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Lowering plasma 1-Deoxysphingolipids improves neuropathy in diabetic rats


Abstract

1-Deoxysphingolipds (1-deoxySLs) are atypical neurotoxic sphingolipids which are formed by the serine-palmitoyltransferase (SPT). Pathologically elevated 1-deoxySL level cause hereditary sensory and autonomic neuropathy type 1 (HSAN1) an axonal neuropathy which is associated with several missense mutations in SPT. Oral L-serine supplementation suppressed 1-deoxySLs formation in HSAN1patients and preserved the nerve function in an HSAN1 mouse model. As 1-deoxySLs are also 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 levels and L-serine supplementation lowered 1-deoxySLs levels in both treatment schemes (p<0.0001). L-serine had no significant effect on hyperglycemia, body weight and food intake. Mechanical sensitivity was significantly improved in the preventive (p < 0.01) and therapeutic scheme (p < 0.001). NCV significantly improved in the preventive group only (p < 0.05). Overall NCV showed a highly significant (p = 5.2E-12) inverse correlation with plasma 1-deoxySL levels. 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.

Abstract

1-Deoxysphingolipds (1-deoxySLs) are atypical neurotoxic sphingolipids which are formed by the serine-palmitoyltransferase (SPT). Pathologically elevated 1-deoxySL level cause hereditary sensory and autonomic neuropathy type 1 (HSAN1) an axonal neuropathy which is associated with several missense mutations in SPT. Oral L-serine supplementation suppressed 1-deoxySLs formation in HSAN1patients and preserved the nerve function in an HSAN1 mouse model. As 1-deoxySLs are also 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 levels and L-serine supplementation lowered 1-deoxySLs levels in both treatment schemes (p<0.0001). L-serine had no significant effect on hyperglycemia, body weight and food intake. Mechanical sensitivity was significantly improved in the preventive (p < 0.01) and therapeutic scheme (p < 0.001). NCV significantly improved in the preventive group only (p < 0.05). Overall NCV showed a highly significant (p = 5.2E-12) inverse correlation with plasma 1-deoxySL levels. 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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Clinical Chemistry
04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:610 Medicine & health
540 Chemistry
Language:English
Date:2015
Deposited On:28 Jan 2015 12:41
Last Modified:08 Dec 2017 10:18
Publisher:American Diabetes Association
ISSN:0012-1797
Additional Information:The accepted manuscript is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Association (ADA), publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes in print and online at http://diabetes.diabetesjournals.org.
Publisher DOI:https://doi.org/10.2337/db14-1325
PubMed ID:25277395

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