Thrombospondin-1: An Islet Endothelial Cell Signal of Importance for β-Cell Function
MetadataShow full item record
CitationOlerud, Johan, Dariush Mokhtari, Magnus Johansson, Gustaf Christoffersson, Jack Lawler, Nils Welsh, and Per-Ola Carlsson. 2011. Thrombospondin-1: an islet endothelial cell signal of importance for β-cell function. Diabetes 60(7): 1946-1954.
AbstractOBJECTIVE: 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.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:10445606
- HMS Scholarly Articles