Lipidome characterisation and sex-specific differences in type 1 and type 2 diabetes mellitus.

BACKGROUND: In this study, we evaluated the lipidome alterations caused by type 1 diabetes (T1D) and type 2 diabetes (T2D), by determining lipids significantly associated with diabetes overall and in both sexes, and lipids associated with the glycaemic state. METHODS: An untargeted lipidomic analysis was performed to measure the lipid profiles of 360 subjects (91 T1D, 91 T2D, 74 with prediabetes and 104 controls (CT)) without cardiovascular and/or chronic kidney disease. Ultra-high performance liquid chromatography-electrospray ionization mass spectrometry (UHPLC-ESI-MS) was conducted in two ion modes (positive and negative). We used multiple linear regression models to (1) assess the association between each lipid feature and each condition, (2) determine sex-specific differences related to diabetes, and (3) identify lipids associated with the glycaemic state by considering the prediabetes stage. The models were adjusted by sex, age, hypertension, dyslipidaemia, body mass index, glucose, smoking, systolic blood pressure, triglycerides, HDL cholesterol, LDL cholesterol, alternate Mediterranean diet score (aMED) and estimated glomerular filtration rate (eGFR); diabetes duration and glycated haemoglobin (HbA1c) were also included in the comparison between T1D and T2D. RESULTS: A total of 54 unique lipid subspecies from 15 unique lipid classes were annotated. Lysophosphatidylcholines (LPC) and ceramides (Cer) showed opposite effects in subjects with T1D and subjects with T2D, LPCs being mainly up-regulated in T1D and down-regulated in T2D, and Cer being up-regulated in T2D and down-regulated in T1D. Also, Phosphatidylcholines were clearly down-regulated in subjects with T1D. Regarding sex-specific differences, ceramides and phosphatidylcholines exhibited important diabetes-associated differences due to sex. Concerning the glycaemic state, we found a gradual increase of a panel of 1-deoxyceramides from normoglycemia to prediabetes to T2D. CONCLUSIONS: Our findings revealed an extensive disruption of lipid metabolism in both T1D and T2D. Additionally, we found sex-specific lipidome changes associated with diabetes, and lipids associated with the glycaemic state that can be linked to previously described molecular mechanisms in diabetes.

Circulating metabolomic and lipidomic changes in subjects with new-onset type 1 diabetes after optimization of glycemic control.

AIMS: To uncover novel candidate metabolomic and lipidomic biomarkers in newly-diagnosed type 1 diabetes (T1DM) after achieving optimal glucose control. METHODS: Comprehensive lipidomic and metabolomic analysis was performed in serum of 12 adults with T1DM at onset and after achieving optimal glycemic control (HbA1c < 7 %) (after 2-6 months). RESULTS: After intensive therapy, subjects (mean age 25.2 years, 58.3 % men) showed decreases in blood glucose (p < 0.001), HbA1c [11.5 % (9.2-13.4) to 6.2 % (5.2 - 6.7); p < 0.001] and changes in 51 identified lipids. Among these changes, we found that triglycerides (TG) containing medium chain fatty acids (TG45:0, TG47:1), sphingomyelins (SM) (SM(d18:2/20:0), SM42:4)), and phosphatidylcholines (PC) (PC(O-26:2), PC(O-30:0), PC(O-32:0), PC(O-42:6), PC(O-44:5), PC(O-38:3), PC(O-33:0), PC(O-46:8), PC(O-44:6), PC(O-40:3), PC(O-42:4), PC(O-46:7), PC(O-46:6), PC(O-44:5), PC(O-42:3), PC(O-44:4)) decreased; whereas PC(35:1), PC(37:1) and TG containing longer chain fatty acids (TG(52:1), TG(55:7), TG(51:2), TG(53:3), TG52:2), TG(53:2), TG(57:3), TG(61:3), TG(61:2) increased. Further, dihydro O-acylceramide (18:1/18:0/16:0), diacylglycerophosphoethanolamine (PE(34:1)), diacylglycerophosphoinositol (PI(38:6), and dihydrosphingomyelins (dihydroSM(36:0), dihydroSM(40:0), dihydroSM(41:0), dihydroSM(42:0)) increased. Uric acid, mannitol, and mannitol-1-acetate levels also increased. CONCLUSIONS: Our data uncovered potential favorable changes in the metabolism of glycerophospholipids, glycerolipids, and sphingolipids in new-onset T1DM after achieving optimal glycemic control. Further research on their potential role in developing diabetes-related complications is needed.

