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

Abstract

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.

International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand

“…Selective deletion of the apelin receptor in pancreatic islet β -cells of mice resulted in a reduction of islet size, density, and cell mass. These cells showed a decreased insulin secretion in vitro, and the mice displayed decreased glucose tolerance (Li et al, 2006; Han et al, 2015). Insulin exerted direct control on apelin gene expression in adipocytes of humans and rodents and there was a large increase in apelin expression in fat cells of all hyperinsulinemia-associated obesities (Boucher et al, 2005).…”

Induction of chronic pancreatitis by pancreatic duct ligation activates BMP2, apelin, and PTHrP expression in mice

“…Pancreatic fibronectin protein levels were measured by means of the Odessey Western blot detection system (LI-COR, Lincoln, NE) (18). In brief, membranes were blocked with LI-COR blocking buffer for 1 h at room temperature, probed with a fibronectin antibody diluted in 0.1% Tween LI-COR blocking buffer.…”

Treatment with didemnin B, an elongation factor 1A inhibitor, improves hepatic lipotoxicity in obese mice

“…Pancreatic islets were categorized as small (<2500 μ m 2 ), medium (2500 μ m 2 ≤ x ≤ 10,000 μ m 2 ), or large (>10,000 μ m 2 ) to determine islet size distribution (Han et al. ).…”

“…Total islet area per section area and average islet density per mouse were evaluated using ImageJ (NIH, Bethesda, MD). Pancreatic islets were categorized as small (<2500 lm 2 ), medium (2500 lm 2 ≤ x ≤ 10,000 lm 2 ), or large (>10,000 lm 2 ) to determine islet size distribution (Han et al 2015).…”