Dissecting the relationship between obesity and hyperinsulinemia: Role of insulin secretion and insulin clearance

Objective: The aim of this study was to better delineate the complex interrelationship among insulin resistance (IR), secretion rate (ISR), and clearance rate (ICR) to increase plasma insulin concentrations in obesity. Methods: Healthy volunteers (92 nondiabetic individuals) had an insulin suppression test to measure IR and graded-glucose infusion test to measure ISR and ICR. Obesity was defined as a body mass index (BMI) ≥30 kg/m², and IR was defined as steady-state plasma glucose (SSPG) ≥10 mmol/L during the insulin suppression test. Plasma glucose and insulin concentrations, ISR, and ICR were compared in three groups: insulin sensitive/overweight; insulin sensitive/obesity; and insulin resistant/obesity. Results: Compared with the insulin-sensitive/overweight group, the insulin-sensitive/obesity had significantly higher insulin area under the curve (AUC) and ISR AUC during the graded-glucose infusion test (P < 0.001). Glucose AUC and ICR were similar. The insulin-resistant/obesity group had higher insulin AUC and ISR AUC compared with the insulin-sensitive/obesity but also had higher glucose AUC and decreased ICR (P < 0.01). In multivariate analysis, both BMI and SSPG were significantly associated with ISR. Conclusions: Plasma insulin concentration and ISR are increased in individuals with obesity, irrespective of degree of IR, but a decrease in ICR is confined to the subset of individuals with IR.