Deoxysphingolipids, Novel Biomarkers for Type 2 Diabetes, Are Cytotoxic for Insulin-Producing Cells
- Richard A. Zuellig1,
- Thorsten Hornemann2,3,4,
- Alaa Othman2,4,
- Adrian B. Hehl5,
- Heiko Bode2,3,
- Tanja Güntert3,6,
- 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, Zurich, Switzerland
- 2Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland
- 3Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
- 4Competence Centre for Systems Physiology and Metabolic Diseases, Zurich, Switzerland
- 5Institute of Parasitology, University of Zurich, Zurich, Switzerland
- 6Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland
- 7Swiss Hepato-Pancreatico-Biliary (HPB)-Center, Division of Surgical Research, Department of Visceral and Transplantation Surgery, University Hospital Zurich, Zurich, Switzerland
- Corresponding author: Sabrina Sonda, .
R.A.Z. and T.H. contributed equally to this work.
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-1042/-/DC1.
See accompanying article, p. 1191.
- Received July 3, 2013.
- Accepted December 14, 2013.
- © 2014 by the American Diabetes Association.
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