Perfil lipoproteico avanzado en individuos con metabolismo glucémico normal y alterado / Advanced lipoprotein profile in individuals with normal and impaired glucose metabolism

Introducción y objetivos: Varios tipos de lipoproteínas, aparte de las lipoproteínas de baja densidad (LDL), tienen relación causal con la enfermedad cardiovascular. Se analizó el perfil lipoproteico avanzado de individuos con metabolismo glucémico normal y alterado provenientes de una región mediterránea.Métodos: Estudio transversal en 929 participantes (463 normoglucémicos, 250 prediabéticos y 216 con diabetes tipo 2) sin insuficiencia renal, enfermedad cardiovascular ni tratamiento hipolipemiante. Se analizaron los perfiles lipoproteicos convencional y avanzado (resonancia magnética [RM] espectroscópica).Resultados: En comparación con los varones, las mujeres normoglucémicas mostraron menores concentraciones de triglicéridos y cLDL, menos partículas (P) de LDL y todas sus subclases y menos contenido en colesterol y triglicéridos, mayor concentración de P de lipoproteínas de alta densidad (HDL) y de todas sus variables relacionadas (p ≤ 0,05 para todas las comparaciones). En comparación con los normoglucémicos, los diabéticos mostraron una mayor concentración de P-VLDL grandes y pequeñas (p <0,05), además de una menor concentración de P-HDL totales y medianas (p <0,05). Se halló relación directa del perímetro de la cintura y el fatty liver index con un perfil proaterogénico.Conclusiones: Las mujeres mostraron un mejor perfil lipoproteico avanzado que los varones. Se halló relación directa de los índices de adiposidad relacionados con resistencia insulínica con un perfil lipídico proaterogénico. La RM mostró alteraciones en partículas lipoproteicas distintas de las LDL en los diabéticos, a menudo asociadas con mayor riesgo cardiovascular. Nuestros hallazgos confirman la utilidad del análisis lipoproteico avanzado mediante RM espectroscópica para descubrir nuevas dianas terapéuticas con que prevenir eventos cardiovasculares en los individuos en riesgo (AU)

Introduction and objectives: Several types of lipoproteins beyond low-density lipoproteins (LDL) are causally related to cardiovascular disease. We aimed to analyze an advanced lipoprotein profile in individuals with normal and impaired glucose metabolism from different cohorts of a Mediterranean region.Methods: Cross-sectional study in 929 participants (463 normoglycemia, 250 prediabetes, and 216 type 2 diabetes mellitus) with normal renal function, free from cardiovascular disease, and without lipid-lowering treatment. Conventional and advanced (nuclear magnetic resonance [NMR] spectroscopy) lipoprotein profiles were analyzed.Results: Compared with men, normoglycemic women showed lower serum triglyceride and LDL cholesterol concentrations, lower total LDL particles (P) as well as their subclasses and their cholesterol and triglyceride content, higher high-density lipoproteins (HDL)-P and all HDL-related variables (P≤ .05 for all comparisons). Compared with normoglycemic participants, diabetic participants showed higher large and small very LDL-P concentrations (P <.05) and lower total HDL-P and medium HDL-P concentrations (P <.05). Waist circumference and Fatty Liver Index were positively associated with a proatherogenic profile.Conclusions: Women had a better advanced lipoprotein profile than did men. Adiposity indexes related to insulin-resistance were positively associated with a proatherogenic lipid profile. NMR revealed altered lipoprotein particles other than LDL in participants with diabetes, frequently associated with an increased cardiovascular risk. Our findings support the usefulness of extended lipoprotein analysis by NMR spectroscopy to uncover new therapeutic targets to prevent cardiovascular events in at-risk participants (AU)

Advanced lipoprotein profile in individuals with normal and impaired glucose metabolism.

INTRODUCTION AND OBJECTIVES: Several types of lipoproteins beyond low-density lipoproteins (LDL) are causally related to cardiovascular disease. We aimed to analyze an advanced lipoprotein profile in individuals with normal and impaired glucose metabolism from different cohorts of a Mediterranean region. METHODS: Cross-sectional study in 929 participants (463 normoglycemia, 250 prediabetes, and 216 type 2 diabetes mellitus) with normal renal function, free from cardiovascular disease, and without lipid-lowering treatment. Conventional and advanced (nuclear magnetic resonance [NMR] spectroscopy) lipoprotein profiles were analyzed. RESULTS: Compared with men, normoglycemic women showed lower serum triglyceride and LDL cholesterol concentrations, lower total LDL particles (P) as well as their subclasses and their cholesterol and triglyceride content, higher high-density lipoproteins (HDL)-P and all HDL-related variables (P≤ .05 for all comparisons). Compared with normoglycemic participants, diabetic participants showed higher large and small very LDL-P concentrations (P <.05) and lower total HDL-P and medium HDL-P concentrations (P <.05). Waist circumference and Fatty Liver Index were positively associated with a proatherogenic profile. CONCLUSIONS: Women had a better advanced lipoprotein profile than did men. Adiposity indexes related to insulin-resistance were positively associated with a proatherogenic lipid profile. NMR revealed altered lipoprotein particles other than LDL in participants with diabetes, frequently associated with an increased cardiovascular risk. Our findings support the usefulness of extended lipoprotein analysis by NMR spectroscopy to uncover new therapeutic targets to prevent cardiovascular events in at-risk participants.

