Compensatory Hyperinsulinemia is a Hidden Risk Factor for Type 2 Diabetes: CARDIA 30-year Follow Up

Abstract

Introduction: Compensatory hyperinsulinemia (CH) is the heightened beta-cell response to early insulin resistance. It maintains glucose, triglycerides, HDL-cholesterol and HbA1c within normal limits. Thus, individuals with CH do not meet the criteria for prediabetes or metabolic syndrome and elude screening for diabetes risk. Hypothesis: CH is an independent risk factor for type 2 diabetes. Methods: We conducted a retrospective analysis of the Coronary Artery Risk Development in Young Adults (CARDIA) study cohort. The parent study enrolled 5,115 participants, ages 18-30 years at baseline, with 30-year follow up. For the retrospective study, the exclusion criteria were hyperglycemia, hypertriglyceridemia, low HDL-cholesterol, pregnancy, not-fasting or diabetes at baseline. Data for 3,507 participants were analyzed using Cox regression models including CH and canonical diabetes risk factors. The top tertile of fasting insulin (9.9 uIU/mL) was the CH cut point. The primary outcome was time-to-incident-diabetes. Effect sizes were hazard ratios (HR) with 95% confidence intervals (CI). Results: In a confounder-adjusted Cox model, CH was associated with incident diabetes: HR 1.79, 95% CI: 1.41, 2.28, p<0.0001. After including an interaction variable between CH and BMI categories, the CH hazard ratios were significant, but markedly different for normal weight (HR 1.45, 95% CI: 1.04, 2.03, p=0.0290) and overweight/obese (HR 2.28, 95% CI: 1.59, 3.26, p<0.0001) participants. This finding was confirmed using models stratified by BMI category. Conclusion: After adjusting for confounders, baseline CH was a diabetes risk factor in apparently healthy CARDIA participants. New screening strategies are needed to identify young adults with this early, hidden condition.