Metabolic alterations in immune cells associate with progression to type 1 diabetes

Abstract

Aims/hypothesis Previous metabolomics studies suggest that type 1 diabetes is preceded by specific metabolic disturbances. The aim of this study was to investigate whether distinct metabolic patterns occur in peripheral blood mononuclear cells (PBMCs) of children who later develop pancreatic beta cell autoimmunity or overt type 1 diabetes. Methods In a longitudinal cohort setting, PBMC metabolomic analysis was applied in children who (1) progressed to type 1 diabetes (PT1D, n = 34), (2) seroconverted to ≥1 islet autoantibody without progressing to type 1 diabetes (P1Ab, n = 27) or (3) remained autoantibody negative during follow-up (CTRL, n = 10). Results During the first year of life, levels of most lipids and polar metabolites were lower in the PT1D and P1Ab groups compared with the CTRL group. Pathway over-representation analysis suggested alanine, aspartate, glutamate, glycerophospholipid and sphingolipid metabolism were over-represented in PT1D. Genome-scale metabolic models of PBMCs during type 1 diabetes progression were developed by using publicly available transcriptomics data and constrained with metabolomics data from our study. Metabolic modelling confirmed altered ceramide pathways, known to play an important role in immune regulation, as specifically associated with type 1 diabetes progression.Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-020-05107-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.* Partho Sen partho.sen@utu.fi * Mikael Knip

Sphingolipids in Type 1 Diabetes: Focus on Beta-Cells

“…The ceramide pathways were found to be specifically associated with T1DM progression [18]. In T1DM progressors a lower content of L-serine was described, in line with the protective effects of L-serine administration against islet autoimmunity observed in the NOD mouse [176].…”

“…Changes in the SL content were associated with beta-cell dysfunction and death. Recent studies demonstrated an altered SL profiles in the blood of T1DM patients [14][15][16]18,130,164]. What are the consequences of these altered SL serum profiles on pancreatic beta-cell function and fate during T1DM development?…”

“…The incidence of T1DM is rising in the last decades in western countries; this suggests an important role of environmental factors in the pathogenesis of this disease. Accumulating evidence points to significant changes in serum metabolome proceeding T1DM development [14,15,18,130,164]. An increased risk of T1DM was described in response to prenatal exposure to perfluoroalkyl substances that modulate neonatal serum phospholipids [188].…”

“…An increased risk of T1DM was described in response to prenatal exposure to perfluoroalkyl substances that modulate neonatal serum phospholipids [188]. Several phospholipids, particularly sphingomyelins and specific phosphocholines, which were shown to be significantly lower in the serum of children who later progress to T1DM [18] were downregulated by perfluoroalkyl substances [188]. Holm and colleagues identified polymorphisms in eight genes encoding proteins involved in the SL metabolism that contribute to the genetic predisposition to T1DM [14].…”

“…Furthermore, an altered SL content in immune cells, peripheral blood mononuclear cells (PBMC) as well as in serum were reported in multiple studies with T1DM individuals [14,15,18,130,164]. The changes in the sphingomyelin content were defined as a new hallmark of progression to T1DM.…”