Insulin clearance is reduced in patients with obesity and has been shown to improve with medical and bariatric surgical weight loss. Impaired insulin clearance is also a major determinant of hyperinsulinemia in obesity. It is unclear if reduced insulin clearance precedes complications of obesity such as type 2 diabetes (T2D). Therefore, we hypothesized that reduced insulin clearance predicts the development of T2D.


Adult Native Americans (n=643; 379M/264F) without diabetes living in the Southwestern U.S. from a longitudinal cohort were included for analysis (375 were followed prospectively with a median follow-up time of 9.9 years [IQR 5.8-13.5]; 120 [31%] progressed to T2D). At baseline, volunteers underwent DEXA or hydrodensitometry (body fat percentage, %fat; 32.5 ± 8.5), a 75-g oral glucose tolerance test, an intravenous glucose tolerance test (acute insulin response, AIR), and a hyperinsulinemic-euglycemic clamp (metabolic clearance rate of insulin, MCRI, calculated as the ratio of the insulin infusion rate and steady state plasma insulin; insulin action, M).


In linear models adjusted for age and sex, MCRI was inversely associated with fasting plasma insulin (r = -0.46, p<0.0001; FPI) and %fat (r = -0.34, p<0.001). In proportional hazards analysis, reduced MCRI at baseline was associated with an increased risk of T2D in a model adjusted for age, sex, heritage, %fat, M, AIR, and fasting and 2-h plasma glucose concentrations (hazard ratio [HR] per 1 standard deviation difference in MCRI, 0.74; 95% confidence interval [CI] 0.60, 0.92; p<0.01). Predictive effects of MCRI remained unchanged after inclusion of FPI to the previous model (HR 0.77; 95% CI 0.60, 0.98; p= 0.04).


Reduced MCRI was associated with an unfavorable metabolic phenotype and was an independent predictor of T2D. The findings support a causal role for MCRI in the development of T2D, indicating this aspect of insulin metabolism as an important target for intervention to prevent T2D in obese patients.