Deoxysphingolipids, a novel biomarker for type 2 diabetes, are cytotoxic for insulin-producing cells.
- Richard A. Zuellig1,#,
- Thorsten Hornemann2,3,4,#,
- Alaa Othman2,3,4,
- Adrian B. Hehl5,
- Heiko Bode2,3,4,
- Tanja Güntert6,
- Omolara O. Ogunshola6,
- Enrica Saponara7,
- Kamile Grabliauskaite7,
- Jae-Hwi Jang7,
- Udo Ungethuem7,
- Yu Wei2,3,4,
- Arnold von Eckardstein2,3,4,
- Rolf Graf7 and
- Sabrina Sonda7,*
- 1Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Zurich
- 2Institute for Clinical Chemistry, University Hospital Zurich
- 3Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
- 4Competence Centre for Systems Physiology and Metabolic Diseases, Zurich
- 5Institute of Parasitology, University of Zurich
- 6Institute of Veterinary Physiology, University of Zurich
- 7Swiss Hepato-Pancreatico-Biliary (HPB)-Center, Division of Surgical Research, Departement of Visceral & Transplantation Surgery, University Hospital Zurich, Switzerland
- *Corresponding author: Sabrina Sonda, Email:
Irreversible failure of pancreatic β-cells is the main culprit in the pathophysiology of diabetes mellitus, a disease that is now a major global epidemic. Recently, elevated plasma levels of deoxysphingolipids, including 1-deoxysphinganine, have been identified as novel biomarkers 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 RhoGTPase Rac1. Moreover, 1-deoxysphinganine selectively up-regulated 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 JNK and p38 MAPK as antagonistic effectors of cellular senescence. Our 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 deoxy-sphingolipid synthesis may complement the currently available therapies of diabetes.
# Contributed equally to this work
- Received July 3, 2013.
- Accepted December 13, 2013.
- © 2013 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.