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      Lipidomic profiling of plasma free fatty acids in type-1 diabetes highlights specific changes in lipid metabolism

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          Abstract

          Type-1 diabetes mellitus (T1DM) is associated with metabolic changes leading to alterations in glucose and lipid handling. While T1DM-associated effects on many major plasma lipids have been characterised, such effects on plasma free fatty acids (FFA) have not been fully examined. Using gas chromatography–mass spectrometry, we measured the plasma concentrations of FFA species in individuals with T1DM ( n = 44) and age/sex-matched healthy controls (n = 44). Relationships between FFA species and various parameters were evaluated. Plasma concentrations of myristate (14:0), palmitoleate (16:1), palmitate (16:0), linoleate (18:2), oleate (18:1c9), cis-vaccenate (18:1c11), eicosapentaenoate (20:5), arachidonate (20:4) and docosahexanoate (22:6) were reduced in the T1DM group ( p < 0.0001 for all, except p = 0.0020 for eicosapentaenoate and p = 0.0068 for arachidonate); α-linolenate (18:3) and dihomo-γ-linolenate (20:3) concentrations were unchanged. The saturated/unsaturated FFA ratio, n-3/n-6 ratio, de novo lipogenesis index (palmitate (main lipogenesis product)/linoleate (only found in diet)) and elongase index (oleate/palmitoleate) were increased in the T1DM group ( p = 0.0166, p = 0.0089, p < 0.0001 and p = 0.0008 respectively). The stearoyl-CoA desaturase 1 (SCD1) index 1 (palmitoleate/palmitate) and index 2 (oleate/stearate) were reduced in T1DM (p < 0.0001 for both). The delta-(5)-desaturase (D5D) index (arachidonate/dihomo-γ-linolenate) was unchanged. Age and sex had no effect on plasma FFA concentrations in T1DM, while SCD1 index 1 was positively correlated ( p = 0.098) and elongase index negatively correlated with age ( p = 0.0363). HbA1c was negatively correlated with all plasma FFA concentrations measured except α-linolenate and dihomo-γ-linolenate. Correlations were observed between plasma FFA concentrations and cholesterol and HDL concentrations, but not LDL concentration or diabetes duration. Collectively, these results aid our understanding of T1DM and its effects on lipid metabolism.

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          Highlights

          • Plasma concentrations of major FFA species are lower in T1DM compared to controls.

          • Plasma FFA concentrations negatively correlates with HbA1c in T1DM.

          • The SCD1 index is reduced in T1DM.

          • Lipogenesis, elongase, n3/n6, saturated/unsaturated indices are increased in T1DM.

          • Collectively, the data highlight specific changes in lipid metabolism in T1DM

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          Most cited references42

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          How to measure and predict the molar absorption coefficient of a protein.

          The molar absorption coefficient, epsilon, of a protein is usually based on concentrations measured by dry weight, nitrogen, or amino acid analysis. The studies reported here suggest that the Edelhoch method is the best method for measuring epsilon for a protein. (This method is described by Gill and von Hippel [1989, Anal Biochem 182:319-326] and is based on data from Edelhoch [1967, Biochemistry 6:1948-1954]). The absorbance of a protein at 280 nm depends on the content of Trp, Tyr, and cystine (disulfide bonds). The average epsilon values for these chromophores in a sample of 18 well-characterized proteins have been estimated, and the epsilon values in water, propanol, 6 M guanidine hydrochloride (GdnHCl), and 8 M urea have been measured. For Trp, the average epsilon values for the proteins are less than the epsilon values measured in any of the solvents. For Tyr, the average epsilon values for the proteins are intermediate between those measured in 6 M GdnHCl and those measured in propanol. Based on a sample of 116 measured epsilon values for 80 proteins, the epsilon at 280 nm of a folded protein in water, epsilon (280), can best be predicted with this equation: epsilon (280) (M-1 cm-1) = (#Trp)(5,500) + (#Tyr)(1,490) + (#cystine)(125) These epsilon (280) values are quite reliable for proteins containing Trp residues, and less reliable for proteins that do not. However, the Edelhoch method is convenient and accurate, and the best approach is to measure rather than predict epsilon.
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            Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes

