ArticleDiabetes care2026
Pathophysiological Risk Factors Preceding Incidence of Type 2 Diabetes Subtypes: A Pooled Cohort Study in the United States.
Article in Diabetes care, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
objectiveUnderstanding the pathophysiology of type 2 diabetes subtypes (severe insulin-deficient diabetes, severe insulin-resistant diabetes, mild obesity-related diabetes, and mild age-related diabetes) before diagnosis can enable precision prevention. We estimated the associations of seven biomarkers with type 2 diabetes subtypes prior to diagnosis. RESEARCH DESIGN AND
methodsWe analyzed 69,725 observations from 9,661 adults without diabetes (median follow-up 10 years [range 0-17 years]) from four U.S. cohorts. Time-dependent Cox models estimated cause-specific hazard ratios (HRs) of seven pathophysiological biomarkers (BMI [kg/m2], systolic blood pressure [SBP] [per 10 mmHg], HbA1c [%], LDL cholesterol [per 10 mg/dL], homeostatic indices [HOMA2 of β-cell function (HOMA2-%B) (per 10 units) and HOMA2 of insulin resistance (HOMA2-IR)], and estimated glomerular filtration rate [eGFR] [per 10 mL/min/1.73 m2]) with incidence of type 2 diabetes and subtypes, adjusting for demographic and clinical covariates. Model performance was evaluated using participants' first and random visits before last follow-up.
resultsOf the pooled cohort, 1,569 individuals developed type 2 diabetes. BMI (HR 1.03 [95% CI 1.02, 1.04]), SBP (HR 1.09 [95% CI 1.05, 1.13]), HbA1c (HR 2.46 [95% CI 1.73, 3.52]), HOMA2-%B (HR 0.89 [95% CI 0.87, 0.91]), HOMA2-IR (HR 1.92 [95% CI 1.78, 2.07]), and LDL cholesterol (HR 1.02 [95% CI 1.00, 1.04]), but not eGFR (HR 1.02 [95% CI 0.98, 1.07]), were independently associated with diabetes. Associations were similar across subtypes. Models based on single time points demonstrated a high C-index (0.81-0.90) but modest F1 scores (0.26-0.51) and varying sensitivity and calibration (slope 0.22-1.24).
conclusionsPathophysiological biomarkers were prospectively associated with type 2 diabetes and subtypes, but single-time-point measurements before diagnosis could not reliably distinguish subtypes at diagnosis.
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