Metabolic signatures of β-cell destruction in type 1 diabetes Original paper

What was studied?

3-phenylpropionic acid biomarker in type 1 diabetes was studied as part of a plasma metabolomics effort to find stage-specific signatures of progressive β-cell destruction that could outperform (or complement) C-peptide and islet autoantibodies. In this cross-sectional observational study, investigators profiled fasting plasma using capillary electrophoresis–Fourier transform mass spectrometry and liquid chromatography–time-of-flight mass spectrometry, generating 737 metabolite peaks. They then used partial least squares (PLS) discriminant analysis to separate clinical stages of type 1 diabetes by residual endogenous insulin secretion and applied receiver operating characteristic (ROC) analyses to test candidate markers across all participants.

Who was studied?

Thirty-three Japanese participants were enrolled at a single university hospital: 23 with type 1 diabetes, seven with type 2 diabetes, and three healthy controls. Type 1 diabetes was subdivided into new-onset (n=6; sampled after diabetic ketoacidosis and 2–4 weeks of insulin therapy), microsecretors (n=9; fasting C-peptide >0.01 and <0.6 ng/mL at least 3 months after onset), and complete lack of endogenous insulin (n=8; fasting C-peptide below detection). Healthy controls had no personal/family autoimmune history and were medication-free; type 2 diabetes comparators were overweight with preserved C-peptide and no ketosis history.

Most important findings

PLS separated the three type 1 diabetes stages, implying that circulating small molecules track β-cell functional loss. The microbiome-relevant signal centered on phenylalanine metabolism: new-onset type 1 diabetes showed higher plasma 3-phenylpropionic acid (3-PPA) and lower phenylalanine than microsecretors, consistent with 3-PPA being an end-product of bacterial degradation of unabsorbed phenylalanine in the intestinal lumen and therefore a proxy for gut microbial activity. Oxidative-stress biology also emerged: hypotaurine (a taurine-pathway precursor that can be consumed under oxidative stress) was lower in new-onset disease, while taurine itself did not differ materially across the type 1 diabetes subgroups—suggesting acute consumption or altered synthesis at onset rather than a stable deficiency. For later-stage disease, 5-methylcytosine was higher in the complete-lack group, aligning with increased circulating DNA methylation fragments as a putative marker of cumulative cell destruction and/or immune-epigenetic remodeling. ROC analyses supported clinical discriminability: 3-PPA (AUC ~0.96) and hypotaurine (AUC ~0.88) identified new-onset type 1 diabetes, and a low phenylalanine/3-PPA ratio best captured new-onset versus other groups, while a high ratio helped identify microsecretors—useful for a “microbiome-metabolite balance” feature rather than a single metabolite alone.

Key implications

Clinically, these data propose a pragmatic staging concept: combine a gut-microbiome–linked metabolite (3-PPA), an oxidative-stress buffer marker (hypotaurine), and a composite ratio (phenylalanine/3-PPA) to flag early, high-intensity β-cell destruction when interventions to preserve residual function are most valuable. For microbiome-signatures databases, 3-PPA provides a mechanistically interpretable host–microbe co-metabolite that can be recorded as “phenylalanine fermentation product (gut bacteria) elevated in new-onset T1D,” while hypotaurine adds a parallel axis capturing redox stress at onset; together they suggest that microbiome activity and oxidative stress may be temporally coupled during autoimmune β-cell failure, even if this study cannot prove causality.

Citation

Noso S, Babaya N, Hiromine Y, Taketomo Y, Niwano F, Yoshida S, Ikegami H. Metabolic signatures of β-cell destruction in type 1 diabetes. J Diabetes Investig. 2023;14(1):48-57. doi:10.1111/jdi.13926