            The risk determinants of type 1 diabetes, initiators of autoimmune response, mechanisms regulating progress toward β cell failure, and factors determining time of presentation of clinical diabetes are poorly understood. We investigated changes in the serum metabolome prospectively in children who later progressed to type 1 diabetes. Serum metabolite profiles were compared between sample series drawn from 56 children who progressed to type 1 diabetes and 73 controls who remained nondiabetic and permanently autoantibody negative. Individuals who developed diabetes had reduced serum levels of succinic acid and phosphatidylcholine (PC) at birth, reduced levels of triglycerides and antioxidant ether phospholipids throughout the follow up, and increased levels of proinflammatory lysoPCs several months before seroconversion to autoantibody positivity. The lipid changes were not attributable to HLA-associated genetic risk. The appearance of insulin and glutamic acid decarboxylase autoantibodies was preceded by diminished ketoleucine and elevated glutamic acid. The metabolic profile was partially normalized after the seroconversion. Autoimmunity may thus be a relatively late response to the early metabolic disturbances. Recognition of these preautoimmune alterations may aid in studies of disease pathogenesis and may open a time window for novel type 1 diabetes prevention strategies.
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              Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group.

              To investigate and monitor the patterns in incidence of childhood type 1 diabetes worldwide. The incidence of type 1 diabetes (per 100,000 per year) from 1990 to 1994 was determined in children 350-fold variation in the incidence among the 100 populations worldwide. The global pattern of variation in incidence was evaluated by arbitrarily grouping the populations with a very low ( or =20/100,000 per year) incidence. Of the European populations, 18 of 39 had an intermediate incidence, and the remainder had a high or very high incidence. A very high incidence (> or =20/ 100,000 per year) was found in Sardinia, Finland, Sweden, Norway Portugal, the U.K., Canada, and New Zealand. The lowest incidence (<1/100,000 per year) was found in the populations from China and South America. In most populations, the incidence increased with age and was the highest among children 10-14 years of age. The range of global variation in the incidence of childhood type 1 diabetes is even larger than previously described. The earlier reported polar-equatorial gradient in the incidence does not seem to be as strong as previously assumed, but the variation seems to follow ethnic and racial distribution in the world population.
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                Author and article information

                Contributors
                Journal
                Biochim Biophys Acta Mol Cell Biol Lipids
                Biochim Biophys Acta Mol Cell Biol Lipids
                Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids
                Elsevier
                1388-1981
                1879-2618
                1 January 2021
                January 2021
                : 1866
                : 1
                : 158823
                Affiliations
                [a ]School of Medicine, University of St Andrews, Medical and Biological Sciences Building, St Andrews, Fife KY16 9TF, United Kingdom
                [b ]Schools of Biology and Chemistry, University of St Andrews, Biomedical Sciences Research Complex, St Andrews, Fife KY16 9ST, United Kingdom
                [c ]Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9DA, United Kingdom
                Author notes
                [* ]Corresponding author. ajs21@ 123456st-andrews.ac.uk
                Article
                S1388-1981(20)30215-8 158823
                10.1016/j.bbalip.2020.158823
                7695620
                33010452
                b2402500-caf6-4d21-9390-bddee3a78e95
                © 2020 The Author(s)

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 13 July 2020
                : 31 August 2020
                : 23 September 2020
                Categories
                Article

                d5d, delta-(5)-desaturase,fame, fatty acid methyl ester,fa, fatty acid,ffa, free fatty acid,hba1c, glycated haemoglobin a1c,gc–ms, gas chromatography–mass spectrometry,hdl, high-density lipoprotein,hsa, human serum albumin,ldl, low-density lipoprotein,scd1, stearoyl-coa desaturase 1,t1dm, type-1 diabetes mellitus,fatty acid metabolism,gc–ms,hba1c,lipid metabolism,lipidomics,non-esterified fatty acid

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