Elevation of plasma 1‐deoxy‐sphingolipids in type 2 diabetes mellitus: a susceptibility to neuropathy?

Dohrn, Maike F.; Othman, Alaa; Hirshman, Sarah; Bode, Heiko; Alecu, Irina; Fähndrich, E; Karges, W; Weis, Joachim; Schulz, Jörg B.; Hornemann, Thorsten; Claeys, Kristl G.

doi:10.1111/ene.12663

Cited by 47 publications

(48 citation statements)

References 27 publications

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“…Deoxy-sphingoid bases levels were found to be significantly elevated in plasma of patients with distal sensorimotor polyneuropathy as confirmed by electroneurographic examinations. Interestingly, the deoxy-sphingoid bases in that study were detectable in early disease stages, but did not correlate with the clinical course (Dohrn et al 2015). Because in that study deoxysphingosine was analyzed after total hydrolysis of the samples (Dohrn et al 2015), measured sphingolipid levels can represent both free deoxy-sphingosine and deoxy-ceramides combined.…”

Section: Discussionmentioning

confidence: 79%

“…Interestingly, the deoxy-sphingoid bases in that study were detectable in early disease stages, but did not correlate with the clinical course (Dohrn et al 2015). Because in that study deoxysphingosine was analyzed after total hydrolysis of the samples (Dohrn et al 2015), measured sphingolipid levels can represent both free deoxy-sphingosine and deoxy-ceramides combined. In the type 1 diabetes patients in the current cross-sectional study, levels of DSL correlated negatively with the advanced clinically defined stages of neuropathy (data not shown).…”

Section: Discussionmentioning

confidence: 79%

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Increased Plasma Levels of Select Deoxy-ceramide and Ceramide Species are Associated with Increased Odds of Diabetic Neuropathy in Type 1 Diabetes: A Pilot Study

Hammad

Baker²,

Abiad

et al. 2016

Neuromol Med

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Plasma deoxy-sphingoid bases are elevated in type 2 diabetes patients and correlate with the stage of diabetic distal sensorimotor polyneuropathy; however, associations between deoxy-sphingolipids (DSL) and neuropathy in type 1 diabetes have not been examined. The primary aim of this exploratory pilot study was to assess the associations between multiple sphingolipid species including DSL and free amino acids and the presence of symptomatic neuropathy in a DCCT/EDIC type 1 diabetes subcohort. Using mass spectroscopy, plasma levels of DSL and free amino acids in DCCT/EDIC type 1 diabetes participants (n = 80), with and without symptoms of neuropathy, were investigated. Patient-determined neuropathy was based on 15-item self-administered questionnaire (Michigan Neuropathy Screening Instrument) developed to assess distal symmetrical peripheral neuropathy in diabetes. Patients who scored ≥4, or reported inability to sense their feet during walking or to distinguish hot from cold water while bathing were considered neuropathic. Plasma levels of ceramide, sphingomyelin, hexosyl- and lactosylceramide species, and amino acids were measured and analyzed relative to neuropathy status in the patient. Deoxy-C24-ceramide, C24- and C26-ceramide were higher in patients with neuropathy than those without neuropathy. Cysteine was higher in patients with neuropathy. No differences in other sphingolipids or amino acids were detected. The covariate-adjusted Odds Ratios of positive patient-reported neuropathy was associated with increased levels of deoxy-C24-, and deoxy-C24:1-ceramide; C22-, C24-, and C26-ceramide; and cysteine. Plasma deoxy-ceramide and ceramide species may have potential diagnostic and prognostic significance in diabetic neuropathy.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 79%

Increased Plasma Levels of Select Deoxy-ceramide and Ceramide Species are Associated with Increased Odds of Diabetic Neuropathy in Type 1 Diabetes: A Pilot Study

Hammad

Baker²,

Abiad

et al. 2016

Neuromol Med

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“…For the pulse-chase experiments, MEF cells were treated with 1 M deuterium-labeled (d3) 1-deoxySA or d7-SA (Avanti Polar Lipids) for 2 h, after which they were chased for 0, 1,4,8,24, and 48 h with unsupplemented growth medium (DMEM), or for 1, 2, The 1-deoxySLs with mass offsets of +6, +5, +4, +3, +2, +1, as well as the unlabeled mass M were quantified in order to account for the natural isotopologues, as well as the +3 labeling arising from the d3-palmitic acid or the d4-alanine (one deuterium is lost from the alanine upon condensation with the palmitoyl-CoA) and the +6 labeling arising from the condensation of both labeled substrates.…”

Section: Metabolic Labeling Assaysmentioning

confidence: 99%

“…They are a hallmark of hereditary sensory autonomic neuropathy type 1 (HSAN1), a rare autosomal dominant inherited peripheral neuropathy that is caused by various mutations in SPT. Plasma 1-deoxySLs are also elevated in patients with nondiabetic metabolic syndrome (MetS) and T2D (6) and may contribute to the development of diabetic sensory polyneuropathy (DSN), which is clinically very similar to HSAN1 (7,8). Both conditions start in the lower extremities with a loss of sensation often accompanied by positive sensory symptoms such as hyperpathia and neuropathic pain, as well as the development of painless wounds leading to ulcers (9, 10).…”

