title: Novel role for matricellular proteins in the regulation of islet β cell survival: the effect of SPARC on survival, proliferation, and signaling.
abstract: Understanding the mechanisms regulating islet growth and survival is critical for developing novel approaches to increasing or sustaining β cell mass in both type 1 and type 2 diabetes patients. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that is important for the regulation of cell growth and adhesion. Increased SPARC can be detected in the serum of type 2 diabetes patients. The aim of this study was to investigate the role of SPARC in the regulation of β cell growth and survival. We show using immunohistochemistry that SPARC is expressed by stromal cells within islets and can be detected in primary mouse islets by Western blot. SPARC is secreted at high levels by pancreatic stellate cells and is regulated by metabolic parameters in these cells, but SPARC expression was not detectable in β cells. In islets, SPARC expression is highest in young mice, and is also elevated in the islets of non-obese diabetic (NOD) mice compared with controls. Purified SPARC inhibits growth factor-induced signaling in both INS-1 β cells and primary mouse islets, and inhibits IGF-1-induced proliferation of INS-1 β cells. Similarly, exogenous SPARC prevents IGF-1-induced survival of primary mouse islet cells. This study identifies the stromal-derived matricellular protein SPARC as a novel regulator of islet survival and β cell growth.
authors.affiliation: Diabetes and Cardiovascular Research Group, Kingston University, Kingston upon Thames, United Kingdom.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Ryall
authors.affiliation: Diabetes and Cardiovascular Research Group, Kingston University, Kingston upon Thames, United Kingdom.
authors.forename: Katrina
authors.initials: K
authors.lastname: Viloria
authors.affiliation: Diabetes and Cardiovascular Research Group, Kingston University, Kingston upon Thames, United Kingdom.
authors.forename: Fadel
authors.initials: F
authors.lastname: Lhaf
authors.affiliation: School of Life Sciences, and Kingston University, Kingston upon Thames, United Kingdom.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Walker
authors.affiliation: Diabetes Research Group, Division of Reproduction & Endocrinology, King's College London, London, United Kingdom.
authors.forename: Aileen
authors.initials: A
authors.lastname: King
authors.affiliation: Diabetes Research Group, Division of Reproduction & Endocrinology, King's College London, London, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Jones
authors.affiliation: Diabetes and Cardiovascular Research Group, Kingston University, Kingston upon Thames, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Mackintosh
authors.affiliation: School of Mathematics, Kingston University, Kingston upon Thames, United Kingdom.
authors.forename: Rosemary
authors.initials: R
authors.lastname: McNeice
authors.affiliation: Barts Cancer Institute, and Queen Mary University of London, London, United Kingdom.
authors.forename: Hemant
authors.initials: H
authors.lastname: Kocher
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Flodstrom-Tullberg
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom, and.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Edling
authors.affiliation: Diabetes and Cardiovascular Research Group, Kingston University, Kingston upon Thames, United Kingdom. Electronic address: n.hill@kingston.ac.uk.
authors.forename: Natasha J
authors.initials: NJ
authors.lastname: Hill
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D005260:Female; D005947:Glucose / Q000502:physiology; D007328:Insulin / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D016688:Mice, Inbred NOD; D015676:Osteonectin / Q000502:physiology*; D010179:Pancreas / Q000166:cytology; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D007328:Insulin; D015676:Osteonectin; C578250:SPARC protein, mouse; D005947:Glucose
keywords: Cell Growth; Diabetes; Extracellular Matrix Protein; Growth Factor; Islet; Regeneration; Signaling; Stromal Cell