Pathophysiological Risk Factors Preceding Incidence of Type 2 Diabetes Subtypes: A Pooled Cohort Study in the United States

Objective: Understanding the pathophysiology of type 2 diabetes subtypes (Severe Insulin-Deficient Diabetes [SIDD], Severe Insulin-Resistant Diabetes [SIRD], Mild Obesity-related Diabetes [MOD], and Mild Age-related Diabetes [MARD]) before diagnosis can enable precision prevention. We estimated the associations of seven biomarkers with type 2 diabetes subtypes prior to diagnosis. Research Design and Methods: We analyzed 69,725 observations from 9,661 adults without diabetes (median follow-up: 10 years [range: 0-17]) from four US cohorts. Time-dependent Cox models estimated cause-specific hazard ratios (HR) of seven pathophysiological biomarkers (body mass index [BMI, kg/m2], systolic blood pressure [SBP, per 10 mmHg], HbA1c (%), LDL cholesterol (per 10 mg/dL), homeostatic indices [HOMA2-%B per 10 units, 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. Results: Of 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 (0.89 [95%CI: 0.87-0.91]), HOMA2-IR (HR: 1.92 [95%CI: 1.78-2.07]) and LDL (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 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). Conclusions: Pathophysiological biomarkers were prospectively associated with type 2 diabetes and subtypes, but single time point measurements before diagnosis could not reliably distinguish subtypes at diagnosis.