Adapting to insulin resistance in obesity: role of insulin secretion and clearance

Aims/hypothesis The aim of this study was to quantify the relative contributions of increased insulin secretion rate (ISR) and decreased insulin clearance rate (ICR) in the compensatory hyperinsulinaemia characteristic of insulin-resistant individuals without diabetes. Methods Obese (BMI ≥30 kg/m 2 ) individuals without diabetes ( n = 91) were identified from a registry of volunteers. Volunteers underwent the following measurements: oral glucose tolerance; insulin resistance (steady-state plasma glucose [SSPG] concentration during the insulin suppression test [IST]); ISR (using the graded glucose infusion test [GGIT]); and ICR (using the IST and GGIT). Participants were stratified into tertiles based on SSPG concentration: SSPG-1(insulin-sensitive); SSPG-2 (intermediate); and SSPG-3 (insulin-resistant). Results There were no differences in BMI and waist circumference among the SSPG tertiles. Serum alanine aminotransferase concentrations were higher in the SSPG-2 and SSPG-3 groups compared with the SSPG-1 group ( p = 0.02). Following an oral glucose challenge, there was a progressive increase in the total integrated insulin response from the most insulin-sensitive to the most insulin-resistant tertiles ( p < 0.001). Following intravenous glucose, the SSPG-3 group had significantly greater integrated glucose (median [interquartile range], 32.9 [30.8–36.3] mmol/l × h) and insulin responses (1711 [1476–2223] mmol/l × h) compared with the SSPG-1 group (30.3 [28.8–32.9] mmol/l × h, p = 0.04, and 851 [600–1057] pmol/l × h, p < 0.001, respectively). Furthermore, only the SSPG-3 group had significant changes in both ISR and ICR ( p < 0.001). In the SSPG-2 group, only the ICR was significantly decreased compared with the SSPG-1 group. Therefore, ICR progressively declined during the IST with increasing insulin resistance (SSPG-1, 0.48 [0.41–0.59]; SSPG-2, 0.43 [0.39–0.50]; SSPG-3, 0.34 [0.31–0.40]). Conclusions/interpretation While both increases in ISR and decreases in ICR compensate for insulin resistance, decreases in ICR may provide the first adaptation to decreased insulin sensitivity.