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Life sciences · Journal article
World Journal of Diabetes · October 8, 2026
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BACKGROUNDPrediabetes is metabolically heterogeneous, but most risk assessment remains glycemia centered.It is unclear whether prediabetes subphenotypes already show coordinated or discordant cardio-kidney-liver risk-score signatures before diabetes.We hypothesized that cluster-defined subphenotypes would differ in projected cardiovascular, kidney, and fibrosis-4 (FIB-4)-defined liver fibrosis-risk profiles.AIM To determine whether cluster-defined prediabetes subphenotypes differ in projected cross-organ risk-score profiles.METHODS We performed a cross-sectional baseline analysis of a prospective multicenter highrisk diabetes program in China.K-means clustering was applied to 621 adults with prediabetes using age, body mass index, glycated hemoglobin, homeostasis model assessment of insulin resistance, and homeostasis model assessment of β-cell function.Framingham-estimated 10-year cardiovascular disease risk, chronic kidney disease (CKD) prognosis consortium-estimated 5-year CKD risk, and FIB-4-defined fibrosis-risk signal were compared across subphenotypes using Poisson regression with HC3 robust standard errors.Sensitivity analyses evaluated whether the observed patterns were robust to threshold choice, missing-data handling, albuminto-creatinine ratio availability, reference group, and age loading.RESULTS Four subphenotypes were identified: (1) Mild obesity-related dysmetabolism (n = 177); (2) Mild age-related dysmetabolism (MARD) (n = 190); (3) Severe insulin resistance (n = 95); and (4) Severe insulin deficiency (SID) (n = 159).MARD and SID together accounted for most threshold-positive participants across the 4 / 43 cardiovascular, kidney, and FIB-4 domains: (1) 75.6%; (2) 86.4%; and (3) 82.9%.Compared with mild obesity-related dysmetabolism, MARD showed the broadest age-loaded projected-risk pattern, with adjusted prevalence ratios of 1.94 (95%CI:1.28-2.94)for Framingham risk, 8.75 (4.12-18.56)for CKD prognosis consortium risk, and 3.00 (1.76-5.13)for FIB-4.SID showed a nonclassical pattern, remaining enriched for projected CKD risk and FIB-4-defined fibrosis-risk signal despite lower adiposity, with adjusted prevalence ratios of 6.41 and 3.51, respectively (all P < 0.05) CONCLUSION Prediabetes subphenotypes show distinct projected cardio-kidney-liver risk patterns: MARD is broadly age-loaded, whereas SID marks a nonclassical kidney/FIB-4 signal requiring organ-outcome validation.