Abstract
Pancreatic islet endothelial cells have in recent years been shown to support beta-cell mass and function by paracrine interactions. Recently, we identified an islets endothelial-specific glycoprotein, thrombospondin-1 (TSP-1), that showed to be of importance for islet angiogenesis and beta-cell function in young mice. The present study aimed to investigate long-term consequences for islet morphology and beta-cell function of TSP-1 deficiency. Islet and beta-cell mass were observed increased at 10–12 weeks of age in TSP-1 deficient mice, but were normalized before 16 weeks of age when compared to wild-type controls. Islet vascularity was normal in 10–12 and 16-week-old TSP-1 deficient animals, whereas islets of one-year-old animals lacking TSP-1 were hypervascular. Beta-cell dysfunction in TSP-1 deficient animals was present at similar magnitudes between 10–12 and 52 weeks of age, as evaluated by glucose tolerance tests. The insulin secretion capacity in vivo of islets in one-year-old TSP-1 deficient animals was only ∼15% of that in wild-type animals. Using a transplantation model, we reconstituted TSP-1 in adult TSP-deficient islets. In contrast to neonatal TSP-1 deficient islets that we previously reported to regain function after TSP-1 reconstitution, adult islets failed to recover. We conclude that TSP-1 deficiency in islets causes changing vascular and endocrine morphological alterations postnatally, but is coupled to a chronic beta-cell dysfunction. The beta-cell dysfunction induced by TSP-1 deficiency is irreversible if not substituted early in life.
Highlights
The pancreatic islets are among the most vascularized of all organs in the body with the capillary network having a glomerular-like angioarchitecture
TSP-1 is mainly known for its anti-angiogenic properties [10], but the absence of TSP-1 has been reported to cause hypervascular and hyperplastic islets in neonatal TSP-1 deficient animals due to its ability to activate transforming growth factor beta-1 (TGFb-1) [11]
Islet Morphology The pancreas weights did not differ between wild-type and TSP-1 deficient mice at either 10–12 weeks, 16 weeks or one year of age (Data not shown)
Summary
The pancreatic islets are among the most vascularized of all organs in the body with the capillary network having a glomerular-like angioarchitecture. Important endothelial cell products mediating beta-cell supporting effects are vascular basement membrane proteins, laminins [5,7], as well as hepatocyte growth factor [6] We identified another factor, the glycoprotein thrombospondin-1 (TSP-1), that in islets is more or less exclusively produced by the endothelium, and of importance for islet morphology and beta-cell function [9]. TSP-1 is mainly known for its anti-angiogenic properties [10], but the absence of TSP-1 has been reported to cause hypervascular and hyperplastic islets in neonatal TSP-1 deficient animals due to its ability to activate transforming growth factor beta-1 (TGFb-1) [11] These animals were recently found to be markedly glucose intolerant, despite having an increased betacell mass, and islets with decreased glucose-stimulated insulin release and capacity for (pro)insulin biosynthesis [9]. The present study aimed to investigate long-term consequences for islet morphology and beta-cell function in TSP-1 deficient mice by a follow-up investigation of animals up to one year of age
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