Thrombospondin-1: an islet endothelial cell signal of importance for β-cell function

Diabetes. 2011 Jul;60(7):1946-54. doi: 10.2337/db10-0277. Epub 2011 May 26.

Abstract

Objective: Loss of thrombospondin (TSP)-1 in pancreatic islets has been shown to cause islet hyperplasia. This study tested the hypothesis that endothelial-derived TSP-1 is important for β-cell function.

Research design and methods: Islet function was evaluated both in vivo and in vitro. Messenger RNA and protein expression were measured by real-time PCR and Western blot, respectively. The role of endothelial-derived TSP-1 for β-cell function was determined using a transplantation design in which recipient blood vessels either were allowed to grow or not into the transplanted islets.

Results: TSP-1-deficient mice were glucose intolerant, despite having an increased β-cell mass. Moreover, their islets had decreased glucose-stimulated insulin release, (pro)insulin biosynthesis, and glucose oxidation rate, as well as increased expression of uncoupling protein-2 and lactate dehydrogenase-A when compared with control islets. Almost all TSP-1 in normal islets were found to be derived from the endothelium. Transplantation of free and encapsulated neonatal wild-type and TSP-1-deficient islets was performed in order to selectively reconstitute with TSP-1-positive or -negative blood vessels in the islets and supported that the β-cell defects occurring in TSP-1-deficient islets reflected postnatal loss of the glycoprotein in the islet endothelial cells. Treatment of neonatal TSP-1-deficient mice with the transforming growth factor (TGF)β-1-activating sequence of TSP-1 showed that reconstitution of TGFβ-1 activation prevented the development of decreased glucose tolerance in these mice. Thus, endothelial-derived TSP-1 activates islet TGFβ-1 of importance for β-cells.

Conclusions: Our study indicates a novel role for endothelial cells as functional paracrine support for pancreatic β-cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Endothelial Cells / metabolism
  • Extracellular Matrix Proteins / metabolism
  • Glucose Intolerance / physiopathology
  • Insulin-Secreting Cells / physiology*
  • Islets of Langerhans / blood supply
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Islets of Langerhans / physiology*
  • Islets of Langerhans Transplantation / physiology
  • Mice
  • Thrombospondin 1 / biosynthesis
  • Thrombospondin 1 / deficiency
  • Thrombospondin 1 / physiology*
  • Transforming Growth Factor beta / metabolism

Substances

  • Extracellular Matrix Proteins
  • Thrombospondin 1
  • Transforming Growth Factor beta
  • betaIG-H3 protein