeding (insula, amygdala and orbitofrontal cortex) in response to food pictures compared with lean individuals (p ≤ 0.04). Meal intake reduced activation in the insula in response to food pictures in both groups (p ≤ 0.05), but this was more pronounced in patients with type 2 diabetes. Blocking actions of endogenous GLP-1 significantly prevented meal-induced reductions in bilateral insula activation in response to food pictures in patients with type 2 diabetes (p ≤ 0.03).
  
  
  CONCLUSIONS
  Our findings support the hypothesis that endogenous GLP-1 is involved in postprandial satiating effects in the CNS of obese patients with type 2 diabetes.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT 01363609. Funding The study was funded in part by a grant from Novo Nordisk.
authors.affiliation: Department of Internal Medicine, Diabetes Center, VU University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands. js.tenkulve@vumc.nl.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: ten Kulve
authors.affiliation: Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Dick J
authors.initials: DJ
authors.lastname: Veltman
authors.affiliation: Department of Internal Medicine, Diabetes Center, VU University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands.
authors.forename: Liselotte
authors.initials: L
authors.lastname: van Bloemendaal
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Frederik
authors.initials: F
authors.lastname: Barkhof
authors.affiliation: The NNF Center for Basic Metabolic Research, Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Carolyn F
authors.initials: CF
authors.lastname: Deacon
authors.affiliation: The NNF Center for Basic Metabolic Research, Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Konrad
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Sloan
authors.affiliation: Department of Internal Medicine/Endocrine Section, VU University Medical Center, Amsterdam, the Netherlands.|Department of Clinical Neuropsychology, VU University, Amsterdam, the Netherlands.
authors.forename: Madeleine L
authors.initials: ML
authors.lastname: Drent
authors.affiliation: Department of Internal Medicine, Diabetes Center, VU University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands.
authors.forename: Michaela
authors.initials: M
authors.lastname: Diamant
authors.affiliation: Department of Internal Medicine, Diabetes Center, VU University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands.
authors.forename: Richard G
authors.initials: RG
authors.lastname: IJzerman
mesh_terms: D000328:Adult; D000368:Aged; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000523:psychology; D005260:Female; D005502:Food; D052216:Glucagon-Like Peptide 1 / Q000819:agonists / Q000378:metabolism*; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000097:blood; D010100:Oxygen / Q000097:blood; D010446:Peptide Fragments / Q000009:adverse effects / Q000627:therapeutic use; D010775:Photic Stimulation; D019518:Postprandial Period; D012201:Reward; D012528:Satiety Response; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; D000067757:Glucagon-Like Peptide-1 Receptor
chemical_list: D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D010100:Oxygen; D010446:Peptide Fragments; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; C083773:exendin (9-39)
keywords: Food intake; GLP-1; Neuroimaging; Obesity; Type 2 diabetes; fMRI