Key result
Difficult-to-control T2D links to 55 upregulated proteins and metabolites alongside decreased pregnenolone sulfate.
Why the study?
Many individuals with T2D remain inadequately controlled despite intensive therapy, with subclinical hypercortisolism proposed as a contributor, but metabolomic and proteomic signatures remained unknown.
Cohort (n=4,189)
Integrated metabolomic and proteomic profiling identified distinct molecular signatures, including glutamate metabolism and vascular signaling proteins, associated with difficult-to-control type 2 diabetes.
Introduction and Objective: A substantial proportion of individuals with type 2 diabetes (T2D) remain inadequately controlled despite intensive pharmacotherapy, and subclinical hypercortisolism has been proposed as a contributor. We aimed to discover metabolomic and proteomic signatures associated with difficult-to-control T2D and assess whether cortisol-related pathways are implicated. Methods: In a hospital-based Korean cohort, 4,189 adults with T2D underwent targeted serum metabolomics (mass spectrometry, 392 analytes). Proteomics (Olink Explore HT, 5,416 analytes) was performed in a subset (n=1,283). Difficult-to-control T2D was defined as HbA1c ≥7.5% while meeting criteria based on glucose-lowering and blood pressure-lowering medication burden, insulin use, and vascular complications. Associations were assessed by linear regression adjusting for age, sex, BMI, diabetes duration, smoking, and statin use. Results: Participants had a mean age of 63 years, 59% male. Of 4,189 participants, 1,025 (24.5%) met criteria for difficult-to-control T2D, with longer diabetes duration (16.4 vs. 11.5 years) and higher HbA1c (8.37% vs. 6.80%; both P<0.001). Analyses identified 10 metabolites associated with difficult-to-control T2D (P FDR < 0.05), all upregulated. The top 3 endogenous metabolites were glutamate, glycyl-glutamine, and glycylvaline, implicating glutamate metabolism, a pathway potentially linked to insulin resistance. Proteomic analyses (n=1,283; 352 difficult-to-control) identified 45 proteins (P FDR < 0.05), with the top 3 being proteins involved in vascular and metabolic signaling (PRCP, PTPRB, PLXNB2). Among 11 cortisol-related metabolites and 13 proteins measured in our assays, pregnenolone sulfate, an adrenal steroid precursor, was significantly decreased (β = −0.144, P FDR = 0.001). Conclusion: This study demonstrates that integrated metabolomic and proteomic profiling can identify molecular signatures of difficult-to-control T2D beyond direct cortisol pathway activation.
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LEE et al. (2026) conducted a cohort in Type 2 diabetes (n=4,189). Difficult-to-control type 2 diabetes vs. Adequately controlled type 2 diabetes was evaluated on Metabolomic and proteomic signatures associated with difficult-to-control T2D (p=<0.05). Difficult-to-control type 2 diabetes was associated with 10 upregulated metabolites and 45 proteins (P FDR < 0.05), and decreased pregnenolone sulfate (β = -0.144, P FDR = 0.001).
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