Pancreatic Islet APJ Deletion Reduces Islet Density and Glucose Tolerance in Mice

Endocrinology. 2015 Jul;156(7):2451-60. doi: 10.1210/en.2014-1631. Epub 2015 May 12.


Protection and replenishment of a functional pancreatic β-cell mass (BCM) are key goals of all diabetes therapies. Apelin, a small regulatory peptide, is the endogenous ligand for the apelin receptor (APJ) receptor. The apelin-APJ signaling system is expressed in rodent and human islet cells. Apelin exposure has been shown to inhibit and to stimulate insulin secretion. Our aim was to assess the influence of a selective APJ deletion in pancreatic islet cells on islet homeostasis and glucose tolerance in mice. Cre-LoxP strategy was utilized to mediate islet APJ deletion. APJ deletion in islet cells (APJ(Δislet)) resulted in a significantly reduced islet size, density and BCM. An ip glucose tolerance test showed significantly impaired glucose clearance in APJ(Δislet) mice. APJ(Δislet) mice were not insulin resistant and in vivo glucose-stimulated insulin secretion was reduced modestly. In vitro glucose-stimulated insulin secretion showed a significantly reduced insulin secretion by islets from APJ(Δislet) mice. Glucose clearance in response to ip glucose tolerance test in obese APJ(Δislet) mice fed a chronic high-fat (HF) diet, but not pregnant APJ(Δislet) mice, was impaired significantly. In addition, the obesity-induced adaptive elevations in mean islet size and fractional islet area were reduced significantly in obese APJ(Δislet) mice when compared with wild-type mice. Together, these findings demonstrate a stimulatory role for the islet cell apelin-APJ signaling axis in regulation of pancreatic islet homeostasis and in metabolic induced β-cell hyperplasia. The results indicate the apelin-APJ system can be exploited for replenishment of BCM.

MeSH terms

  • Adipokines
  • Animals
  • Apelin
  • Apelin Receptors
  • Blood Glucose / metabolism*
  • Diet, High-Fat
  • Female
  • Gene Deletion
  • Glucose Tolerance Test
  • Homeostasis
  • In Vitro Techniques
  • Insulin / metabolism*
  • Insulin Resistance / genetics*
  • Insulin-Secreting Cells / metabolism*
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Male
  • Mice
  • Obesity / metabolism*
  • Organ Size
  • Pregnancy
  • Receptors, G-Protein-Coupled / genetics*


  • Adipokines
  • Apelin
  • Apelin Receptors
  • Apln protein, mouse
  • Aplnr protein, mouse
  • Blood Glucose
  • Insulin
  • Intercellular Signaling Peptides and Proteins
  • Receptors, G-Protein-Coupled