title: Thrombospondin-1: an islet endothelial cell signal of importance for β-cell function.
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.
  
  
  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.
authors: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
authors: Johan
authors: J
authors: Olerud
authors: Dariush
authors: D
authors: Mokhtari
authors: Magnus
authors: M
authors: Johansson
authors: Gustaf
authors: G
authors: Christoffersson
authors: Jack
authors: J
authors: Lawler
authors: Nils
authors: N
authors: Welsh
authors: Per-Ola
authors: PO
authors: Carlsson
references: Diabetes. 2005 Aug;54(8):2287-93
references: 16046293
references: Diabetes Care. 1999 Mar;22 Suppl 2:B121-6
references: 10097912
references: Science. 2003 Feb 7;299(5608):890-3
references: 12574630
references: Diabetes Res. 1986 Jul;3(6):277-85
references: 3093130
references: J Biol Chem. 1999 May 7;274(19):13586-93
references: 10224129
references: Dev Cell. 2006 Mar;10(3):397-405
references: 16516842
references: Int J Biochem Cell Biol. 2004 Jun;36(6):961-8
references: 15094109
references: Diabetes. 2006 Nov;55(11):2965-73
references: 17065332
references: J Biol Chem. 1994 Feb 18;269(7):4895-902
references: 8106462
references: Endocrinology. 2008 Jun;149(6):3046-53
references: 18308848
references: Am J Physiol Heart Circ Physiol. 2006 Feb;290(2):H560-76
references: 16172168
references: Cell. 1998 Jun 26;93(7):1159-70
references: 9657149
references: Endocrinology. 2006 May;147(5):2315-24
references: 16439446
references: PLoS Biol. 2006 Feb;4(2):e39
references: 16435884
references: Immunol Today. 1993 Mar;14(3):131-6
references: 8385467
references: Biochem Biophys Res Commun. 1982 Jul 30;107(2):525-32
references: 6751329
references: Diabetes. 2002 May;51(5):1362-6
references: 11978631
references: J Biol Chem. 2003 Jan 31;278(5):2997-3005
references: 12438314
references: Diabetes. 2004 Apr;53(4):948-54
references: 15047609
references: Diabetes. 2008 Jul;57(7):1870-7
references: 18420490
references: Acta Physiol Scand. 2002 Dec;176(4):275-81
references: 12444933
references: Diabetes Technol Ther. 2006 Oct;8(5):536-45
references: 17037968
references: Science. 2001 Oct 19;294(5542):559-63
references: 11577199
references: J Clin Endocrinol Metab. 2002 Dec;87(12):5418-23
references: 12466329
references: Cancer Res. 2001 Nov 1;61(21):7830-9
references: 11691800
references: Science. 2001 Oct 19;294(5542):564-7
references: 11577200
references: Diabetes. 2001 Jun;50(6):1302-10
references: 11375330
references: Diabetes. 2007 Jun;56(6):1544-50
references: 17400931
references: Cytokine Growth Factor Rev. 2000 Mar-Jun;11(1-2):59-69
references: 10708953
references: J Cell Sci. 1990 Jun;96 ( Pt 2):257-62
references: 2211866
references: Proc Natl Acad Sci U S A. 1990 Sep;87(17):6624-8
references: 1697685
references: Diabetologia. 2009 Nov;52(11):2385-94
references: 19669728
references: Pancreatology. 2006;6(1-2):86-95
references: 16327285
references: Nat Med. 2003 Jun;9(6):661-8
references: 12778164
references: Diabetes. 2006 Feb;55(2):367-74
references: 16443769
references: Diabetes. 1982 Oct;31(10):883-9
references: 6759221
references: Nat Med. 2000 Jan;6(1):41-8
references: 10613822
references: Am J Transplant. 2006 Nov;6(11):2601-11
references: 16981910
references: Am J Physiol Endocrinol Metab. 2003 Mar;284(3):E499-504
references: 12419776
references: Diabetologia. 2007 Feb;50(2):334-42
references: 17180350
references: Diabetes. 2006 Nov;55(11):2974-85
references: 17065333
references: Diabetologia. 1978 Jun;14(6):397-404
references: 352776
references: J Clin Invest. 1999 Dec;104(11):1621-9
references: 10587526
references: Am J Physiol. 1991 May;260(5 Pt 1):C1046-51
references: 2035613
references: Curr Biol. 2003 Jun 17;13(12):1070-4
references: 12814555
references: Mol Cell Endocrinol. 2002 Apr 25;190(1-2):75-82
references: 11997180
references: J Clin Invest. 1998 Mar 1;101(5):982-92
references: 9486968
references: Diabetes. 1989 Apr;38(4):510-5
references: 2494093