title: Deoxysphingolipids, novel biomarkers for type 2 diabetes, are cytotoxic for insulin-producing cells.
abstract: Irreversible failure of pancreatic β-cells is the main culprit in the pathophysiology of diabetes, a disease that is now a global epidemic. Recently, elevated plasma levels of deoxysphingolipids, including 1-deoxysphinganine, have been identified as a novel biomarker for the disease. In this study, we analyzed whether deoxysphingolipids directly compromise the functionality of insulin-producing Ins-1 cells and primary islets. Treatment with 1-deoxysphinganine induced dose-dependent cytotoxicity with senescent, necrotic, and apoptotic characteristics and compromised glucose-stimulated insulin secretion. In addition, 1-deoxysphinganine altered cytoskeleton dynamics, resulting in intracellular accumulation of filamentous actin and activation of the Rho family GTPase Rac1. Moreover, 1-deoxysphinganine selectively upregulated ceramide synthase 5 expression and was converted to 1-deoxy-dihydroceramides without altering normal ceramide levels. Inhibition of intracellular 1-deoxysphinganine trafficking and ceramide synthesis improved the viability of the cells, indicating that the intracellular metabolites of 1-deoxysphinganine contribute to its cytotoxicity. Analyses of signaling pathways identified Jun N-terminal kinase and p38 mitogen-activated protein kinase as antagonistic effectors of cellular senescence. The results revealed that 1-deoxysphinganine is a cytotoxic lipid for insulin-producing cells, suggesting that the increased levels of this sphingolipid observed in diabetic patients may contribute to the reduced functionality of pancreatic β-cells. Thus, targeting deoxysphingolipid synthesis may complement the currently available therapies for diabetes.
authors.affiliation: Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Zuellig
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hornemann
authors.forename: Alaa
authors.initials: A
authors.lastname: Othman
authors.forename: Adrian B
authors.initials: AB
authors.lastname: Hehl
authors.forename: Heiko
authors.initials: H
authors.lastname: Bode
authors.forename: Tanja
authors.initials: T
authors.lastname: Güntert
authors.forename: Omolara O
authors.initials: OO
authors.lastname: Ogunshola
authors.forename: Enrica
authors.initials: E
authors.lastname: Saponara
authors.forename: Kamile
authors.initials: K
authors.lastname: Grabliauskaite
authors.forename: Jae-Hwi
authors.initials: JH
authors.lastname: Jang
authors.forename: Udo
authors.initials: U
authors.lastname: Ungethuem
authors.forename: Yu
authors.initials: Y
authors.lastname: Wei
authors.forename: Arnold
authors.initials: A
authors.lastname: von Eckardstein
authors.forename: Rolf
authors.initials: R
authors.lastname: Graf
authors.forename: Sabrina
authors.initials: S
authors.lastname: Sonda
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D001786:Blood Glucose / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008055:Lipids; D051379:Mice; D051381:Rats; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D008055:Lipids; D013110:Sphingosine; C408363:spisulosine