Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes

Abstract

The risk determinants of type 1 diabetes, initiators of autoimmune response, mechanisms regulating progress toward ␤ 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 profi les 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 proinfl ammatory 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 profi le 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.

Causes of early-onset type 1 diabetes: toward data-driven environmental approaches

“…Increased levels of lysophosphatidylcholine (LPC) were detected by Orešič et al in future T1D children at birth and during their fi rst years ( 6 ). These lipid changes might result from events starting in utero, possibly linked to the mother ' s nutrition and metabolism.…”

“…Orešič et al compared serum metabolite profi les between children who eventually developed T1D and those who remained healthy and autoantibody-free ( 6 ). This analysis uncovered characteristic metabolic changes only in the children who later developed T1D, including reduced serum succinate, phoshatidylcholine, and phospholipids, as well as decreased ketoleucine and elevated glutamic acid.…”

“…Mendelian randomization provides a means of overcoming these problems, because the inheritance of genetic variant is independent of (i.e., randomized in respect to) the inheritance of other traits, according to Mendel ' s law of independent assortment. Regarding the study by Orešič et al ( 6 ), it is conceivable that genetic variants having suffi cient infl uence on glutamate or lysophosphatidyl choline metabolism may help confi rm the postulated implication of these metabolites in T1D.…”

“…The authors report characteristic changes in specifi c serum metabolites that precede the appearance of GADand insulin-specifi c autoantibodies and other metabolic changes that predict which children will eventually develop T1D ( 6 ).…”

Erythrocyte lipid composition at different stages of type 1 diabetes in children

“…Эти данные не были подтверждены в исследовании [9], где обнаружили достоверное увеличение лФХ, сфингомиелина (СМ), фосфатидилэтаноламина (ФЭ), фосфатидилинозитола (ФИ) и ФС в эритроцитах детей, болеющих СД1 в течении 10 лет. В выше цитируемых исследованиях нарушение липидного состава рассматривали как изменения в соотношении общих классов липидов, и лишь небольшая часть работ посвящена изучению содержания отдельных молекулярных видов внутри класса, которые определялись методом высокоэффективной жидкостной хроматографии с масс-спектрометрическим детектированием (ВЭЖХ/МС) [10].…”