The results of this study provide additional evidence that measurements of whole body insulin-mediated glucose disposal obtained with the EC and the IST are highly correlated, regardless of the method used to suppress endogenous insulin secretion, i.e
., epinephrine/propranolol or octreotide (8
). The finding is perhaps not surprising given the goals of either of the two tests. Both the EC and IST quantify the ability of a steady-state of physiological hyperinsulinemia to stimulate glucose disposal. They differ in that the measure of insulin action derived from the EC is the amount of glucose infused
(M) in order to maintain basal plasma glucose concentration, whereas the IST quantifies insulin action by determining the ability of the hyperinsulinemia to limit the height of the ensuing plasma glucose (SSPG) concentration in response to the fixed-load of infused glucose.
During both the EC and IST, the hepatic glucose production (HGP) is suppressed by the combination of physiological hyperinsulinemia and the infusion of glucose. However, it has been argued that the extent to which the HGP is inhibited depends on the degree of hyperinsulinemia achieved. In this regard, Conte and colleagues have recently reported that HGP was suppressed to 90% of the baseline value in response to mean steady-state insulin concentration of 595 pmol/L in obese individuals with normal glucose tolerance (18
). Regarding the influence of infusion of glucose on HGP, our research group has shown that HGP was decreased to approximately half of the original value in response to glucose infusion rate of 200 μmol/m2
/min (36 mg/m2
/min) under conditions in which the ambient insulin concentrations ranged from 60 to 70 pmol/L (19
). In the present study, as we did not perform the measurements of HGP, we cannot comment regarding the extent to which the physiological hyperinsulinemia and the glucose infusion suppressed the HGP. However, in light of the published evidence, we believe that the degree of hyperinsulinemia achieved during both the EC (792 ± 95 pmol/L) and IST (549 ± 102 pmol/L), as well as the infusion of glucose, was sufficient to suppress HGP in all individuals and that the residual HGP contributed marginally, if at all, to the quantification of insulin resistance.
In the present study, the measurements of insulin action were performed in subjects whose clinical and metabolic characteristics were rather heterogeneous (). There were an approximately 4-fold variability in SSPG concentration and an 8-fold variability in M values (). However, the M value of the study participants (49.8 ± 22.9 μmol/min/kg-LBM) was similar to that observed in a cohort of 1146 individuals (49.7 ± 18.0 μmol/min/kg-LBM) in the EGIR study (20
). Likewise, the SSPG concentration of our participants (7.4 ± 3.0 mmol/L) was comparable to that noted by us (8.4 ± 4.4 mmol/L) in a group of 490 healthy individuals (2
). These similarities in the distributions of M values and SSPG concentration support our belief that the measurements of insulin sensitivity in the present study were representative of the population at large. Furthermore, we would like to point out that our original description of a highly significant relationship between M and SSPG was also observed in a group of individuals with heterogeneous characteristics (8
). On the other hand, it can be argued that different mathematical relationships between SSPG concentration and M values would emerge if these measures of peripheral insulin action are compared in homogenous populations, especially those enriched with insulin resistant or insulin sensitive individuals. Our study, however, did not have sufficient number of individuals to address this issue, but we believe that it can be addressed by others in the future.
A high correlation between two measurements does not necessarily guarantee successful derivation of one measure from the other at the individual level. However, our Bland-Altman plots using our optimized transformation equations suggest very good agreement at the individual level regardless of the direction of transformation. Nevertheless, investigators employing the conversion equations should be mindful of the following issues. First, we conducted the EC at the insulin infusion rate of 40 mU/m2/min and the IST at the insulin infusion rate of 32 mU/m2/min. Second, we used mixed venous blood instead of arterialized blood to perform both tests. Although these factors might not have affected the relationship between the M values and the SSPG concentration, it can be argued that they influenced the coefficients of the transformation equations.
In conclusion, the observations made in our study have important implications for association studies focused on identifying novel determinants of insulin-mediated glucose disposal, including studies trying to identify the genetic basis of insulin sensitivity using high-density genotyping or high throughput sequencing platforms, given the challenges of quantifying insulin action using the IST or the EC in large numbers. Our findings suggest that cohorts with insulin sensitivity measurements with either method can be combined analytically with no major concerns. The ability to increase sample size in this manner is likely to translate to substantially increased power to identify novel determinants of this important physiologic parameter with the hope that such discoveries can then be leveraged to develop new therapeutic options that will reduce the risk of the myriad of adverse health effects associated with insulin resistance.