A hyperbolic relationship between insulin sensitivity and responses using intravenous measures (3
) has been widely accepted. This study demonstrates that measures of insulin sensitivity and response derived from an OGTT are also compatible with a hyperbolic association and that this relationship is present not only in subjects with NGT but also in subjects with IGM and diabetes. Importantly, the existence of this relationship allows calculation of a DIO
, which was predictive of future development of diabetes above and beyond traditional risk factors, such as family history and fasting and 2-h glucose levels. The DIO
as a composite measure was a better predictor for diabetes than either ΔI0–30
or 1/fasting insulin alone.
Our finding that the relationship between insulin sensitivity and insulin response based on OGTT measures is shifted downward and to the left as glucose tolerance deteriorates is consistent with previous work using intravenous tests (6
). With the use of intravenous measures, the disposition index was lower at baseline and declined further in those whose glucose metabolism deteriorated over time (9
). Our current findings extend use of this approach to measure β-cell function using OGTT-derived measures. Importantly, we have shown that the DIO
was inversely correlated with the risk of future diabetes. Thus, the DIO
may be useful to help identify subjects in large epidemiological studies who have an increased risk of developing diabetes.
The statistical methodology for assessment of this hyperbolic relationship is critical when both the x
variables are measured with error, as the slope will be underestimated if measurement error in the independent variable is not accounted for (23
). The absence of a hyperbolic relationship between these same OGTT measures in a previously published study (15
) may have been due to this issue. Although Retnekaran et al. (14
) did account for error estimates in both variables, the slopes for the relationships between ΔI0–30
and measures of insulin sensitivity (1/HOMA for insulin resistance and the Matsuda index) were <−1 (−1.61 and −1.60, respectively) and because of the wide CIs that included 0 were not considered to be hyperbolic. In contrast, we found that the slopes for subjects with NGT for the log-relationships between ΔI0–30
and 1/fasting insulin (slope = −0.87) or HOMA-S (slope = −0.91) were slightly >−1, but the CI still included −1, consistent with a hyperbolic relationship. Differences in results between our study and that by Retnakaran et al. could be due to differences in error estimates, as the slopes are quite sensitive to changes in error estimates. Of note, our results are consistent with the slope estimates for the log-relationship between the acute insulin response to glucose and the insulin sensitivity index (SI
) derived from a frequently sampled intravenous glucose tolerance test (slope = −0.97) (3
) or between ΔI0–30
(slope = −0.86) (10
The strengths of this study include the large number of subjects and the longitudinal study design. However, we failed to show a hyperbolic relationship for some regressions when the iIFG and iIGT groups were examined separately. It is possible that glucose tolerance in these subpopulations fails to follow a hyperbolic relationship, although it seems unlikely because when they are combined the hyperbolic relationship is present. In the group with diabetes, the log-relationships between ΔI0–30/ΔG0–30 and insulin sensitivity measures were flatter and did not include −1 when HOMA-S was used. This may reflect the much broader range of glucose tolerance (and fasting glucose levels) in this group. Finally, the CIs for the slopes using the incAUCins/glu ratio, although including −1, were much wider and thus less reliable. Other limitations include the fact that we excluded 17 subjects (2.7%) with outlier data from this analysis, as outliers can have a disproportionate effect on regression analysis. Finally, this study was performed in Japanese Americans, and, thus, we cannot generalize the conclusions to other ethnic populations, although it is likely that the same physiological feedback processes would occur in other ethnic groups.
There are limitations to application of the DIO
that need to be kept in mind. In particular, because of the increased variability of OGTT measures compared with intravenous testing, the DIO
will be more variable and, hence, appropriately large sample sizes will be needed. Second, it cannot be assumed that all measures of insulin sensitivity or response will follow a hyperbolic pattern and thus simply multiplying any two measures together without first demonstrating a hyperbolic function is not appropriate. Also, it should be kept in mind that the compensatory insulin response includes both changes in insulin secretion as well as adaptations in hepatic insulin extraction (24
) and changes in incretin hormone responses that may modulate both insulin secretion and hepatic insulin extraction (25
In summary, we have demonstrated that use of OGTT-derived measures of insulin response and insulin sensitivity can delineate differences in β-cell function between glucose tolerance categories. Furthermore, the composite measure DIO can be used to assess β-cell function and was independently associated with future diabetes risk. Thus, the disposition index approach using these specific measures offers a way to assess β-cell function using an OGTT and could be used to identify subjects with poor β-cell function for intervention trials and to assess the impact of interventions in large clinical studies.