Highlight
– Six plasma proteins were identified as significantly associated with progression from impaired fasting glucose (IFG) to diabetes within 3 years.
– Key proteins included adiponectin and receptor-type tyrosine-protein phosphatase S, implicating altered carbohydrate metabolism and glycolysis pathways.
– Incorporation of these protein markers improved diabetes risk prediction models beyond traditional clinical and demographic factors.
– Two proteins were externally validated in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, enhancing generalizability.
Study Background
Impaired fasting glucose (IFG), defined as fasting plasma glucose levels between 100 and 125 mg/dL without diabetes, represents a high-risk intermediate metabolic state predisposing individuals to type 2 diabetes mellitus (T2DM). Globally, diabetes remains a major public health concern due to its increasing prevalence and associated vascular complications. Early identification of individuals with IFG who will progress to overt diabetes is crucial for timely intervention to prevent or delay disease onset. However, conventional risk stratification relies largely on clinical parameters and demographics, which have limited predictive accuracy. Proteomics—the large-scale study of proteins in biological samples—offers a promising approach to discover novel biomarkers that can capture underlying pathophysiological processes and improve risk prediction in prediabetes.
Study Design
The current investigation analyzed data from the Atherosclerosis Risk in Communities (ARIC) study, a well-characterized community-based cohort. Participants with IFG at visit 2 (1990-1992) were followed until visit 3 (1993-1995), approximately 3 years later, to observe progression to diabetes defined by one or more of the following: fasting glucose ≥126 mg/dL, physician diagnosis, or diabetes medication use. Plasma proteomics were measured at baseline using SomaScan version 4.0, quantifying 4,955 proteins. Associations between baseline protein levels and 3-year diabetes progression were evaluated using logistic regression models adjusted for demographics, cardiometabolic risk factors, and baseline fasting glucose. A stringent Bonferroni-corrected significance level (P < 1×10⁻⁵) was applied. Identified proteins were subjected to pathway enrichment analysis to clarify involved biological mechanisms. Prediction model performance improvements by adding proteins to standard risk factors were assessed by changes in the area under the receiver operating characteristic curve (ΔAUC) and net reclassification improvement (NRI). Internal validation was performed using training and test subsets, and external validation was done in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort.
Key Findings
Among 3,786 participants with IFG (mean age 57 years, 52% female, 28% Black), the 3-year cumulative incidence of diabetes was 6%. Six proteins showed statistically significant associations with progression to diabetes:
- Lower levels of receptor-type tyrosine-protein phosphatase S (PTPRS)
- Lower anthrax toxin receptor 2 (ANTXR2)
- Lower adiponectin (ADIPOQ)
- Lower ciliary neurotrophic factor receptor subunit α (CNTFR)
- Lower transmembrane protein 132C (TMEM132C)
- Higher ADAMTS-like protein 2 (ADAMTSL2)
Pathway analysis implicated altered carbohydrate metabolism and glycolysis pathways as central to progression. Incorporation of these six proteins into predictive models led to statistically significant enhancement in discriminative performance (optimism-corrected AUC 0.81 versus baseline model, ΔAUC 0.03, P=0.005). Net reclassification improvement was also meaningful (approximately 12% in both training and internal validation subsets), with predicted 3-year diabetes risk ranging from less than 1% to about 20% across risk quintiles. Importantly, two of these proteins demonstrated consistent associations in the independent MESA cohort (P < 0.008), reinforcing their validity as biomarkers.
Expert Commentary
The identification of these protein biomarkers sheds light on molecular pathways that may drive progression from IFG to diabetes, such as impaired insulin signaling and altered cellular metabolism. Adiponectin, a well-studied adipokine, is known for its insulin-sensitizing and anti-inflammatory effects—its lower levels here reaffirm its protective role. PTPRS and ANTXR2 are less characterized in diabetes pathogenesis but may influence receptor signaling and extracellular matrix interactions. The detection of these proteins extends the understanding beyond traditional risk factors and supports a precision medicine approach to diabetes prevention. However, limitations include the observational design with a relatively short follow-up period and the need for further validation across diverse populations and settings. Future work should explore mechanistic studies and evaluate the clinical utility of implementing proteomic risk stratification in routine care.
Conclusion
This proteomic study in a large, community-based cohort demonstrated the feasibility of identifying plasma protein signatures that predict short-term progression from impaired fasting glucose to diabetes. Six proteins linked to carbohydrate metabolism pathways were associated with increased progression risk, and their incorporation improved discrimination and reclassification of traditional risk models. These findings provide potential novel biomarkers for early diabetes risk stratification and highlight molecular pathways that could be targeted to prevent or delay diabetes onset. Clinically, proteomic profiling might enable tailored prevention strategies in individuals at highest risk, ultimately improving outcomes.
Funding and Registration
The Atherosclerosis Risk in Communities (ARIC) study and Multi-Ethnic Study of Atherosclerosis (MESA) are NIH-supported cohorts. Specific funding details were not provided in the source abstract. No clinical trial registration was noted.
References
- Rooney MR, Echouffo Tcheugui JB, Chen J, et al. Proteomic Signatures of 3-Year Progression From Impaired Fasting Glucose to Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study. Diabetes Care. 2026 Jun 25. PMID: 42347027.
- Zhao X, et al. Proteomic biomarkers for type 2 diabetes: current status and future perspectives. Diabetes Metab Res Rev. 2020;36(7):e3301.
- Kahn SE, et al. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2014;383(9922):1068–1083.