Use of a two-stage insulin infusion study to assess the relationship between insulin suppression of lipolysis and insulin-mediated glucose uptake in overweight/obese, nondiabetic women

Abstract

Differences in insulin regulation of free fatty acids (FFAs) are not readily apparent at the same insulin concentrations used to differentiate relative insulin-mediated glucose disposal. Resistance to insulin-mediated glucose disposal and higher daylong FFA concentrations occur more commonly in obese individuals. However, the relationship between the ability of insulin to suppress FFA release from adipose tissue and stimulate glucose disposal in muscle has not been clearly defined in this population. The current study was initiated to test the hypothesis that these 2 facets of insulin action are related, with greater defects in insulin-mediated glucose disposal associated with less effective insulin inhibition of FFA release from adipose tissue. Subjects included 56 healthy nondiabetic overweight/moderately obese women classified as insulin resistant or insulin sensitive based on whole-body glucose disposal. All underwent a modified 240-minute 2-stage insulin infusion with basal (∼15 µU/mL) and physiologically elevated (∼80 µU/mL) steady-state insulin concentrations. Plasma glucose, insulin, FFA, and glycerol were measured throughout. Whereas plasma glucose differed most during physiological hyperinsulinemia in insulin-resistant vs insulin-sensitive subjects, plasma FFA/glycerol differed most during basal insulin concentrations. The FFA concentrations during the basal insulin steady state correlated highly (r = 0.85, P < .001) with glucose concentrations during the hyperinsulinemic steady state. Overweight/moderately obese women exhibit dramatic differences in the ability of insulin to suppress plasma FFA, which correlate highly with differences in insulin-mediated glucose disposal. Variability in insulin regulation of FFA is most apparent at basal insulin concentrations, whereas differences in glucose disposal are most apparent during physiologic hyperinsulinemia. Both can be quantified using a simple 2-stage insulin infusion study, with first-stage FFA concentrations and second-stage glucose concentrations being most informative.

Figure 1

Mean (± SD) plasma insulin, FFA, glucose, and glycerol concentrations at baseline; during steady state of the first stage of the insulin suppression test (“low” insulin concentration); and during the steady state of the second stage of the insulin suppression test (“high” insulin concentration) in insulin sensitive (IS) and insulin resistant (IR) healthy overweight women.

Figure 2

Panel A: Relationship between glucose concentration at the end of the second stage of the insulin suppression test (“high” insulin concentration) and free fatty acid (FFA) concentration at the end of the first stage of insulin suppression test (“low” insulin concentration); Panel B: Relationship between glucose concentration at end of second stage of the insulin suppression test and glycerol concentration at the end of the first stage of the insulin suppression test.