title: Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice.
abstract: OBJECTIVE
  Incretin-based therapies improve glycaemic control in patients with type 2 diabetes. In animal models of diabetes, glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase beta cell mass. GLP-1RAs are also evaluated in non-diabetic individuals with obesity and cardiovascular disease. However, their effect on beta cell mass in normoglycaemic conditions is not clear. Here, we investigate the effects of the GLP-1RA liraglutide on beta cell mass and function in normoglycaemic mice.
  
  
  METHODS
  C57BL/6J mice were treated with the GLP-1RA liraglutide or PBS and fed a control or high-fat diet (HFD) for 1 or 6 weeks. Glucose and insulin tolerance tests were performed after 6 weeks. BrdU was given to label proliferating cells 1 week before the animals were killed. The pancreas was taken for either histology or islet isolation followed by a glucose-induced insulin-secretion test.
  
  
  RESULTS
  Treatment with liraglutide for 6 weeks led to increased insulin sensitivity and attenuation of HFD-induced insulin resistance. A reduction in beta cell mass was observed in liraglutide-treated control and HFD-fed mice at 6 weeks, and was associated with a lower beta cell proliferation rate after 1 week of treatment. A similar reduction in alpha cell mass occurred, resulting in an unchanged alpha to beta cell ratio. In contrast, acinar cell proliferation was increased. Finally, islets isolated from liraglutide-treated control mice had enhanced glucose-induced insulin secretion.
  
  
  CONCLUSIONS
  Our data show that GLP-1RA treatment in normoglycaemic mice leads to increases in insulin sensitivity and beta cell function that are associated with reduced beta cell mass to maintain normoglycaemia.
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Postal Zone C7-P, PO Box 9600, 2300 RC Leiden, the Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Ellenbroek
authors.forename: H A M
authors.initials: HA
authors.lastname: Töns
authors.forename: M J A
authors.initials: MJ
authors.lastname: Westerouen van Meeteren
authors.forename: N
authors.initials: N
authors.lastname: de Graaf
authors.forename: M A
authors.initials: MA
authors.lastname: Hanegraaf
authors.forename: T J
authors.initials: TJ
authors.lastname: Rabelink
authors.forename: F
authors.initials: F
authors.lastname: Carlotti
authors.forename: E J P
authors.initials: EJ
authors.lastname: de Koning
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D059305:Diet, High-Fat; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D007150:Immunohistochemistry; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects*; D000069450:Liraglutide; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018027:Receptors, Glucagon / Q000819:agonists*
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D018027:Receptors, Glucagon; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1