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Pharmacology and Therapeutics

Lowering Plasma 1-Deoxysphingolipids Improves Neuropathy in Diabetic Rats

  1. Alaa Othman1,2,3,
  2. Roberto Bianchi4,
  3. Irina Alecu1,2,
  4. Yu Wei1,
  5. Carla Porretta-Serapiglia4,
  6. Raffaella Lombardi4,
  7. Alessia Chiorazzi5,
  8. Cristina Meregalli5,
  9. Norberto Oggioni5,
  10. Guido Cavaletti5,
  11. Giuseppe Lauria4,
  12. Arnold von Eckardstein1,2,3 and
  13. Thorsten Hornemann1,2,3⇑
  1. 1Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland
  2. 2Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
  3. 3Competence Centre for Systems Physiology and Metabolic Diseases, Zurich, Switzerland
  4. 4Neuroalgology and Headache Unit, IRCCS Foundation, Carlo Besta Neurological Institute, Milan, Italy
  5. 5Experimental Neurology Unit and Milan Center for Neuroscience, Department of Surgery and Translational Medicine, University of Milan-Bicocca, Milan, Italy
  1. Corresponding author: Thorsten Hornemann, thorsten.hornemann{at}usz.ch.
  1. A.O. and R.B. contributed equally to this study.

Diabetes 2015 Mar; 64(3): 1035-1045. https://doi.org/10.2337/db14-1325
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Abstract

1-Deoxysphingolipids (1-deoxySLs) are atypical neurotoxic sphingolipids that are formed by the serine-palmitoyltransferase (SPT). Pathologically elevated 1-deoxySL concentrations cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), an axonal neuropathy associated with several missense mutations in SPT. Oral L-serine supplementation suppressed the formation of 1-deoxySLs in patients with HSAN1 and preserved nerve function in an HSAN1 mouse model. Because 1-deoxySLs also are elevated in patients with type 2 diabetes mellitus, L-serine supplementation could also be a therapeutic option for diabetic neuropathy (DN). This was tested in diabetic STZ rats in a preventive and therapeutic treatment scheme. Diabetic rats showed significantly increased plasma 1-deoxySL concentrations, and L-serine supplementation lowered 1-deoxySL concentrations in both treatment schemes (P < 0.0001). L-serine had no significant effect on hyperglycemia, body weight, or food intake. Mechanical sensitivity was significantly improved in the preventive (P < 0.01) and therapeutic schemes (P < 0.001). Nerve conduction velocity (NCV) significantly improved in only the preventive group (P < 0.05). Overall NCV showed a highly significant (P = 5.2E-12) inverse correlation with plasma 1-deoxySL concentrations. In summary, our data support the hypothesis that 1-deoxySLs are involved in the pathology of DN and that an oral L-serine supplementation could be a novel therapeutic option for treating DN.

Footnotes

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db14-1325/-/DC1.

  • See accompanying article, p. 706.

  • Received August 27, 2014.
  • Accepted September 22, 2014.
  • © 2015 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.
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Diabetes: 64 (3)

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March 2015, 64(3)
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Lowering Plasma 1-Deoxysphingolipids Improves Neuropathy in Diabetic Rats
Alaa Othman, Roberto Bianchi, Irina Alecu, Yu Wei, Carla Porretta-Serapiglia, Raffaella Lombardi, Alessia Chiorazzi, Cristina Meregalli, Norberto Oggioni, Guido Cavaletti, Giuseppe Lauria, Arnold von Eckardstein, Thorsten Hornemann
Diabetes Mar 2015, 64 (3) 1035-1045; DOI: 10.2337/db14-1325

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Lowering Plasma 1-Deoxysphingolipids Improves Neuropathy in Diabetic Rats
Alaa Othman, Roberto Bianchi, Irina Alecu, Yu Wei, Carla Porretta-Serapiglia, Raffaella Lombardi, Alessia Chiorazzi, Cristina Meregalli, Norberto Oggioni, Guido Cavaletti, Giuseppe Lauria, Arnold von Eckardstein, Thorsten Hornemann
Diabetes Mar 2015, 64 (3) 1035-1045; DOI: 10.2337/db14-1325
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