Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice

Diabetologia. 2013 Sep;56(9):1980-6. doi: 10.1007/s00125-013-2957-2. Epub 2013 Jun 16.

Abstract

Aims/hypothesis: 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/interpretation: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • Diet, High-Fat
  • Glucagon-Like Peptide 1 / analogs & derivatives*
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucagon-Like Peptide-1 Receptor
  • Glucose Tolerance Test
  • Immunohistochemistry
  • Insulin Resistance / physiology*
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / drug effects*
  • Liraglutide
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Glucagon / agonists*

Substances

  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Receptors, Glucagon
  • Liraglutide
  • Glucagon-Like Peptide 1