title: Lowering plasma 1-deoxysphingolipids improves neuropathy in diabetic rats.
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.
authors.affiliation: Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland Competence Centre for Systems Physiology and Metabolic Diseases, Zurich, Switzerland.
authors.forename: Alaa
authors.initials: A
authors.lastname: Othman
authors.affiliation: Neuroalgology and Headache Unit, IRCCS Foundation, Carlo Besta Neurological Institute, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bianchi
authors.affiliation: Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Irina
authors.initials: I
authors.lastname: Alecu
authors.affiliation: Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Neuroalgology and Headache Unit, IRCCS Foundation, Carlo Besta Neurological Institute, Milan, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Porretta-Serapiglia
authors.affiliation: Neuroalgology and Headache Unit, IRCCS Foundation, Carlo Besta Neurological Institute, Milan, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Lombardi
authors.affiliation: Experimental Neurology Unit and Milan Center for Neuroscience, Department of Surgery and Translational Medicine, University of Milan-Bicocca, Milan, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Chiorazzi
authors.affiliation: Experimental Neurology Unit and Milan Center for Neuroscience, Department of Surgery and Translational Medicine, University of Milan-Bicocca, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Meregalli
authors.affiliation: Experimental Neurology Unit and Milan Center for Neuroscience, Department of Surgery and Translational Medicine, University of Milan-Bicocca, Milan, Italy.
authors.forename: Norberto
authors.initials: N
authors.lastname: Oggioni
authors.affiliation: Experimental Neurology Unit and Milan Center for Neuroscience, Department of Surgery and Translational Medicine, University of Milan-Bicocca, Milan, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Cavaletti
authors.affiliation: Neuroalgology and Headache Unit, IRCCS Foundation, Carlo Besta Neurological Institute, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lauria
authors.affiliation: Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland Competence Centre for Systems Physiology and Metabolic Diseases, Zurich, Switzerland.
authors.forename: Arnold
authors.initials: A
authors.lastname: von Eckardstein
authors.affiliation: Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland Competence Centre for Systems Physiology and Metabolic Diseases, Zurich, Switzerland thorsten.hornemann@usz.ch.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hornemann
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003929:Diabetic Neuropathies / Q000097:blood* / Q000188:drug therapy; D004435:Eating / Q000187:drug effects; D004594:Electrophysiology; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000097:blood / Q000188:drug therapy; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000627:therapeutic use; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood
chemical_list: C514304:1-deoxysphingosine; D012694:Serine; D013110:Sphingosine