Circulating CD5L is associated with cardiovascular events and all-cause mortality in individuals with chronic kidney disease.

This study assessed the association of CD5L and soluble CD36 (sCD36) with the risk of a cardiovascular event (CVE), including CV death and all-cause mortality in CKD. We evaluated the association of CD5L and sCD36 with a predefined composite CV endpoint (unstable angina, myocardial infarction, transient ischemic attack, cerebrovascular accident, congestive heart failure, arrhythmia, peripheral arterial disease [PAD] or amputation by PAD, aortic aneurysm, or death from CV causes) and all-cause mortality using Cox proportional hazards regression, adjusted for CV risk factors. The analysis included 1,516 participants free from pre-existing CV disease followed up for 4 years. The median age was 62 years, 38.8% were female, and 26.8% had diabetes. There were 98 (6.5%) CVEs and 72 (4.8%) deaths, of which 26 (36.1%) were of CV origin. Higher baseline CD5L concentration was associated with increased risk of CVE (HR, 95% CI, 1.17, 1.0-1.36), and all-cause mortality (1.22, 1.01-1.48) after adjusting for age, sex, diabetes, systolic blood pressure, dyslipidemia, waist circumference, smoking, and CKD stage. sCD36 showed no association with adverse CV outcomes or mortality. Our study showed for the first time that higher concentrations of CD5L are associated with future CVE and all-cause mortality in individuals with CKD.

mWISE: An Algorithm for Context-Based Annotation of Liquid Chromatography-Mass Spectrometry Features through Diffusion in Graphs.

Untargeted metabolomics using liquid chromatography coupled to mass spectrometry (LC-MS) allows the detection of thousands of metabolites in biological samples. However, LC-MS data annotation is still considered a major bottleneck in the metabolomics pipeline since only a small fraction of the metabolites present in the sample can be annotated with the required confidence level. Here, we introduce mWISE (metabolomics wise inference of speck entities), an R package for context-based annotation of LC-MS data. The algorithm consists of three main steps aimed at (i) matching mass-to-charge ratio values to the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, (ii) clustering and filtering the potential KEGG candidates, and (iii) building a final prioritized list using diffusion in graphs. The algorithm performance is evaluated with three publicly available studies using both positive and negative ionization modes. We have also compared mWISE to other available annotation algorithms in terms of their performance and computation time. In particular, we explored four different configurations for mWISE, and all four of them outperform xMSannotator (a state-of-the-art annotator) in terms of both performance and computation time. Using a diffusion configuration that combines the biological network obtained from the FELLA R package and raw scores, mWISE shows a sensitivity mean (standard deviation) across data sets of 0.63 (0.07), while xMSannotator achieves a sensitivity of 0.55 (0.19). We have also shown that the chemical structures of the compounds proposed by mWISE are closer to the original compounds than those proposed by xMSannotator. Finally, we explore the diffusion prioritization separately, showing its key role in the annotation process. mWISE is freely available on GitHub (https://github.com/b2slab/mWISE) under a GPL license.

The Circulating Fatty Acid Transporter Soluble CD36 Is Not Associated with Carotid Atherosclerosis in Subjects with Type 1 and Type 2 Diabetes Mellitus.

This study aimed to determine the association of fatty acid transporter plasma soluble cluster of differentiation 36 (sCD36) with subclinical carotid atherosclerosis (SCA). A cross-sectional study was conducted in 1023 subjects, 225 with type 1 diabetes (T1D), 276 with type 2 diabetes (T2D) and 522 who were nondiabetic. Carotid atherosclerotic plaque (CAP) presence was determined using B-mode carotid ultrasound imaging. sCD36 were analysed by ELISA, and CD36 surface receptor and mRNA expression were measured by flow cytometry and real-time PCR. Logistic regression models were used to evaluate sCD36 as a biomarker of SCA. Up to 376 (36.75%) participants had at least one CAP, 76 T1D, 164 T2D and 136 without diabetes, while the remaining 647 (63.25%) did not have any CAP. There were no differences in sCD36 between patients with and without CAP in T1D (p = 0.287) or T2D (p = 0.513). Although nondiabetic subjects with plaques had lower sCD36 levels than those without (p = 0.023), the multivariate models revealed no association of sCD36 with CAP in any of the three study groups. No differences were found in surface CD36 or CD36 mRNA expression between the patients with and without CAP. sCD36 is not associated with SCA in type 1 or type 2 diabetic or in nondiabetic subjects.