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. 2023 Sep 6:14:1211015.
doi: 10.3389/fendo.2023.1211015. eCollection 2023.

Circulating metabolic signatures of rapid and slow progression to type 1 diabetes in islet autoantibody-positive children

Santosh Lamichhane  1 , Partho Sen  1 , Alex M Dickens  1   2 , Matilda Kråkström  1 , Jorma Ilonen  3 , Johanna Lempainen  3   4   5 , Heikki Hyöty  6   7 , Riitta Lahesmaa  1   8   9 , Riitta Veijola  10   11 , Jorma Toppari  4   12 , Tuulia Hyötyläinen  13 , Mikael Knip  14   15 , Matej Orešič  1   16
Affiliations

Circulating metabolic signatures of rapid and slow progression to type 1 diabetes in islet autoantibody-positive children

Santosh Lamichhane et al. Front Endocrinol (Lausanne). .

Abstract

Aims/hypothesis: Appearance of multiple islet cell autoantibodies in early life is indicative of future progression to overt type 1 diabetes, however, at varying rates. Here, we aimed to study whether distinct metabolic patterns could be identified in rapid progressors (RP, disease manifestation within 18 months after the initial seroconversion to autoantibody positivity) vs. slow progressors (SP, disease manifestation at 60 months or later from the appearance of the first autoantibody).

Methods: Longitudinal samples were collected from RP (n=25) and SP (n=41) groups at the ages of 3, 6, 12, 18, 24, or ≥ 36 months. We performed a comprehensive metabolomics study, analyzing both polar metabolites and lipids. The sample series included a total of 239 samples for lipidomics and 213 for polar metabolites.

Results: We observed that metabolites mediated by gut microbiome, such as those involved in tryptophan metabolism, were the main discriminators between RP and SP. The study identified specific circulating molecules and pathways, including amino acid (threonine), sugar derivatives (hexose), and quinic acid that may define rapid vs. slow progression to type 1 diabetes. However, the circulating lipidome did not appear to play a major role in differentiating between RP and SP.

Conclusion/interpretation: Our study suggests that a distinct metabolic profile is linked with the type 1 diabetes progression. The identification of specific metabolites and pathways that differentiate RP from SP may have implications for early intervention strategies to delay the development of type 1 diabetes.

Keywords: birth cohort; gut microbial metabolites; lipidomics; metabolomics; type 1 diabetes mellitus.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
An overview of the study design. The study cohort comprised children rapidly progressing to overt type 1 diabetes (RP) and children slowly progressing to clinical disease (SP) during the follow-up until the age of 15 years. For each child, longitudinal serum samples were drawn, corresponding to the age of 3, 6, 12, 18, 24 or ≥36 months. Moreover, the age at diagnosis of type 1 diabetes is shown in the participating children.
Figure 2
Figure 2
Polar metabolite profiles in serum during the follow-up. (A-D) Local polynomial regression fitting (LOESS) curve plot of metabolite concentration over time for the two study groups. Blue, Slow Progressors, SP; red, Rapid Progressors. Solid line, mean value; shaded area, 95% CI. e) Age matched comparison of polar metabolite between SP and RP. The plot shows the most discriminating metabolites between the two study groups compared using multivariable linear model (metabolite ~ sex +case), where case indicate (SP vs. RP). Red and blue colors signify linear correlation coefficient up-, down-regulation SP vs. RP.
Figure 3
Figure 3
Polar metabolite profiles in serum before and after the first appearance of islet autoantibodies comparing rapid (RP) and slow progressors (SP) to type 1 diabetes. (A-D) Violin plot showing the selected discriminating metabolites between the SP and RP. Here, RP and SP is analyzed after the appearance of the first islet autoantibody.
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