Proteomic signatures of 3-year progression from impaired fasting glucose to diabetes: The Atherosclerosis Risk in Communities (ARIC) Study

Authors: ROONEY, MARY - Johns Hopkins School Of Public Health; ECHOUFFO TCHEUGUI, JUSTIN - Johns Hopkins School Of Public Health; CHEN, JINGSHA - Johns Hopkins School Of Public Health; WALKER, KEENAN - National Institute On Aging (NIA, NIH); BALLANTYNE, CHRISTIE - Baylor College Of Medicine; BOERWINKLE, ERIC - University Of Texas Health Science Center; KELLY, TANIKA - University Of Illinois Chicago; NDUMELE, CHIADI - Johns Hopkins School Of Public Health; PANKOW, JAMES - University Of Minnesota; GRAMS, MORGAN - New York University School Of Medicine; POST, WENDY - Johns Hopkins School Of Public Health; GANZ, PETER - University Of California San Francisco (UCSF); WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC); ROTTER, JEROME - Harbor-Ucla Medical Center; SELVIN, ELIZABETH - Johns Hopkins School Of Public Health; CORESH, JOSEF - New York University School Of Medicine

Submitted to: Diabetes Care
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/22/2026
Publication Date: 6/25/2026
Citation: Rooney, M.R., Echouffo Tcheugui, J.B., Chen, J., Walker, K.A., Ballantyne, C.M., Boerwinkle, E., Kelly, T.N., Ndumele, C.E., Pankow, J.S., Grams, M.E., Post, W.S., Ganz, P.J., Wood, A.C., Rotter, J.I., Selvin, E., Coresh, J. 2026. Proteomic signatures of 3-year progression from impaired fasting glucose to diabetes: The Atherosclerosis Risk in Communities (ARIC) Study. Diabetes Care. 49(8);1-9. https://doi.org/10.2337/dc26-0498.
DOI: https://doi.org/10.2337/dc26-0498

Interpretive Summary: Prediabetes affects millions of adults, but only some people progress to type 2 diabetes, and current screening methods do not fully explain who is at highest risk. This study examined nearly 5,000 blood proteins to identify biological signals that predict progression from prediabetes to diabetes over the following three years. Six proteins were discovered, which improved the ability to predict who would develop diabetes beyond traditional risk factors such as body weight and fasting glucose levels. The proteins also highlighted disruptions in carbohydrate metabolism and glycolysis as a predictor of diabetes, suggesting that important biological changes occur before diabetes is diagnosed. Overall, this research demonstrates that prediabetes is biologically diverse and that blood protein profiles may help identify individuals most likely to benefit from intensive prevention strategies. These results are important for clinicians, researchers, policymakers, and the public because they could support earlier, more personalized approaches to preventing type 2 diabetes and its complications.

Technical Abstract: Our objective was to identify proteomic signatures underlying 3-year progression from impaired fasting glucose (IFG) to diabetes. 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 (DAUC 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. 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 alpha (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, DAUC 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). We identified proteins associated with 3-year IFG progression, with improvements in diabetes risk stratification.