Proteomic Signatures of 3-Year Progression From Impaired Fasting Glucose to Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study

Authors

• Mary R Rooney
• Justin B Echouffo Tcheugui
• Jingsha Chen
• Keenan A Walker
• Christie M Ballantyne
• Eric Boerwinkle
• Tanika N Kelly
• Chiadi E Ndumele
• James S Pankow
• Morgan E Grams
• Wendy S Post
• Peter J Ganz
• Alexis C Wood
• Jerome I Rotter
• Elizabeth Selvin
• Josef Coresh

Language

English

Publication Date

8-1-2026

Journal

Diabetes Care

DOI

10.2337/dc26-0498

PMID

42347027

PMCID

PMC13385941

PubMedCentral® Posted Date

6-25-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Objective: To identify proteomic signatures underlying 3-year progression from impaired fasting glucose (IFG) to diabetes.

Research design and methods: We examined IFG progression in the Atherosclerosis Risk in Communities (ARIC) study from visit 2 (1990-1992) to visit 3 (1993-1995). We tested associations of 4,955 plasma proteins (SomaScan version 4.0) with ∼3-year progression from IFG (FG 100-125 mg/dL without diabetes) to diabetes (diagnosis, medication, or FG ≥126 mg/dL) using logistic regression models adjusted for demographics, cardiometabolic risk factors, and baseline glucose with Bonferroni correction (P < 10-5). We explored biological pathways enriched among the top proteins and calculated improvements in prediction (ΔAUC and net reclassification using 3-year risk thresholds of 6% and 15% in 80% training and 20% internal validation subsamples). We validated results in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort.

Results: There were 3,786 ARIC participants with IFG (mean [SD] age 57 [6] years, 52% female, 28% Black individuals). The 3-year cumulative incidence of diabetes was 6%. Six proteins were associated with ∼3-year progression to diabetes, namely lower receptor-type tyrosine-protein phosphatase S (PTPRS), anthrax toxin receptor 2 (ANTXR2), adiponectin (ADIPOQ), ciliary neurotrophic factor receptor subunit α (CNTFR), transmembrane protein 132C (TMEM132C), and higher ADAMTS-like protein 2 (ADAMTSL2). Altered carbohydrate metabolism and glycolysis were key pathways. Adding the six proteins to covariates improved discrimination (optimism-corrected AUC 0.81, ΔAUC 0.03, P = 0.005) and net reclassification (training 12.2%, internal validation 12.0%) with predicted diabetes risk quintiles spanning < 1% to ∼20%. Two of the six proteins were validated in MESA (P < 0.008).

Conclusions: We identified proteins associated with 3-year IFG progression, with improvements in diabetes risk stratification.

Keywords

Humans, Female, Male, Atherosclerosis, Middle Aged, Proteomics, Blood Glucose, Diabetes Mellitus, Disease Progression, Fasting, Risk Factors

Published Open-Access

yes

Recommended Citation

Rooney, Mary R; Echouffo Tcheugui, Justin B; Chen, Jingsha; et al., "Proteomic Signatures of 3-Year Progression From Impaired Fasting Glucose to Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study" (2026). Faculty, Staff and Students Publications. 7777.
https://digitalcommons.library.tmc.edu/baylor_docs/7777