Dataset Information

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

ABSTRACT:

AIMS: 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.

CONCLUSIONS: Our data suggest that systemic dysregulation of lipid metabolism, as observed in plasma, may impact the metabolism and function of immune cells during progression to overt type 1 diabetes.

Links:

The GEMs for PBMCs have been submitted to BioModels, under accession number MODEL1905270001.

OTHER RELATED OMICS DATASETS IN: MODEL1905270001

INSTRUMENT(S): Liquid Chromatography MS -, Gas Chromatography MS -

SUBMITTER: Partho Sen

PROVIDER: MTBLS1015 | MetaboLights | 2020-08-10

REPOSITORIES: MetaboLights

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Dataset's files

Source:

			Action	DRS
	MTBLS1015	Other
	FILES	Other
	a_MTBLS1015_GC-MS___metabolite_profiling.txt	Txt
	a_MTBLS1015_LC-MS___metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt

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Publications

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

Sen Partho P Dickens Alex M AM López-Bascón María Asunción MA Lindeman Tuomas T Kemppainen Esko E Lamichhane Santosh S Rönkkö Tuukka T Ilonen Jorma J Toppari Jorma J Veijola Riitta R Hyöty Heikki H Hyötyläinen Tuulia T Knip Mikael M Orešič Matej M

Diabetologia 20200211 5

<h4>Aims/hypothesis</h4>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.<h4>Methods</h4>In a longitudinal cohort setting, PBMC metabolomic analysis was applied in children who (1) progressed to type 1 diabetes (PT1D, n = 34 ...[more]

PMID: 32043185

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Project description:Aims/hypothesis: Biomarkers are needed to accurately predict and monitor type 1 diabetes progression during the substantially heterogeneous presymptomatic period of the disease development. To address this concern, we studied temporal changes in the plasma and serum proteomes of < 5-year-old children with HLA-conferred risk for type 1 diabetes, by analysing longitudinal sample series that were collected at regular intervals between birth and diagnosis. Methods: Using mass spectrometry-based discovery proteomics, longitudinal sample series from children positive for multiple autoantibodies who had rapidly progressed to type 1 diabetes before 4 years of age (n=10) were analysed and compared with similar measurements from children, matched from age and gender who were either positive for single autoantibody (n=10) or autoantibody negative (n=10). Following analysis of the data with an additive Gaussian process regression model (LonGP), targeted proteomics was used to verify 11 biomarker candidates in a similar yet independent cohort of children who progressed to the disease within 5 years of age (n=31) and matched autoantibody negative children (n=31). Results: These data reiterated extensive age related trends for protein levels in young children. Further, by combining the utility of LonGP together with the targeted analysis in an extended cohort with more frequent sampling points, these analysis demonstrated that the serum levels of two peptides unique for apolipoprotein C1 (APOC1) were decreased after the appearance of the first islet autoantibody and remained relatively less abundant in children who later progressed to type 1 diabetes, in comparison to autoantibody negative children. Conclusions/interpretation: Through the comparative analysis of prospectively collected samples, our data indicate that the serum/plasma levels of APOC1 are decreased in islet autoantibody positive children who develop type 1 diabetes at a young age. In future studies, APOC1 could be used as an additional measurement to improve early prediction of type 1 diabetes and selection of subjects for intervention studies.

Project description:Aims/hypothesis AGEs are considered environmental contributors of type 1 diabetes, but the exact role AGEs play early in pathogenesis of the disease, remains unidentified. We aimed to reduce AGEs with the pharmacotherapy alagebrium chloride in MIN6N8 cells and early in life in NOD mice to determine its impact on beta cell immunogenicity, function, and disease progression. Methods MIN6N8 cells were cultured with AGEs with or without short-term alagebrium therapy to determine the effect on ER stress and beta cell antigen presentation via a reporter assay for protein responses in the unfolded protein response, the enzymatic activity of endoplasmic reticulum aminopeptidase-1 (ERAP1) and the immunopeptidome. To determine the effect of short-term alagebrium therapy on beta cells in vivo, female NOD mice were treated with alagebrium and insulin secretion, insulitis, and immune cell repertoire were studied. Adoptive transfer studies and diabetes progression studies were used to consider the impact of alagebrium on immune cell function and disease outcome. Results In MIN6N8 cells, alagebrium therapy inhibited the induction of endoplasmic reticulum (ER) stress and the activity of ERAP1 by AGE-modified proteins. Alagebrium treated-MIN6N8 cells did not change the MHC Class I presentation of known beta cell antigens but did induce proteomic changes related to ER homeostatic pathways. Prior to overt autoimmune diabetes, female NOD mice treated with alagebrium for 30-40 days had improved insulin secretion, reduced insulitis and amplified proportions of pancreatic CD8+ T cells, mature B cells and F4/80+ macrophages. Splenocytes from alagebrium-treated mice adoptively transferred disease to NODscid recipients and maintained interferon production in vitro. While partial protection of islets by alagebrium was seen following the adoptive transfer of activated NOD G9C8 transgenic TCR CD8+ T cells, alagebrium therapy in NOD mice did not reduce diabetes progression. Conclusions/interpretation Our data suggests that in experimental models of diabetes, short-term alagebrium treatment allows for beta cell improvement, and maintenance of immune cell function, which does not fully mitigate diabetes progression.