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.