mentioning

confidence: 99%

Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

Alecu¹,

Othman²,

Penno³

et al. 2017

Journal of Lipid Research

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This article is available online at http://www.jlr.org Sphingolipid (SL) de novo synthesis typically starts with the condensation of serine and palmitoyl-CoA, a reaction catalyzed by serine palmitoyltransferase (SPT) (1-3). SPT can also use alanine in certain conditions (4), which results in the formation of the atypical cytotoxic 1-deoxysphingolipids (1-deoxySLs). These lack the C1-hydroxyl group of regular SLs, which is essential for further metabolic steps and degradation (4, 5). As such, 1-deoxySLs are commonly believed to be "dead-end" metabolites that accumulate within cells, tissues, and body fluids.Pathologically elevated 1-deoxySLs have been found in a number of neurological and metabolic disorders. They are a hallmark of hereditary sensory autonomic neuropathy type 1 (HSAN1), a rare autosomal dominant inherited peripheral neuropathy that is caused by various mutations in SPT. Plasma 1-deoxySLs are also elevated in patients with nondiabetic metabolic syndrome (MetS) and T2D (6) and may contribute to the development of diabetic sensory polyneuropathy (DSN), which is clinically very similar to HSAN1 (7,8). Both conditions start in the lower extremities with a loss of sensation often accompanied by positive sensory symptoms such as hyperpathia and neuropathic pain, as well as the development of painless wounds leading to ulcers (9, 10). L-serine supplementation was shown to effectively lower 1-deoxySL levels while improving Abstract The 1-deoxysphingolipids (1-deoxySLs) are atypical sphingolipids (SLs) that are formed when serine palmitoyltransferase condenses palmitoyl-CoA with alanine instead of serine during SL synthesis. The 1-deoxySLs are toxic to neurons and pancreatic -cells. Pathologically elevated 1-deoxySLs cause the inherited neuropathy, hereditary sensory autonomic neuropathy type 1 (HSAN1), and are also found in T2D. Diabetic sensory polyneuropathy (DSN) and HSAN1 are clinically very similar, suggesting that 1-deoxySLs may be implicated in both pathologies. The 1-deoxySLs are considered to be dead-end metabolites, as they lack the C1-hydroxyl group, which is essential for the canonical degradation of SLs. Here, we report a previously unknown metabolic pathway, which is capable of degrading 1-deoxySLs. Using a variety of metabolic labeling approaches and high-resolution high-accuracy MS, we identified eight 1-deoxySL downstream metabolites, which appear to be formed by cytochrome P450 (CYP)4F enzymes. Comprehensive inhibition and induction of CYP4F enzymes blocked and stimulated, respectively, the formation of the downstream metabolites. Consequently, CYP4F enzymes might be novel therapeutic targets for the treatment of HSAN1 and DSN, as well as for the prevention of T2D. (I.A., A.O., T.H., and A.v.E.) Abbreviations: ATRA, all-trans retinoic acid; CYP, cytochrome P450; DB, double bond; 1-deoxySA, 1-deoxysphinganine; 1-deoxySAdiene, deoxysphingadiene; 1-deoxySA-OH, hydroxyl-deoxysphinganine; 1-deoxySA-2OH, dihydroxyl-deoxysphinganine; 1-deoxySL, 1-deoxysphingolipid; 1-deoxySO, 1-deoxysphingosi...

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“…A recent study links DSPN with elevated 1-deoxysphingolipids (1-deoxySLs) in blood [10]. Sphingolipids play an important role in the formation of plasma membranes and lipoproteins; they are usually formed by the precursors L-serine and palmitoyl-CoA.…”

Section: Introductionmentioning

confidence: 99%

Metabolic Syndrome, Neurotoxic 1-Deoxysphingolipids and Nervous Tissue Inflammation in Chronic Idiopathic Axonal Polyneuropathy (CIAP)

et al. 2017

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AimChronic idiopathic axonal polyneuropathy (CIAP) is a slowly progressive, predominantly sensory, axonal polyneuropathy, with no aetiology being identified despite extensive investigations. We studied the potential role of the metabolic syndrome, neurotoxic 1-deoxysphingolipids (1-deoxySLs), microangiopathy and inflammation in sural nerve biopsies.MethodsWe included 30 CIAP-patients, 28 with diabetic distal symmetrical polyneuropathy (DSPN) and 31 healthy controls. We assessed standardised scales, tested for the metabolic syndrome, measured 1-deoxySLs in plasma, performed electroneurography and studied 17 sural nerve biopsies (10 CIAP; 7 DSPN).ResultsOne third of the CIAP-patients had a metabolic syndrome, significantly less frequent than DSPN-patients (89%). Although the metabolic syndrome was not significantly more prevalent in CIAP compared to healthy controls, hypercholesterolemia did occur significantly more frequent. 1-deoxySLs were significantly and equally elevated in both patient groups compared to healthy controls. Mean basal lamina thickness of small endoneurial vessels and the number of CD68- or CD8-positive cells in biopsies of CIAP- and DSPN-patients did not differ significantly. However, the number of leucocyte-common-antigen positive cells was significantly increased in CIAP.ConclusionsA non-significant trend towards a higher occurrence of the metabolic syndrome in CIAP-patients compared to healthy controls was found. 1-deoxySLs were significantly increased in plasma of CIAP-patients. Microangiopathy and an inflammatory component were present in CIAP-biopsies.

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Elevation of plasma 1‐deoxy‐sphingolipids in type 2 diabetes mellitus: a susceptibility to neuropathy?

Cited by 47 publications

References 27 publications

Increased Plasma Levels of Select Deoxy-ceramide and Ceramide Species are Associated with Increased Odds of Diabetic Neuropathy in Type 1 Diabetes: A Pilot Study

Increased Plasma Levels of Select Deoxy-ceramide and Ceramide Species are Associated with Increased Odds of Diabetic Neuropathy in Type 1 Diabetes: A Pilot Study

Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

Metabolic Syndrome, Neurotoxic 1-Deoxysphingolipids and Nervous Tissue Inflammation in Chronic Idiopathic Axonal Polyneuropathy (CIAP)

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