Exendin-4 Normalizes Islet Vascularity in Intrauterine Growth Restricted Rats: Potential Role of VEGF

Abstract

Intrauterine growth restriction (IUGR) induced by uterine artery ligation in pregnant rats leads to low birth weight and early insulin secretory defects followed by the development of insulin resistance, decline in ␤-cell mass, and diabetes in adulthood. Neonatal administration of Exendin-4 (Ex-4) prevents the deterioration of ␤-cell mass and the onset of adult-onset diabetes. Our aim was to determine whether this effect occurs through preservation of islet vascularization. In 2 wk-old IUGR rats, endothelial-specific lectin staining revealed a 40% reduction in islet vascular density (p ϭ 0.027), which was normalized by neonatal Ex-4. VEGF-A protein expression was reduced in IUGR islets compared with controls at postnatal d 1 (P). Neonatal Ex-4 normalized islet VEGF protein expression at P7. Neither IUGR nor Ex-4 administration to IUGR rats affected relative VEGF splice isoform RNA levels. Together, the reduced vascularity in IUGR islets before the deterioration of ␤-cell mass, and the enhancement of VEGF expression and normalization of islet vascularity by neonatal Ex-4, suggest islet vascularity as an early determinant of ␤-cell mass and as a potential therapeutic target for diabetes prevention. Uteroplacental insufficiency, leading to reduced delivery of nutrients, oxygen, growth factors, and hormones to the developing fetus, is a common cause of fetal growth restriction. Epidemiologic studies in humans have established a correlation between intrauterine growth restriction (IUGR) and an increased risk of type 2 diabetes, obesity, and coronary artery disease in later life (1). This demonstration of the fetal origins hypothesis, the idea that the fetal environment has a crucial influence on development of adult-onset disease, has been reproduced in multiple human populations and in various animal models (1). In a rat model of uteroplacental insufficiency, bilateral uterine artery ligation in late gestation results in IUGR and low birth weight (2). IUGR rats develop a phenotype similar to that of type 2 diabetes in humans, with the development of obesity, insulin resistance, and insulinsecretory deficits. Although normal early in life, there is a progressive decline in ␤-cell mass of IUGR rats, preceding the development of hyperglycemia and diabetes by several weeks of age (2).Extensive islet remodeling occurs during the immediate postnatal period in rodent pancreatic development, with waves of ␤-cell proliferation, apoptosis, and neogenesis in the first weeks of life (3,4). Similar to the impact that a negative fetal environment has on future pancreatic function, therapeutic intervention within this critical neonatal period may permanently improve ␤-cell mass throughout adulthood. The incretin hormone glucagon-like peptide-1 (GLP-1) and the long-acting GLP-1 receptor agonist, Exendin-4 (Ex-4), augment insulin secretion and improve glucose tolerance in diabetes (5). GLP-1 also promotes expansion of ␤-cell mass by increasing proliferation and stimulating neogenesis (5). Importantly, Ex-4 when given in t...

Experimental Intrauterine Growth Restriction Induces Alterations in DNA Methylation and Gene Expression in Pancreatic Islets of Rats

“…Interestingly, folate supplementation of protein-restricted dams, known to buffer against changes in DNA methylation (32), prevented the development of hypertension and reduced NO synthesis and endothelial dysfunction that was otherwise observed in male offspring (33,34). We hypothesize that the Gch1 down-regulation we observed with IUGR could play a role in the progressive ␤-cell decline that we have previously observed (9), through direct effects on the ␤-cells or islet vascularization (27).…”

“…8). Taken together, these changes and functional associations are suggestive of a deficient ␤-cell microenvironment in IUGR and may explain some of the ␤-cell phenotype observed in IUGR islets (3,6,27).…”

“…Furthermore, some of these loci are in proximity to genes manifesting concordant changes in gene expression and are enriched near genes that regulate processes that are markedly impaired in IUGR islets (e.g. vascularization, proliferation, insulin secretion, and cell death) (3,6,9,27). This epigenomic dysregulation precedes the development of diabetes and is therefore a potential mediator of the pathogenesis of the disease, preserving cellular memory of the long antecedent intrauterine event.…”

Stressing diabetes? The hidden links between insulinotropic peptides and the HPA axis

“…These phenomena restore chromatin structure at the PDX-1 promoter and prevent DNA methylation, thereby preserving PDX-1 transcription (Pinney et al 2011). In addition, Ex-4 normalizes islet vascularization in these animals (Ham et al 2009). The vascular bed plays an important role in normal pancreatic function, producing signals for differentiation and development, and delivering of nutrients to β-cells.…”

Nutritional programming of pancreatic β-cell plasticity

“…Intraislet vascular volume and endothelial cell vascular endothelial growth factor (VEGF) receptor abundance were reduced in LP-fed offspring and both were reversed by supplementation of the LP diet with taurine, an amino acid which normally is present at high concentrations within islets but which is depleted in animals exposed to a LP diet [7] . Islet vasculature is also diminished in other models of intrauterine growth retardation such as uterine artery ligation of the mother [8] and in that study, it was reversible by administration of the glucagon-like polypeptide-1 analog, exendin 4, to the offspring, presumably by increasing β-cell-derived VEGF which promoted local angiogenesis. We recently applied the LP diet model to the mouse and found that the β-cell regeneration that normally occurs in juveniles following depletion of β-cell mass with streptozotocin (STZ) treatment was prevented if the offspring had been previously exposed to a LP diet [9] .…”